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Pharmacological Targeting of Microglial Activation: New Therapeutic Approach

Cai-Yun Liu, Xu Wang, Chang Liu and 1 more

Frontiers in Cellular Neuroscience · 2019 · Review · CC BY

doi:10.3389/fncel.2019.00514

Abstract

Mounting evidence suggests that neuroinflammation is not just a consequence but a vital contributor to the development and progression of Parkinson's disease (PD). Microglia in particular, may contribute to the induction and modulation of inflammation in PD. Upon stimulation, microglia convert into activated phenotypes, which exist along a dynamic continuum and bear different immune properties depending on the disease stage and severity. Activated microglia release various factors involved in neuroinflammation, such as cytokines, chemokines, growth factors, reactive oxygen species (ROS), reactive nitrogen species (RNS), and prostaglandins (PGs). Further, activated microglia interact with other cell types (e.g., neurons, astrocytes and mast cells) and are closely associated with α-synuclein (α-syn) pathophysiology and iron homeostasis disturbance. Taken together, microglial activation and microglia-mediated inflammatory responses play essential roles in the pathogenesis of PD and elucidation of the complexity and imbalance of microglial activation may shed light on novel therapeutic approaches for PD.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

Generic View of PD Pathogenesis

1Parkinson’s disease, a prevalent movement disorder which affects almost 2% of the aged population worldwide, is the second most common neurodegenerative disease. Pathologically, PD is characterized by the selective and progressive degeneration of dopaminergic neurons in the SNpc and dopaminergic terminals in the striatum. The exact molecular mechanisms of neuronal loss are not fully understood, but several pathways and mechanisms are known to be implicated in PD pathophysiology, including neuroinflammation, impairment of autophagy, oxidative stress, severe endoplasmic reticulum stress, mitochondrial dysfunction, dysfunction of axonal transport, motor circuit pathophysiology, α-syn aggregation, and prion-like cell-to-cell transmission of α-syn. Although it may not be the initial trigger of PD, neuroinflammation is considered to be a vital promoter to the development of PD, in which microglia perform significant roles.

2first proposed that innate immunity was involved in PD in 1988 when a substantial number of HLA-DR-positive reactive microglia were detected in the SN of brains from post-mortem PD patients using immunohistochemical staining. Another neuropathologic study showed that the number of reactive microglia expressing MHC class II molecules not only in the SN and putamen but also in the hippocampus, cingulate cortex, temporal cortex and transentorhinal cortex was increased as the neuronal degeneration proceeded. Similar up-regulated expression of MHC, as well as T-cell infiltration, has been reported in the SN and striatum of MPTP mouse model of PD. Moreover, GWAS further indicated that common genetic variation in the HLA region was related to sporadic PD. In vivo studies using PET confirmed that microglia were widespread activated at the early stage of PD and levels remained relatively stable, possibly driving the disease process via inflammatory reaction.

3The brain of PD patients and animal models induced by MPTP or 6-OHDA showed several signs of increased inflammatory reaction and programmed cell death (or apoptosis) of neurons and/or neuroglia: (a) microgliosis which was observerd in various toxin-based models, such as MPTP, 6-OHDA, and rotenone, as well as in mutant α-syn transgenic models of PD; (b) elevated levels of inflammatory cytokines, such as IL-1β, IL-2, IL-4, IL-6, IFN-γ and TNF-α, TGF-α, TGF-β1, TGF-β2, EGF, bFGF; (c) increased levels of cytokine receptors, such as TNF-α receptor R1 (p55); (d) increased levels of caspase activities, such as caspase-1 and caspase-3; (e) enzymes related to inflammation, such as COX-1, COX-2, and iNOS; (f) reduced levels of neurotrophins, such as NGF and BDNF; (g) elevated levels of bcl-2 and soluble Fas, which could protect and promote apoptosis, respectively.

4A remarkable percentage of monocytic precursors were found in the peripheral blood of patients with PD. Moreover, increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells, and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified PD Rating Scale III (UPDRS-III) scores. Collectively, the immune responses, notably the CD4+-cell sub-set imbalance and Tem activation, may mirror the pathobiology of PD in the CNS.

5Several meta-analyses revealed the association between the use of NSAIDs and the risk of PD, whereas the relationship was inconclusive. NSAIDs as a whole seemed not to be related to the risk of PD. Interestingly, subgroup analysis indicated that use of nonaspirin NSAIDs may have a protective effect, though not shared by aspirin or acetaminophen. One prospective study suggested that the use of nonaspirin NSAIDs may reduce PD risk in males but not in females. One population-based study reported that the effect of aspirin also differed by gender, namely a protective role only in females, especially for longer duration of use (≥24 months) or at higher doses (≥14 pills/week). This gender-specific association between NSAIDs and lower PD risk warrants further investigation. As regards ibuprofen, whether there is a potential therapeutic effect or not is still controversial. Further, in MPTP-induced mouse models, indomethacin exerted anti-inflammatory effects and promoted survival of new neurons in the hippocampus without reversing dopaminergic neuronal loss. Rofecoxib and ibuprofen were also shown to directly protect MPTP-induced damage. In an in vitro study, 6-OHDA-induced PC12 cells pretreated with celecoxib, indomethacin and ibuprofen for 24 h showed significantly increased cell viability, GSH content, and cytoplasmic level of NF-κB, as well as decreased levels of ROS and several apoptosis biomarkers, including cleaved caspase-3, Bax, P-SAPK/JNK and cleaved PARP. Further studies are still needed to elucidate the underlying inflammation process in PD and possible protective effects of NSAIDs.

6Taken together, neuroinflammation appears to play central roles in the development of PD. Glial cells, particularly microglia, are involved in this scenario.

Generic View of Microglial Functions

7Microglia are resident macrophage-like immune cells in the CNS. “Resting” microglia exhibit a ramified morphology with elongated motile cytoplasmic protrusions and processes; they constantly survey the CNS microenvironment and dynamically interact with other neighboring elements, such as neuronal cell bodies, astrocytes, and blood vessels.

8Microglia actively contribute to brain development, injury repair, as well as homeostasis maintenance and surveillance. In the developing CNS, microglia control its patterning by regulating apoptosis of neuronal subpopulations as well as neuron survival and proliferation, and control the wiring of neurons by modulating synapse function and maturation, activity-dependent synaptic pruning, as well as synapse number. Acting similarly to peripheral macrophages, microglia in the mature CNS are able to phagocytize excess synapses, dead cells, protein aggregates, pathogens, and other particulate and dissolvable antigens that may endanger the CNS. Moreover, microglia secrete cytokines, chemokines, growth factors, ROS and RNS, and PGs. These functions of microglia can be regulated by interactions with the BBB and other cellular elements, including astrocytes, neurons, infiltrating T cells and mast cells (; Figure 1). Microglia show brain region-dependent diversity and selective regional sensitivities to aging, which could underlie region-specific sensitivities to microglial dysregulation and involvement in age-related neurodegeneration.

Polarization of Microglia and Its Roles in Neuroinflammation

9In various neurodegenerative diseases or in response to any insult, microglia become activated, including morphological changes, alterations of gene expression and surface markers, and proliferation. Activated microglia may present epithelioid, rod, amoeboid, multinucleated or “dystrophic” morphological appearance. Growing evidence shows that microglial activation in the CNS is heterogeneous, similarly to peripheral macrophages, which is often simplified into two polarization states: the M1 phenotype (known as “classical activation”) and the M2 phenotype (known as “alternative activation”). Activation of microglia can be induced by various factors through numerous pattern recognition receptors like TLRs, SRs and cytokine receptors and chemokine receptors. Microglial cells may present distinctive phenotypes and exhibit specific effects depending on the nature, intensity and duration of the stimulus (;;; Figure 1).

10The M1 polarized microglia with an IL-12high, IL-23high, IL-10low phenotype, present markers such as MHC-II, COX-2, iNOS, and CD86, which are associated with the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-12, IFN-γ, and TNF-α), chemokines (CCL-2, CCL-20), CXCL-10, cytotoxic substances (ROS, RNS, NO, EAA), and prostaglandin E2 (PGE2). M1 microglia are able to promote neurogenesis and astrocytogenesis from NSPCs, participate as inducer and effector cells in polarized Th1 responses, and mediate resistance against tumor cells and intracellular parasites. This polarized phenotype can be induced in experimental animals by using IFN-γ or LPS. IFN-γ mediates M1 polarization of microglia mainly through the JAK/STAT intracellular signal transduction pathway; also by “priming”, enhancing TLR-activated signal transduction and then reinforcing microglial responsiveness to inflammatory stimuli (e.g., TLR ligands and TNF-α). Studies in vivo and in vitro on macrophage showed that TRPC1-mediated Ca2+ influx is crucial for IFN-γ-induced polarization to the M1 phenotype. LPS, an endotoxin in the outer membrane of Gram-negative bacteria, induces M1 polarization via binding to TLR4, which is coupled to myeloid differentiation protein 2, with participation of LPS-binding protein and co-receptors CD14. The TLR4-mediated signaling typically involves an MyD88-dependent pathway, in which activation of transcription factor NF-κB is followed by production of several inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α), and an MyD88-independent pathway, in which activation of transcription factors NF-κB and IRF-3 is followed by the production of IFN-β mediating IFN-β-induced STAT1-dependent gene expression. In this way, expressions of numerous M1-associated cytokines, chemokines and other inflammatory factors are increased. These cytokines activate iNOS and NADPH oxidase, leading to the production of NO, ROS, and RNS.

11The mechanism of M2 polarization in microglia, as compared to macrophages, is much less clear. The characteristics of M2 microglia may parallel those of macrophages to some extent. The M2 state in macrophages can be divided into three sub-classes named M2a, M2b, and M2c, respectively, which might be extrapolated to microglia. The M2 polarized microglia with an IL-12low, IL-23low, IL-10high phenotype, generally present high levels of scavenger, mannose-type and galactose-type receptors, which are associated with the production of anti-inflammatory cytokines (e.g., IL-4, IL-10, and TGF-β), glucocorticoids, neurotrophic factors (e.g., BDNF and IGF-1), and extracellular matrix proteins (e.g., fibronectin). M2 microglia are able to promote oligodendrogenesis and neurogenesis (especially oligodendrogenesis) from NSPCs via the PPAR-γ signaling pathway and perform vital roles in various situations, such as immune regulation, inflammation inhibition and tissue repair. The activation mechanisms of these three sub-classes as well as their functions are different. The M2a activation state, which performs phagocytosis, functions to suppress inflammation, and contributes to tissue repair, can be induced by IL-4 or IL-13. IL-4 per se mediates M2a polarization through binding to various receptor pairs, then stimulating JAK1 or JAK3, activating STAT6 and resulting in expression of M2a-associated genes, such as intracellular components (e.g., SOCS3), cell surface markers (SRs and CD206), Ym1 (chitinase-like protein), Fizz1 (found in inflammatory zone) and IL-10. The M2b polarized state, which is involved in inflammation regulation and selective phagocytosis, can be induced by agonists of TLRs and IL-1 receptors. TLRs become activated by fusing Fc gamma receptors, which bind to immunoglobulin G complexes, resulting in macrophage/microglia polarization to an M2b phenotype and then leading to the secretion of IL-10 and the production of cell surface markers (MHC-II, CD86). The M2c polarized state, which plays vital roles in immune regulation, matrix deposition and tissue remodeling, can be induced by IL-10 and glucocorticoid hormones. IL-10 can activate JAK1 through binding to IL-10 receptor 1 and 2 subunits, then resulting in the translocation of STAT3 to the nucleus, which consequently inhibits the production of M1-associated pro-inflammatory cytokines.

12In general, the M1 phenotype is considered to be the first line of defense with pro-inflammatory roles, while the M2 phenotype to suppress inflammation and to promote tissue repair. Of note is that activated microglia may exist along a dynamic continuum and get different profiles depending on their surrounding microenvironment, rather than be simply polarized into either category (Figure 1).

13As mentioned above, the over-simplified “polarization” designation of activated microglia is still controversial. Additional microglia phenotypes which do not align with the traditional binary classification have been discovered. Therefore, polarization of microglia or the continuum from M1 to M2 state has not been fully supported by experimental data; more importantly, the microglial polarization paradigm may impede rather than facilitate research progress as this schema tends to simplify data interpretation. Current research is focused on the characterization of activated microglia for discovering new drug target.

Activation of Microglia and Pathogenesis of PD, What Have We Learned?

14The complexity and imbalance of microglial activation has become an area of intense focus, aiming to elucidate a potential mechanism of PD pathogenesis and to identify potential targets for anti-inflammatory treatment.

Microglial Activation and Associated Neuroinflammation and Oxidative Stress

15Studies in PD patients, alongside with mounting data in experimental models of this disease, clearly indicate that microglial activation and microglia-mediated inflammation exert dual (beneficial/harmful) effects in PD pathophysiology, as discussed above. A variant in the TREM2 gene of microglia, p.R47H, is a risk factor for PD. In the MPTP-induced mouse models of progressive PD, the degeneration of dopaminergic neurons was associated with gradual polarization of microglia to an M1 (pro-inflammatory) phenotype, which could become even more obvious with age. Furthermore, microglia seemed to present dynamically changing phenotypes depending on disease-stage, accounting for the dynamic changes of pro-inflammatory and anti-inflammatory cytokines.

16Activated microglia proliferate and exhibit a stage- and region-specific secretion of cytokines and mediators (neurotoxic molecules including NO, ROS, RNS and pro-inflammatory cytokines), leading to progressive degeneration of dopaminergic neurons, while microglia in the SNpc are more abundant (approximately 4.5 times) than in other brain regions. In addition, dopaminergic neurons in the SNpc have decreased anti-oxidant potentials, while the redox reaction of DA could be enhanced by the intensified generation of ROS, resulting in the production of toxic DA metabolites. All these features render midbrain dopaminergic neurons more susceptible to oxidative/inflammatory attacks. Hence, neuroinflammatory mechanisms could contribute to neuronal degeneration via cascade events.

17With regard to the mechanism(s) of dopaminergic neuron degeneration and death, non-cell-autonomous mechanisms might play vital roles as well. Activation of glial cells (especially microglia), triggered by dopaminergic neurons in a death process, could induce inflammatory responses as well as oxidative stress and cytokine-receptor-mediated apoptosis, which in turn promote recruitment of peripheral leucocytes (mainly T cells) and lead to an inflammatory network around neuronal injury. The non-cell-autonomous mechanism is considered to drive dopaminergic cell death and hence neurodegeneration in PD. During microglial activation, activation of NADPH oxidase, iNOS, as well as expression of COX-2 results in the synthesis of high levels of ROS, RNS, NO, and PGE2, contributing to the enhanced oxidative stress, which not only exerts toxic effects on dopaminergic neurons but also further amplifies the pro-inflammatory microenvironment. Peroxynitrite, a potent toxin produced when NADPH oxidase and iNOS are present together, promotes the nitration of proteins (e.g., tyrosine) and further production of hydroxyl radicals, which can damage lipids, proteins, DNA and RNA, resulting in dysfunction and eventual death of neurons. In this way, neuroinflammation and oxidative stress interact to engender a vicious cycle, leading to the exacerbation of neurodegeneration (Figure 1). However, microgliosis and increase of pro-inflammatory molecules could be detected at the early stage and well before dopaminergic neuron death in the α-syn transgenic models, implying that cell death is not necessarily a prerequisite for the activation of microglia and mutated α-syn could also initiate the vicious cycle.

18The interaction between α-syn and microglia is considered to be vital in the pathogenesis of PD (Figure 1). α-syn, a presynaptic protein secreted by neurons in small amounts which prevalently exists as monomers in physiology, is over-expressed and aggregates into oligomers or protofibrils in PD. Oligomers/protofibrils could propagate between cells as free floating proteins or via extracellular vesicles, exert toxic effects on the synapses, resulting in disruption of electrophysiological properties, and act as chemoattractants to direct microglial migration toward damaged neurons. In addition, α-syn over-expression promotes the polarization of microglia to the pro-inflammatory phenotype with elevated production of cytokines such as IL-1β, IL-6, and TNF-α as well as COX-2, iNOS and free radicals. Oligomeric α-syn induces the M1 phenotype by directly engaging the TLR1/2 heterodimer, resulting in the nuclear translocation of NF-κB and the elevated production of these cytokines by an MyD88-dependent pathway: After α-syn activates TLR1/2 heterodimer, the C-terminal intracellular TIR domains of TLR interact with MyD88, activating the IRAK complex, which in return activates the TRAF6 via its K63-linked auto-ubiquitination. Then, the subsequent activation of the TAK1 complex and its downstream effector IKK complex lead to the degradation of IκBα and the production of pro-inflammatory cytokines via the activation of MAPK and translocation of NF-κB, p38 and JNK. TLR4 could also mediate α-syn-dependent activation of microglia, including the production of ROS and pro-inflammatory cytokines as well as the phagocytic activity of microglia. Scavenger receptor CD36 and P2X7 receptor are also involved in α-syn-mediated microglial activation. Moreover, α-syn-stimulated microglia secrete MMPs, activating PAR-1 and amplifying microglial inflammatory signals. In this way, α-syn is a vital regulator of microglial activation and phagocytosis. Activated microglia which exert enhanced phagocytosis of α-syn in turn, could on one hand directly play a beneficial role in controlling α-syn spread, and on the other hand, notably, promote the prion-like behavior of α-syn misfolding, aggregation and spread. This may be associated with the increased accumulation of intracellular α-syn in microglia and accelerated secretion of α-syn into extracellular space via exosomal pathways, as well as the toxic effects of cytokines generated from activated microglia on the vulnerable neuronal cells. Taken together, microglia-derived oxidative stress is considered to bridge α-syn pathogenic alteration and neuroinflammation, contributing to chronic progression of neurodegeneration in PD. Those mentioned receptors on microglia could be therapeutic targets for microglial activation and α-syn pathogenesis.

Cross-Talks Between Microglia and Other Cell Types

19The microglial polarization status and associated neuroinflammation are tightly connected with astrocyte-microglia and neuron-glia interactions via ligand-receptor pairings (Figure 1). TREM2, exclusively expressed by microglia, could enhance the phagocytosis function of microglia, and attenuate inflammatory responses by negatively regulating the TLR4-mediated activation of NF-κB signaling and shifting M1 polarization to the M2 phenotype. In addition, TREM2-DAP12 signaling complex exerts vital roles in promoting phagocytosis, microglial activation, as well as microglial survival. The fractalkine receptor CX3CR1, another receptor specifically expressed in microglia, plays a fundamental role in the communication between microglia and neurons by binding to neuronal fractalkine, namely CX3CL1. Accumulating evidence suggests that the CX3CL1-CX3CR1 axis is involved in homeostatic suppression of microglial activation and regulation of chemoattraction and synaptic plasticity, inhibiting microglia-mediated inflammatory responses and neurotoxicity. CD200, a transmembrane glycoprotein present on neurons, can regulate microglial activation status by binding to microglial CD200R. Deficits in the CD200-CD200R axis could exacerbate activation of microglia and dopaminergic neurodegeneration.

20Notably, the mast cell-glia cross-talk is also involved in regulation of neuroinflammation (,; Figure 1). In inflammatory tissues, the expression of ligand-receptor pairings is increased, enhancing chemotactic actions of glial cells and mast cells and facilitating intercellular communication. Activated mast cells could induce microglial activation and subsequent production of TNF-α and IL-6 via the MAPK signaling pathway. In turn, microglia-derived IL-6 could induce expression of surface TLR2 and TLR4 and consequent release of cytokines by mast cells, which recruit immune cells (including microglia) to the injured areas. Conceivably, these two cell types form a feedback loop in concert to promote neuroinflammation.

Activation of Microglia and Imbalance of Iron Metabolism

21Importantly, disturbance of iron homeostasis is a cardinal feature and contributes to the pathogenesis of multiple neurodegenerative diseases including PD, and microglia are capable of modulating the neuronal iron metabolism. Iron is essential for oxygen transport and the related metabolic activities, especially for brain, the highest oxygen-consuming organ. In addition, iron is necessary for various activities exclusively in the brain, such as the maintenance of myelin, the synthesis and metabolism of neurotransmitters including serotonin, norepinephrine and DA. Iron accumulation is a physiological feature of aging brain, the degree of which seems to be even greater in PD. The first observation of abnormal deposits of iron in post-mortem brain especially in the basal ganglia of one PD patient was reported by in 1924, and was later verified by pathological studies, magnetic resonance imaging studies and transcranial ultrasound. However, there has long been a debate as to whether iron is a cause or a consequence of this disorder. Abnormal iron accumulation can induce oxidative stress via ROS, especially hydroxyl radical production, leading to the oxidation and modification of proteins, carbohydrates, lipids, and DNA. Loss of transferrin receptor 1 (involved in iron uptake) rather than ferroportin could cause age-progressive degeneration of dopaminergic neurons and motor deficits in mice. Iron might modulate the expression of α-syn and facilitate its aggregation and toxicity via oxidative stress-induced nitration and phosphorylation, contributing to degeneration of dopaminergic neurons. Furthermore, neurodegeneration in the injured regions could be exacerbated by the strong redox coupling of iron and DA. Regarding microglial contributions to the disturbance of iron metabolism in PD, the expressed transporters/molecules and the released factors such as pro-inflammatory factors, neurotropic factors and lactoferrin, exert fundamental roles. Microglia are more efficient to accumulate and safely store abundant iron than astrocytes and neurons, as evidenced by the finding that ferritin was abundant in microglia while rarely detected in astrocytes and neurons. Even in the case of acute oxidative stress-induced ferritin reduction, the increased iron storage capacity of microglia might be achieved by elevated iron saturation of the existing ferritin molecules, coupled with the aggregation of activated microglia around degenerative neurons. Further, pro-inflammatory factors released by activated microglia (e.g., IL-1β, IL-6, and TNF-α) contribute to the iron deposition by up-regulating the expression of IRP1 and iron transporters (e.g., DMT1) through production of ROS and RNS. These findings provide compelling evidence that microglia could aggravate iron-mediated neurodegeneration in PD. Understanding iron metabolism and roles of microglia in iron dyshomeostasis might provide new therapeutic strategies for PD via restoring brain iron homeostasis.

Microbiome-Gut-Brain Axis

22In the last decade, the microbiome-gut-brain axis in the pathogenesis of neurodegenerative disorders has attracted increasingly more attention. The gut microbiota could affect BBB permeability, and microbiome-derived SCFAs were involved in regulation of microglia homeostasis. Further, a multi-faceted TLR signaling network is essential for the immune-mediated processes both in the gut and in the CNS, exerting inflammatory or regulatory effects in the pathogenesis of PD. Dietary tryptophan metabolites produced by symbiotic microbiota could influence microglial activities, TGF-α production, and neuroinflammatory pathology in EAE, a mouse model of MS. Future investigations should be focused on whether probiotics or antibiotics or dietary protocols can be utilized to modulate microglial function and to alleviate progress of neurodegenerative diseases including PD.

23In brief, as far as PD pathogenesis is concerned, microglial activation and microglia-mediated inflammatory responses play essential roles. Further, α-syn-microglia, neuron-glia, astrocyte-microglia, and mast cell-glia cross-talks (Figure 1), as well as the microbiome-gut-brain axis, are considered to be involved in the regulation of these processes.

Potentials of Microglia as a Therapeutic Target for PD

24Drugs are currently available to relieve PD symptoms by limiting the extent of inflammation, and thus to enhance the life quality of patients. Nevertheless, these drugs are incapable of repairing or regenerating the damaged neurons. Given that the balance of M1/M2 polarization states of microglia has been concerned in connection with the pathogenesis of neurodegenerative disorders, including PD, some small molecular compounds have been studied to determine their potentials to modulate the balance and to elucidate the underlying mechanisms.

Novel Agents or Approaches Targeting the M1 Polarization State

25Drugs targeting pro-inflammatory and pro-killing M1 polarization state could potentially help reduce neuronal damage caused by inflammation. These drugs listed in Table 1 can be divided into several categories:

26Firstly, regulation or modification of receptors on microglia, such as TLRs and CB2 receptors, provides a novel pharmacological target for neurodegenerative disorders including PD. In patients with PD, stage and region-dependent TLR2 expression is consistent with region-specific polarization states of microglia, indicating that TLR2 plays a critical role in the microglia-associated responses in this disorder. Candesartan cilexetil, an FDA-approved drug for treating cerebrovascular diseases, hypertension, and chronic heart failure, also able to inhibit the expression of TLR2 and TLR4, might reverse the pro-inflammatory phenotype of microglia activated by oligomeric α-syn. Moreover, one recent study showed that the antibiotic rifampin and its autoxidation product rifampicin quinone prevented α-syn-induced TLR2- and P2X7-dependent microglial inflammatory responses in vitro, which needs further investigation to confirm their potentials as anti-parkinsionian drugs. Interestingly, endurance exercise could exert neuroprotective effects in MPTP-induced PD mice by regulating the expression of TLR2 and its downstream signaling such as MyD88, TRAF6, and TAK1. As previously discussed, TLR4, another receptor involved in microglial activation, is a potential therapeutic target. Hughes et al. found that pretreatment with TAK-242 or RSLA, small molecule antagonists of TLR4, significantly attenuated α-syn-mediated oxidative stress, TNF-α production by microglia and neuronal death in vitro, but has not been tested in vivo. The endocannabinoid system is considered to be closely associated with the neuropathological processes of PD. A naturally occurring agonist of CB2 receptors, β-caryophyllene, could negatively regulate microglial activation and suppress expressions of pro-inflammatory cytokines, whereby eliciting significant neuroprotective effects on nigral dopaminergic neurons. JWH133, another selective CB2 receptor agonist, could protect the MPTP induced PD mice by alleviating BBB disruption and by suppressing the peripheral immune cell infiltration as well as by reducing the M1 microglia-production of iNOS and pro-inflammatory cytokines.

27Secondly, the JAK/STAT signaling pathway and the NF-κB signaling pathway are vital for the polarization of microglia to the M1 state. Targeting these signaling pathways may serve as a potential to regulate M1 activation. For example, α-asarone, a chemical component found in various plants (e.g., Annonaceae and Araceae species), was shown to significantly suppress M1 polarization and to attenuate the production of pro-inflammatory cytokines by inhibiting the NF-κB signaling, and to eventually mitigate PD-like behavioral anomalies in the MPTP-induced mouse model. Tanshinone I, a bioactive flavonoid, could selectively inhibit the activation of NF-κB signaling and the production of M1-pro-inflammatory molecules including IL-1β, IL-6, TNF-α and NO, partially reserve the expression of M2-anti-inflammatory markers such as IL-10, and prevent nigrostriatal dopaminergic neurodegeneration.

28Thirdly, some compounds targeting NADPH oxidase, such as apocynin, resveratrol and diphenyleneiodonium, could inhibit microglial activation, suppress the generation of various toxic factors (e.g., ROS, RNS, and pro-inflammatory cytokines), and promote microglial phenotype toward anti-inflammatory state, thereby offering promising candidates for clinical trials in patients with neurodegenerative diseases including PD and AD.

29Finally, targeting pro-inflammatory cytokines (e.g., IL-1β and TNF-α) may provide new possibilities to inhibit M1 polarization. In mouse models induced by MPTP or 6-OHDA, selective suppression of solTNF via intranigral lentiviral delivery of DN-TNF or nigral infusion of DN-TNF compound XENP345 or peripheral application of DN-TNF inhibitor XPro1595 could alleviate glial activation, dopaminergic neuron loss and final behavioral deficits, suggesting that blocking the solTNF signaling by DN-TNF gene transfer or novel agents is therapeutically feasible for PD.

30Interestingly, ghrelin, an endogenous ligand for growth hormone secretagogue receptor 1a, was demonstrated to prevent the activation of microglia, the production of pro-inflammatory factors (e.g., TNF-α and IL-1β) and the activation of iNOS, and to attenuate dopaminergic neuron loss in the MPTP-induced mouse models of PD. The inhibitory effect of ghrelin seems to be exerted by suppressing the expression of MMP-3 in stressed dopaminergic neurons.

31In addition, several drugs approved for other distinct diseases [e.g., lenalidomide for multiple myeloma or myelodysplastic syndrome, zonisamide for epilepsy, minocycline for infectious diseases, dimethyl fumaratefor MS] and some bioactive compounds [e.g., ginsenoside Rg1, piperine, curcumin, rosmarinic acid, astilbin] are capable of inhibiting activation of microglia and attenuating production of pro-inflammatory cytokines in mouse models of PD. These drugs might offer novel alternative therapeutic approaches for PD. However, the underlying mechanisms or involved signaling pathways are not fully understood and require further investigations.

32Several promising targets have been proposed to modulate microglial activation. For example, microglia-mediated immune responses could be enhanced by CD73-derived adenosine A2A signaling. CD73 inactivation substantially limited adenosine production, inhibited A2A receptor (A2AR)-mediated pro-inflammatory state of microglia, enhanced the activity of dopaminergic neurons, and mitigated the motor symptoms in animal models of PD. Histamine-4 receptor is another regulator of microglial activation. Lateral ventricle infusion of H4R antagonist JNJ7777120 could suppress the pro-inflammatory activation of microglia, prevent the degeneration of dopaminergic neurons, reduce the Lewy body-like neuropathology, and improve parkinsonian behaviors. Another potential target for PD, NLRP3 inflammasome in microglia can be activated by fibrillar α-syn. Oral administration of a small-molecule inhibitor of NLRP3 inflammasome, MCC950, effectively prevented dopaminergic degeneration and α-syn pathology, and alleviated motor behaviors in PD models.

Novel Agents or Approaches Capable of Enhancing the M2 Phenotype or Induce the Phenotypic Switch From M1 to M2

33Some molecules (e.g., IL-10, cyclic AMP, and vitamin D), which have the capability of enhancing the anti-inflammatory phenotype or of inducing the phenotypic switch from pro-inflammatory to anti-inflammatory, may have therapeutic feasibility for PD (Table 2).

34IL-10 is a potent anti-inflammatory cytokine capable of suppressing iNOS expression via the inhibition of the NF-κB activity. Several studies have demonstrated that intracerebral injection of AAV2-hIL-10 in MPTP-induced mouse models of PD could enhance the expression of the striatal tyrosine hydroxylase protein associated with down-regulated expressions of pro-inflammatory iNOS, and promote the production of anti-inflammatory factors like TGF-β, suggesting the neuroprotective properties of AAV2-hIL-10.

35Cyclic AMP is considered to be a key intracellular regulator of microglial phenotypic conversion. The M1 to M2a conversion could be promoted by cyclic AMP combined with IL-4, but neither alone, in in vitro microglia cell culture. The M2a-converted microglia showed abated production of oxidative molecules (e.g., ROS) and pro-inflammatory factors (e.g., TNF-α and IP-10), as well as improved phagocytic properties. The cyclic AMP-protein kinase A signaling pathway was involved in the conversion process. Based on this finding, application of synthetic analogs of cyclic AMP, activators of adenylyl cyclase, or inhibitors of PDE might suppress the pro-inflammatory phenotype of microglial cells via elevation of cyclic AMP. Notably, PDE inhibitors, such as rolipram for PDE4, sildenafil and yonkenafil for PDE5, and non-selective PDE inhibitors (e.g., ibudilast), have been proposed as potential therapeutic drugs for neurodegenerative disorders, including MS, AD, and PD.

36Vitamin D is capable of protecting dopaminergic neurons against neuroinflammation and oxidative stress via inhibition of microglial activation, shifting M1 to M2 polarized states, which has been demonstrated in mouse models of PD induced by 6-OHDA/MPTP and in microglial HMO6/BV-2 cells. Vitamin D treatment could attenuate M1 polarization with decreased expression of iNOS and TLR4 and reduced production of pro-inflammatory factors (IL-1β, IL-6, IL-12, TNF-α, and NO), and facilitate M2 polarization with elevated expression of TLR10 and increased generation of anti-inflammatory mediators (IL-4, IL-10, TGF-β, and chemokine CCL17) and typical hallmarks of M2 microglia (CD163, CD204, and CD206). Regulatory effects of vitamin D on microglial activation might be associated with suppression of ERK activation and an IL-10 dependent SOCS3 mechanism.

37Peroxisome proliferator-activated receptors, nuclear receptors involved in the pathogenesis of neurodegenerative disorders, have garnered much attention as a promising therapeutic target. PPARs down-regulate microglial activation, neuroinflammation and oxidative stress. PPAR-γ agonists, such as pioglitazone and rosiglitazone, could modulate microglial polarization, thus playing neuroprotective roles on dopaminergic neurons. Oral administration of pioglitazone improved motor symptoms of parkinsonian rhesus monkeys induced by MPTP via anti-inflammatory and neuroprotective effects. Pioglitazone might sequentially act via activation of PPAR-γ, induction of IκBα, blockade of NF-κB activation, iNOS induction and NO-mediated toxicity in an MPTP-induced mouse model of PD. In addition, an in vitro study indicated that the anti-inflammatory and neuroprotective effects of PPAR-γ agonists might be closely associated with the interaction between CD200 and CD200R1. Similarly, rosiglitazone could boost the M2 (anti-inflammatory) phenotype, and regulate cytokine production, whereby alleviating the degeneration of dopaminergic neurons in both SNpc and striatum. However, clinical studies as to whether glitazone protected against PD yielded controversial results. Notably, a phase 2, multi-center, double-blind, placebo-controlled, randomized clinical trial reported that pioglitazone seemed incapable of modifying progression in early PD. Some novel PPAR-γ agonists, such as an N-carbamylated urethane compound SNU-BP, may inhibit M1-pro-inflammatory cytokine and NO production, and enhance M2 marker expression. Further studies are still needed to confirm the therapeutic potentials of PPAR agonists in neurodegeneration and to explore the underlying mechanisms.

38In summary, a variety of drugs may play neuroprotective roles in PD by regulating microglial activation and microglia-induced inflammation; nevertheless, the therapeutic mechanisms are not fully understood (Tables 1, 2). In view of roles of iron metabolism in PD pathogenesis, the protective effects of iron chelation has been explored in the MPTP mouse model by both genetic (transgenic expression of the iron binding protein ferritin) and pharmacological (oral administration of the bioavailable metal chelator clioquinol) means. Deferiprone, another oral iron chelator used to treat systemic iron overload diseases, was demonstrated to increase hippocampal BDNF levels, rescue memory deficits and ameliorate iron-induced harmful effects. Further investigations are warranted to explore the underlying mechanisms of beneficial effects of these drugs and to discover other novel potentially therapeutic approaches. It is noteworthy, however, that the pharmacological modulation of microglia could also have adverse effects as microglia have such physiological functions mentioned aboved. One recent study found that blockade of CD22, a canonical B-cell receptor which is up-regulated on aged microglia, reprogramed microglia toward a homeostatic transcriptional state and restored homeostatic microglial phagocytosis of α-syn fibrils.

39Apart from these pharmacological treatments, rTMS have been reported to have modulating effect (promoting/suppressing) on microglial activation, which may depend on the intensity and frequency of rTMS. Further research are needed to clarify the specific effect of rTMS on microglia as well as on astrocytes and neurons. In addition, accumulating evidence indicates that physical exercise could inhibit microglial activation and regulate neuroinflammation as well as improve the synaptic plasticity, whereby enhancing brain function and attenuating neurodegeneration.

Future Perspectives

40Accumulating studies on PD pathogenesis have focused on activation of microglia and cross-talks between microglia and other immune factors. Activated microglia bear pro-inflammatory or anti-inflammatory properties depending on the nature, intensity and duration of the stimulus and associated with disease stage and severity. Importantly, activated microglia may exist along a dynamic continuum rather than be simply polarized into two categories. Activation of microglia triggered by damaged dopaminergic neurons could cause neuroinflammation, oxidative stress and cytokine-receptor-mediated apoptosis, which in turn enhance peripheral leucocyte recruitment. In this way, a vicious cycle comes into being, resulting in the exacerbation of the neurodegenerative process. In addition, cross-talks of α-syn-microglia, neuron-glia, astrocyte-microglia, and mast cell-glia as well as the microbiome-gut-brain axis are thought to be involved in the regulation of microglial activation and neuroinflammation. The existing available drugs of PD are able to mitigate symptoms by limiting the extent of inflammation. Remarkably, the strategy of the biological therapy should be to restore the immune balance, rather than simply inhibit the immune responses. A variety of agents or approaches, including candesartan cilexetil, rifampicin/rifampicin quinone, TAK-242, RSLA, β-caryophyllene, JWH133, α-asarone, tanshinone I, apocynin, resveratrol, diphenyleneiodonium, DN-TNF, lenalidomide, zonisamide, minocycline, dimethyl fumarate, some bioactive compounds extracted from various plants, JNJ7777120, MCC950, AAV2-hIL-10, Vitamin D, PDE inhibitors (rolipram, ibudilast), and PPAR-γ agonists (pioglitazone, rosiglitazone), might exert neuroprotective effects due to their regulatory effects on microglial activation. In addition, intervention of iron metabolism balance or microbiome-gut-brain axis as well as rTMS and physical exercise may offer emerging therapeutic strategies. In conclusion, microglial activation is a key point to understand the pathogenesis of PD and a potential therapeutic target for PD. Further investigations should focus on the dual role of reactive microglia to elucidate PD pathogenesis and detect emerging agents/approaches for PD.

Author Contributions

41C-YL, XW, and CL searched the literature and drafted the manuscript. C-YL and H-LZ critically revised the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.

Conflict of Interest

42The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 256

1.
Acuna L. Hamadat S. Corbalan N. S. Gonzalez-Lizarraga F. Dos-Santos-Pereira M. Rocca J. (2019 ). Rifampicin and its derivative rifampicin quinone reduce microglial inflammatory responses and neurodegeneration induced in vitro by alpha-synuclein fibrillary aggregates. Cells 8:E776.
Not in our library10.3390/cells8080776
2.
Agarwal S. Yadav A. Chaturvedi R. K. (2017 ). Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem. Biophys. Res. Commun. 483 1166–1177.
Not in our library10.1016/j.bbrc.2016.08.043
3.
Aguirre A. Maturana C. J. Harcha P. A. Saez J. C. (2013 ). Possible involvement of TLRs and hemichannels in stress-induced CNS dysfunction via mastocytes, and glia activation. Mediators Inflamm. 2013:893521.
Not in our library10.1155/2013/893521
4.
Alcalde L. A. de Freitas B. S. Machado G. D. B. de Freitas Crivelaro P. C. Dornelles V. C. Gus H. (2018 ). Iron chelator deferiprone rescues memory deficits, hippocampal BDNF levels and antioxidant defenses in an experimental model of memory impairment. Biometals 31 927–940.
Not in our library10.1007/s10534-018-0135-1
5.
Austin S. A. Floden A. M. Murphy E. J. Combs C. K. (2006 ). Alpha-synuclein expression modulates microglial activation phenotype. J. Neurosci. 26 10558–10563.
Not in our library10.1523/jneurosci.1799-06.2006
6.
Barnum C. J. Chen X. Chung J. Chang J. Williams M. Grigoryan N. (2014 ). Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro(R)1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats. J. Parkinsons Dis. 4 349–360.
Not in our library10.3233/jpd-140410
7.
Becker G. Berg D. (2001 ). Neuroimaging in basal ganglia disorders: perspectives for transcranial ultrasound. Mov. Disord. 16 23–32.
Not in our library10.1002/1531-8257(200101)16:1<23::aid-mds1003>3.0.co;2-2
8.
Belloli S. Pannese M. Buonsanti C. Maiorino C. Di Grigoli G. Carpinelli A. (2017 ). Early upregulation of 18-kDa translocator protein in response to acute neurodegenerative damage in TREM2-deficient mice. Neurobiol. Aging 53 159–168.
Not in our library10.1016/j.neurobiolaging.2017.01.010
9.
Bishop G. M. Dang T. N. Dringen R. Robinson S. R. (2011 ). Accumulation of non-transferrin-bound iron by neurons, astrocytes, and microglia. Neurotox. Res. 19 443–451.
Not in our library10.1007/s12640-010-9195-x
10.
Boche D. Perry V. H. Nicoll J. A. (2013 ). Review: activation patterns of microglia and their identification in the human brain. Neuropathol. Appl. Neurobiol. 39 3–18.
Not in our library10.1111/nan.12011
11.
Boontanrart M. Hall S. D. Spanier J. A. Hayes C. E. Olson J. K. (2016 ). Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism. J. Neuroimmunol. 292 126–136.
Not in our library10.1016/j.jneuroim.2016.01.015
12.
Bove J. Perier C. (2012 ). Neurotoxin-based models of Parkinson’s disease. Neuroscience 211 51–76.
Not in our library10.1016/j.neuroscience.2011.10.057
13.
Brakedal B. Flones I. Reiter S. F. Torkildsen O. Dolle C. Assmus J. (2017 ). Glitazone use associated with reduced risk of Parkinson’s disease. Mov. Disord. 32 1594–1599.
Not in our library10.1002/mds.27128
14.
Braniste V. Al-Asmakh M. Kowal C. Anuar F. Abbaspour A. Toth M. (2014 ). The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6:263ra158.
Not in our library10.1126/scitranslmed.3009759
15.
Brauer R. Bhaskaran K. Chaturvedi N. Dexter D. T. Smeeth L. Douglas I. (2015 ). Glitazone Treatment and incidence of Parkinson’s Disease among people with diabetes: a retrospective cohort study. PLoS Med. 12:e1001854.
Not in our library10.1371/journal.pmed.1001854
16.
Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson's Disease · 2018
No notice
17.
Butovsky O. Ziv Y. Schwartz A. Landa G. Talpalar A. E. Pluchino S. (2006 ). Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31 149–160.
Not in our library10.1016/j.mcn.2005.10.006
18.
Cacace F. Mineo D. Viscomi M. T. Latagliata E. C. Mancini M. Sasso V. (2017 ). Intermittent theta-burst stimulation rescues dopamine-dependent corticostriatal synaptic plasticity and motor behavior in experimental parkinsonism: possible role of glial activity. Mov. Disord. 32 1035–1046.
Not in our library10.1002/mds.26982
19.
Calo L. Wegrzynowicz M. Santivanez-Perez J. Grazia Spillantini M. (2016 ). Synaptic failure and alpha-synuclein. Mov. Disord. 31 169–177.
Not in our library10.1002/mds.26479
20.
Calvello R. Cianciulli A. Nicolardi G. De Nuccio F. Giannotti L. Salvatore R. (2017 ). Vitamin D treatment attenuates neuroinflammation and dopaminergic neurodegeneration in an animal model of Parkinson’s Disease. Shifting M1 to M2 microglia responses. J. Neuroimmune Pharmacol. 12 327–339.
Not in our library10.1007/s11481-016-9720-7
21.
Campolo M. Casili G. Biundo F. Crupi R. Cordaro M. Cuzzocrea S. (2017 ). The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson’s Disease: involvement of Reactive Oxygen Species/Nuclear Factor-kappaB/Nuclear Transcription Factor Related to NF-E2. Antioxid. Redox Signal. 27 453–471.
Not in our library10.1089/ars.2016.6800
22.
Microbiome-Gut-Brain Axis and Toll-Like Receptors in Parkinson’s Disease · 2018
No notice
23.
Cardona A. E. Pioro E. P. Sasse M. E. Kostenko V. Cardona S. M. Dijkstra I. M. (2006 ). Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9 917–924.
Not in our library10.1038/nn1715
24.
Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target · 2017
No notice
25.
Catalin B. Stopper L. Balseanu T. A. Scheller A. (2017 ). The in situ morphology of microglia is highly sensitive to the mode of tissue fixation. J. Chem. Neuroanat. 86 59–66.
Not in our library10.1016/j.jchemneu.2017.08.007
26.
Charvin D. Medori R. Hauser R. A. Rascol O. (2018 ). Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs. Nat. Rev. Drug Discov. 17 804–822.
Not in our library10.1038/nrd.2018.136
27.
Chauhan A. Sun Y. Sukumaran P. Quenum Zangbede F. O. Jondle C. N. Sharma A. (2018 ). M1 macrophage polarization is dependent on TRPC1-mediated calcium entry. Science 8 85–102.
Not in our library10.1016/j.isci.2018.09.014
28.
Chen H. Jacobs E. Schwarzschild M. A. McCullough M. L. Calle E. E. Thun M. J. (2005 ). Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. Ann. Neurol. 58 963–967.
Not in our library10.1002/ana.20682
29.
Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro · 2013
No notice
30.
Cho C. E. Damle S. S. Wancewicz E. V. Mukhopadhyay S. Hart C. E. Mazur C. (2019 ). A modular analysis of microglia gene expression, insights into the aged phenotype. BMC Genomics 20:164.
Not in our library10.1186/s12864-019-5549-9
31.
Choi S. H. Aid S. Kim H. W. Jackson S. H. Bosetti F. (2012 ). Inhibition of NADPH oxidase promotes alternative and anti-inflammatory microglial activation during neuroinflammation. J. Neurochem. 120 292–301.
Not in our library10.1111/j.1471-4159.2011.07572.x
32.
Chow J. C. Young D. W. Golenbock D. T. Christ W. J. Gusovsky F. (1999 ). Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J. Biol. Chem. 274 10689–10692.
Not in our library10.1074/jbc.274.16.10689
33.
Chung Y. C. Shin W. H. Baek J. Y. Cho E. J. Baik H. H. Kim S. R. (2016 ). CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Exp. Mol. Med. 48:e205.
Not in our library10.1038/emm.2015.100
34.
Colonna M. Butovsky O. (2017 ). Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35 441–468.
Not in our library10.1146/annurev-immunol-051116-052358
35.
Connolly J. G. Bykov K. Gagne J. J. (2015 ). Thiazolidinediones and parkinson disease: a cohort study. Am. J. Epidemiol. 182 936–944.
Not in our library10.1093/aje/kwv109
36.
Crielaard B. J. Lammers T. Rivella S. (2017 ). Targeting iron metabolism in drug discovery and delivery. Nat. Rev. Drug Discov. 16 400–423.
Not in our library10.1038/nrd.2016.248
37.
Cullen C. L. Young K. M. (2016 ). How Does Transcranial Magnetic Stimulation Influence Glial Cells in the Central Nervous System? Front. Neural Circuits 10:26.
Not in our library10.3389/fncir.2016.00026
38.
Daniele S. G. Beraud D. Davenport C. Cheng K. Yin H. Maguire-Zeiss K. A. (2015 ). Activation of MyD88-dependent TLR1/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal. 8:ra45
Not in our library10.1126/scisignal.2005965
39.
Dasu M. R. Riosvelasco A. C. Jialal I. (2009 ). Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo. Atherosclerosis 202 76–83.
Not in our library10.1016/j.atherosclerosis.2008.04.010
40.
Davalos D. Grutzendler J. Yang G. Kim J. V. Zuo Y. Jung S. (2005 ). ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8 752–758.
Not in our library10.1038/nn1472
41.
Dehmer T. Heneka M. T. Sastre M. Dichgans J. Schulz J. B. (2004 ). Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J. Neurochem. 88 494–501.
Not in our library10.1046/j.1471-4159.2003.02210.x
42.
Dentesano G. Serratosa J. Tusell J. M. Ramon P. Valente T. Saura J. (2014 ). CD200R1 and CD200 expression are regulated by PPAR-gamma in activated glial cells. Glia 62 982–998.
Not in our library10.1002/glia.22656
43.
Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients · 2014
No notice
44.
Du L. Zhang Y. Chen Y. Zhu J. Yang Y. Zhang H. L. (2017 ). Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol. Neurobiol. 54 7567–7584.
Not in our library10.1007/s12035-016-0245-0
45.
Dulla Y. A. Kurauchi Y. Hisatsune A. Seki T. Shudo K. Katsuki H. (2016 ). Regulatory mechanisms of vitamin D3 on production of nitric oxide and pro-inflammatory cytokines in microglial BV-2 cells. Neurochem. Res. 41 2848–2858.
Not in our library10.1007/s11064-016-2000-3
46.
Edison P. Ahmed I. Fan Z. Hinz R. Gelosa G. Ray Chaudhuri K. (2013 ). Microglia, amyloid, and glucose metabolism in Parkinson’s disease with and without dementia. Neuropsychopharmacology 38 938–949.
Not in our library10.1038/npp.2012.255
47.
Erny D. Hrabe, de Angelis A. L. Jaitin D. Wieghofer P. Staszewski O. (2015 ). Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18 965–977.
Not in our library10.1038/nn.4030
48.
Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia · 2012
No notice
49.
Femminella G. D. Ninan S. Atkinson R. Fan Z. Brooks D. J. Edison P. (2016 ). Does microglial activation influence hippocampal volume and neuronal function in alzheimer’s disease and parkinson’s disease dementia? J. Alzheimers Dis. 51 1275–1289.
Not in our library10.3233/jad-150827
50.
Microglia Response During Parkinson’s Disease: Alpha-Synuclein Intervention · 2018
No notice
51.
Role of Microglia TLRs in Neurodegeneration · 2018
No notice
52.
Franco R. Fernandez-Suarez D. (2015 ). Alternatively activated microglia and macrophages in the central nervous system. Prog. Neurobiol. 131 65–86.
Not in our library10.1016/j.pneurobio.2015.05.003
53.
Fricke I. B. Viel T. Worlitzer M. M. Collmann F. M. Vrachimis A. Faust A. (2016 ). 6-hydroxydopamine-induced Parkinson’s disease-like degeneration generates acute microgliosis and astrogliosis in the nigrostriatal system but no bioluminescence imaging-detectable alteration in adult neurogenesis. Eur. J. Neurosci. 43 1352–1365.
Not in our library10.1111/ejn.13232
54.
Funk N. Wieghofer P. Grimm S. Schaefer R. Buhring H. J. Gasser T. (2013 ). Characterization of peripheral hematopoietic stem cells and monocytes in Parkinson’s disease. Mov. Disord. 28 392–395.
Not in our library10.1002/mds.25300
55.
Gagne J. J. Power M. C. (2010 ). Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74 995–1002.
Not in our library10.1212/wnl.0b013e3181d5a4a3
56.
Gao H. M. Hong J. S. (2008 ). Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol. 29 357–365.
Not in our library10.1016/j.it.2008.05.002
57.
Gao X. Chen H. Schwarzschild M. A. Ascherio A. (2011 ). Use of ibuprofen and risk of Parkinson disease. Neurology 76 863–869.
Not in our library10.1212/wnl.0b013e31820f2d79
58.
Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease · 2019
No notice
59.
Gerhard A. Pavese N. Hotton G. Turkheimer F. Es M. Hammers A. (2006 ). In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol. Dis. 21 404–412.
Not in our library10.1016/j.nbd.2005.08.002
60.
Ghadery C. Koshimori Y. Coakeley S. Harris M. Rusjan P. Kim J. (2017 ). Microglial activation in Parkinson’s disease using [(18)F]-FEPPA. J. Neuroinflamm. 14:8.
Not in our library10.1186/s12974-016-0778-1
61.
Ghasemi F. Bagheri H. Barreto G. E. Read M. I. Sahebkar A. (2019 ). Effects of curcumin on microglial cells. Neurotox. Res. 36 12–26.
Not in our library10.1007/s12640-019-00030-0
62.
Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines · 2016
No notice
63.
Glass C. K. Saijo K. Winner B. Marchetto M. C. Gage F. H. (2010 ). Mechanisms underlying inflammation in neurodegeneration. Cell 140 918–934.
Not in our library10.1016/j.cell.2010.02.016
64.
Gonzalez H. Elgueta D. Montoya A. Pacheco R. (2014 ). Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J. Neuroimmunol. 274 1–13.
Not in our library10.1016/j.jneuroim.2014.07.012
65.
Gordon R. Albornoz E. A. Christie D. C. Langley M. R. Kumar V. Mantovani S. (2018 ). Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med. 10:eaah4066.
Not in our library10.1126/scitranslmed.aah4066
66.
Gosselin D. Skola D. Coufal N. G. Holtman I. R. Schlachetzki J. C. M. Sajti E. (2017 ). An environment-dependent transcriptional network specifies human microglia identity. Science 356:eaal3222.
Not in our library10.1126/science.aal3222
67.
Grabert K. Michoel T. Karavolos M. H. Clohisey S. Baillie J. K. Stevens M. P. (2016 ). Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19 504–516.
Not in our library10.1038/nn.4222
68.
Gupta A. Dhir A. Kumar A. Kulkarni S. K. (2009 ). Protective effect of cyclooxygenase (COX)-inhibitors against drug-induced catatonia and MPTP-induced striatal lesions in rats. Pharmacol. Biochem. Behav. 94 219–226.
Not in our library10.1016/j.pbb.2009.07.018
69.
Hain E. G. Sparenberg M. Rasinska J. Klein C. Akyuz L. Steiner B. (2018 ). Indomethacin promotes survival of new neurons in the adult murine hippocampus accompanied by anti-inflammatory effects following MPTP-induced dopamine depletion. J. Neuroinflamm. 15:162.
Not in our library10.1186/s12974-018-1179-4
70.
Hamza T. H. Zabetian C. P. Tenesa A. Laederach A. Montimurro J. Yearout D. (2010 ). Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat. Genet. 42 781–785.
Not in our library10.1038/ng.642
71.
Hansen C. Angot E. Bergstrom A. L. Steiner J. A. Pieri L. Paul G. (2011 ). alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121 715–725.
Not in our library10.1172/jci43366
72.
Hare D. J. Double K. L. (2016 ). Iron and dopamine: a toxic couple. Brain 139 1026–1035.
Not in our library10.1093/brain/aww022
73.
Harms A. S. Barnum C. J. Ruhn K. A. Varghese S. Trevino I. Blesch A. (2011 ). Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol. Ther. 19 46–52.
Not in our library10.1038/mt.2010.217
74.
Harrison J. K. Jiang Y. Chen S. Xia Y. Maciejewski D. McNamara R. K. (1998 ). Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. U.S.A. 95 10896–10901.
Not in our library10.1073/pnas.95.18.10896
75.
Healy S. McMahon J. Owens P. FitzGerald U. (2016 ). Significant glial alterations in response to iron loading in a novel organotypic hippocampal slice culture model. Sci. Rep. 6:36410.
Not in our library10.1038/srep36410
76.
Heng Y. Zhang Q. S. Mu Z. Hu J. F. Yuan Y. H. Chen N. H. (2016 ). Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting alpha-synuclein abnormalities in the substantia nigra. Toxicol. Lett. 243 7–21.
Not in our library10.1016/j.toxlet.2015.12.005
77.
Hernan M. A. Logroscino G. Garcia Rodriguez L. A. (2006 ). Nonsteroidal anti-inflammatory drugs and the incidence of Parkinson disease. Neurology 66 1097–1099.
Not in our library10.1212/01.wnl.0000204446.82823.28
78.
Hill-Burns E. M. Factor S. A. Zabetian C. P. Thomson G. Payami H. (2011 ). Evidence for more than one Parkinson’s disease-associated variant within the HLA region. PLoS One 6:e27109.
Not in our library10.1371/journal.pone.0027109
79.
Hirsch E. C. Hunot S. (2009 ). Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8 382–397.
Not in our library10.1016/s1474-4422(09)70062-6
80.
Hirsch L. Jette N. Frolkis A. Steeves T. Pringsheim T. (2016 ). The incidence of parkinson’s disease: a systematic review and meta-analysis. Neuroepidemiology 46 292–300.
Not in our library10.1159/000445751
81.
Ho M. S. (2019 ). Microglia in parkinson’s disease. Adv. Exp. Med. Biol. 1175 335–353.
Not in our library10.1007/978-981-13-9913-8_13
82.
Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis · 2015
No notice
83.
Hossain M. M. Weig B. Reuhl K. Gearing M. Wu L. J. Richardson J. R. (2018 ). The anti-parkinsonian drug zonisamide reduces neuroinflammation: role of microglial Nav 1.6. Exp. Neurol. 308 111–119.
Not in our library10.1016/j.expneurol.2018.07.005
84.
The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? · 2017
No notice
85.
Hu X. Ivashkiv L. B. (2009 ). Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 31 539–550.
Not in our library10.1016/j.immuni.2009.09.002
86.
Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis · 2018
Corrected
87.
Hunot S. Hirsch E. C. (2003 ). Neuroinflammatory processes in Parkinson’s disease. Ann. Neurol. 53 S49–S58.
Not in our library10.1002/ana.10481
88.
Iannaccone S. Cerami C. Alessio M. Garibotto V. Panzacchi A. Olivieri S. (2013 ). In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson’s disease. Parkinsonism Relat. Disord. 19 47–52.
Not in our library10.1016/j.parkreldis.2012.07.002
89.
Imamura K. Hishikawa N. Sawada M. Nagatsu T. Yoshida M. Hashizume Y. (2003 ). Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol. 106 518–526.
Not in our library10.1007/s00401-003-0766-2
90.
Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders · 2016
No notice
91.
Iravani M. M. Kashefi K. Mander P. Rose S. Jenner P. (2002 ). Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. Neuroscience 110 49–58.
Not in our library10.1016/s0306-4522(01)00562-0
92.
Microglial Phagocytosis and Its Regulation: A Therapeutic Target in Parkinson’s Disease? · 2018
No notice
93.
Jang Y. Koo J. H. Kwon I. Kang E. B. Um H. S. Soya H. (2017 ). Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson’s disease mice. Brain Res. 1655 186–193.
Not in our library10.1016/j.brainres.2016.10.029
94.
Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson's Disease · 2016
No notice
95.
Jiang H. Li L. J. Wang J. Xie J. X. (2008 ). Ghrelin antagonizes MPTP-induced neurotoxicity to the dopaminergic neurons in mouse substantia nigra. Exp. Neurol. 212 532–537.
Not in our library10.1016/j.expneurol.2008.05.006
96.
Jiang T. Hoekstra J. Heng X. Kang W. Ding J. Liu J. (2015 ). P2X7 receptor is critical in alpha-synuclein–mediated microglial NADPH oxidase activation. Neurobiol. Aging 36 2304–2318.
Not in our library10.1016/j.neurobiolaging.2015.03.015
97.
Jiang T. Zhang Y. D. Chen Q. Gao Q. Zhu X. C. Zhou J. S. (2016 ). TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105 196–206.
Not in our library10.1016/j.neuropharm.2016.01.028
98.
Joers V. Tansey M. G. Mulas G. Carta A. R. (2017 ). Microglial phenotypes in Parkinson’s disease and animal models of the disease. Prog. Neurobiol. 155 57–75.
Not in our library10.1016/j.pneurobio.2016.04.006
99.
Joniec-Maciejak I. Ciesielska A. Wawer A. Sznejder-Pacholek A. Schwenkgrub J. Cudna A. (2014 ). The influence of AAV2-mediated gene transfer of human IL-10 on neurodegeneration and immune response in a murine model of Parkinson’s disease. Pharmacol. Rep. 66 660–669.
Not in our library10.1016/j.pharep.2014.03.008
100.
Kaur D. Yantiri F. Rajagopalan S. Kumar J. Mo J. Q. Boonplueang R. (2003 ). Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37 899–909.
Not in our library10.1016/s0896-6273(03)00126-0
101.
Kawabori M. Kacimi R. Kauppinen T. Calosing C. Kim J. Y. Hsieh C. L. (2015 ). Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J. Neurosci. 35 3384–3396.
Not in our library10.1523/jneurosci.2620-14.2015
102.
Kawai T. Akira S. (2007 ). Signaling to NF-kappaB by Toll-like receptors. Trends Mol. Med. 13 460–469.
Not in our library10.1016/j.molmed.2007.09.002
103.
Kawai T. Akira S. (2010 ). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11 373–384.
Not in our library10.1038/ni.1863
104.
Kawai T. Takeuchi O. Fujita T. Inoue J. Muhlradt P. F. Sato S. (2001 ). Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167 5887–5894.
Not in our library10.4049/jimmunol.167.10.5887
105.
Kettenmann H. Hanisch U. K. Noda M. Verkhratsky A. (2011 ). Physiology of microglia. Physiol. Rev. 91 461–553.
Not in our library10.1152/physrev.00011.2010
106.
Kierdorf K. Prinz M. (2017 ). Microglia in steady state. J. Clin. Invest. 127 3201–3209.
Not in our library10.1172/jci90602
107.
Kim B. W. Koppula S. Kumar H. Park J. Y. Kim I. W. More S. V. (2015 ). alpha-Asarone attenuates microglia-mediated neuroinflammation by inhibiting NF kappa B activation and mitigates MPTP-induced behavioral deficits in a mouse model of Parkinson’s disease. Neuropharmacology 97 46–57.
Not in our library10.1016/j.neuropharm.2015.04.037
108.
Kim C. Ho D. H. Suk J. E. You S. Michael S. Kang J. (2013 ). Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4:1562.
Not in our library10.1038/ncomms2534
109.
Kim J. S. Ryu S. Y. Yun I. Kim W. J. Lee K. S. Park J. W. (2006 ). 1alpha,25-dihydroxyvitamin D(3) protects dopaminergic neurons in rodent models of Parkinson’s disease through inhibition of microglial activation. J. Clin. Neurol. 2 252–257.
Not in our library10.3988/jcn.2006.2.4.252
110.
Kinoshita K. I. Muroi Y. Unno T. Ishii T. (2017 ). Rolipram improves facilitation of contextual fear extinction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson’s disease. J. Pharmacol. Sci. 134 55–58.
Not in our library10.1016/j.jphs.2017.04.002
111.
Knott C. Stern G. Wilkin G. P. (2000 ). Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol. Cell. Neurosci. 16 724–739.
Not in our library10.1006/mcne.2000.0914
112.
Kobayashi K. Imagama S. Ohgomori T. Hirano K. Uchimura K. Sakamoto K. (2013 ). Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 4:e525.
Not in our library10.1038/cddis.2013.54
113.
Microglial TREM2/DAP12 Signaling: A Double-Edged Sword in Neural Diseases · 2018
No notice
114.
Koo J. H. Jang Y. C. Hwang D. J. Um H. S. Lee N. H. Jung J. H. (2017 ). Treadmill exercise produces neuroprotective effects in a murine model of Parkinson’s disease by regulating the TLR2/MyD88/NF-kappaB signaling pathway. Neuroscience 356 102–113.
Not in our library10.1016/j.neuroscience.2017.05.016
115.
Kouli A. Horne C. B. Williams-Gray C. H. (2019 ). Toll-like receptors and their therapeutic potential in Parkinson’s disease and alpha-synucleinopathies. Brain Behav. Immun. 81 41–51.
Not in our library10.1016/j.bbi.2019.06.042
116.
Kumar A. Singh N. (2017 ). Inhibitor of Phosphodiestearse-4 improves memory deficits, oxidative stress, neuroinflammation and neuropathological alterations in mouse models of dementia of Alzheimer’s Type. Biomed. Pharmacother. 88 698–707.
Not in our library10.1016/j.biopha.2017.01.059
117.
Kurkowska-Jastrzebska I. Wronska A. Kohutnicka M. Czlonkowski A. Czlonkowska A. (1999 ). The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse. Exp. Neurol. 156 50–61.
Not in our library10.1006/exnr.1998.6993
118.
La Vitola P. Balducci C. Cerovic M. Santamaria G. Brandi E. Grandi F. (2018 ). Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2. Brain Behav. Immun. 69 591–602.
Not in our library10.1016/j.bbi.2018.02.012
119.
Lawand N. B. Saade N. E. El-Agnaf O. M. Safieh-Garabedian B. (2015 ). Targeting alpha-synuclein as a therapeutic strategy for Parkinson’s disease. Expert Opin. Ther. Targets 19 1351–1360.
Not in our library10.1517/14728222.2015.1062877
120.
Lawson L. J. Perry V. H. Dri P. Gordon S. (1990 ). Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39 151–170.
Not in our library10.1016/0306-4522(90)90229-w
121.
Le W. Rowe D. Xie W. Ortiz I. He Y. Appel S. H. (2001 ). Microglial activation and dopaminergic cell injury: an in vitro model relevant to Parkinson’s disease. J. Neurosci. 21 8447–8455.
Not in our library10.1523/jneurosci.21-21-08447.2001
122.
Lee E. J. Woo M. S. Moon P. G. Baek M. C. Choi I. Y. Kim W. K. (2010 ). Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J. Immunol. 185 615–623.
Not in our library10.4049/jimmunol.0903480
123.
Lee M. K. Stirling W. Xu Y. Xu X. Qui D. Mandir A. S. (2002 ). Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 –> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 99 8968–8973.
Not in our library10.1073/pnas.132197599
124.
Lehericy S. Bardinet E. Poupon C. Vidailhet M. Francois C. (2014 ). 7 Tesla magnetic resonance imaging: a closer look at substantia nigra anatomy in Parkinson’s disease. Mov. Disord. 29 1574–1581.
Not in our library10.1002/mds.26043
125.
Microglia Polarization, Gene-Environment Interactions and Wnt/β-Catenin Signaling: Emerging Roles of Glia-Neuron and Glia-Stem/Neuroprogenitor Crosstalk for Dopaminergic Neurorestoration in Aged Parkinsonian Brain · 2018
Not checked
126.
Lhermitte J. Kraus W. M. McAlpine D. (1924 ). Original Papers: on the occurrence of abnormal deposits of iron in the brain in parkinsonism with special reference to its localisation. J. Neurol. Psychopathol. 5 195–208.
Not in our library10.1136/jnnp.s1-5.19.195
127.
Li J. Y. Englund E. Holton J. L. Soulet D. Hagell P. Lees A. J. (2008 ). Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 14 501–503.
Not in our library10.1038/nm1746
128.
Lima L. A. R. Lopes M. J. P. Costa R. O. Lima F. A. V. Neves K. R. T. Calou I. B. F. (2018 ). Vitamin D protects dopaminergic neurons against neuroinflammation and oxidative stress in hemiparkinsonian rats. J. Neuroinflamm. 15:249.
Not in our library10.1186/s12974-018-1266-6
129.
Lin S. C. Lo Y. C. Wu H. (2010 ). Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465 885–890.
Not in our library10.1038/nature09121
130.
Longhena F. Faustini G. Spillantini M. G. Bellucci A. (2019 ). Living in promiscuity: the multiple partners of alpha-synuclein at the synapse in physiology and pathology. Int. J. Mol. Sci. 20:E141.
Not in our library10.3390/ijms20010141
131.
Lopez Gonzalez I. Garcia-Esparcia P. Llorens F. Ferrer I. (2016 ). Genetic and transcriptomic profiles of inflammation in neurodegenerative diseases: alzheimer, parkinson, creutzfeldt-jakob and tauopathies. Int. J. Mol. Sci. 17:206.
Not in our library10.3390/ijms17020206
132.
Lv R. Du L. Liu X. Zhou F. Zhang Z. Zhang L. (2019 ). Rosmarinic acid attenuates inflammatory responses through inhibiting HMGB1/TLR4/NF-kappaB signaling pathway in a mouse model of Parkinson’s disease. Life Sci. 223 158–165.
Not in our library10.1016/j.lfs.2019.03.030
133.
Manocha G. D. Floden A. M. Puig K. L. Nagamoto-Combs K. Scherzer C. R. Combs C. K. (2017 ). Defining the contribution of neuroinflammation to Parkinson’s disease in humanized immune system mice. Mol. Neurodegener. 12:17.
Not in our library10.1186/s13024-017-0158-z
134.
Mantovani A. Sica A. Locati M. (2005 ). Macrophage polarization comes of age. Immunity 23 344–346.
Not in our library10.1016/j.immuni.2005.10.001
135.
Maresz K. Carrier E. J. Ponomarev E. D. Hillard C. J. Dittel B. N. (2005 ). Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J. Neurochem. 95 437–445.
Not in our library10.1111/j.1471-4159.2005.03380.x
136.
Marinova-Mutafchieva L. Sadeghian M. Broom L. Davis J. B. Medhurst A. D. Dexter D. T. (2009 ). Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson’s disease. J. Neurochem. 110 966–975.
Not in our library10.1111/j.1471-4159.2009.06189.x
137.
Martinez F. O. Gordon S. (2014 ). The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6:13.
Not in our library10.12703/p6-13
138.
Martinez F. O. Gordon S. Locati M. Mantovani A. (2006 ). Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177 7303–7311.
Not in our library10.4049/jimmunol.177.10.7303
139.
Matak P. Matak A. Moustafa S. Aryal D. K. Benner E. J. Wetsel W. (2016 ). Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice. Proc. Natl. Acad. Sci. U.S.A. 113 3428–3435.
Not in our library10.1073/pnas.1519473113
140.
McCoy M. K. Martinez T. N. Ruhn K. A. Szymkowski D. E. Smith C. G. Botterman B. R. (2006 ). Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J. Neurosci. 26 9365–9375.
Not in our library10.1523/jneurosci.1504-06.2006
141.
McCoy M. K. Ruhn K. A. Martinez T. N. McAlpine F. E. Blesch A. Tansey M. G. (2008 ). Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol. Ther. 16 1572–1579.
Not in our library10.1038/mt.2008.146
142.
McGeer P. L. Itagaki S. Boyes B. E. McGeer E. G. (1988 ). Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38 1285–1291.
Not in our library10.1212/wnl.38.8.1285
143.
Microglia and Aging: The Role of the TREM2–DAP12 and CX3CL1-CX3CR1 Axes · 2018
No notice
144.
Physical Exercise Inhibits Inflammation and Microglial Activation · 2019
No notice
145.
Mehlhase J. Sandig G. Pantopoulos K. Grune T. (2005 ). Oxidation-induced ferritin turnover in microglial cells: role of proteasome. Free Radic. Biol. Med. 38 276–285.
Not in our library10.1016/j.freeradbiomed.2004.10.025
146.
Meng F. Guo Z. Hu Y. Mai W. Zhang Z. Zhang B. (2019 ). CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling. Brain 142 700–718.
Not in our library10.1093/brain/awy351
147.
Michell-Robinson M. A. Touil H. Healy L. M. Owen D. R. Durafourt B. A. Bar-Or A. (2015 ). Roles of microglia in brain development, tissue maintenance and repair. Brain 138 1138–1159.
Not in our library10.1093/brain/awv066
148.
Miron V. E. Boyd A. Zhao J. W. Yuen T. J. Ruckh J. M. Shadrach J. L. (2013 ). M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16 1211–1218.
Not in our library10.1038/nn.3469
149.
Mogi M. Harada M. Kondo T. Riederer P. Inagaki H. Minami M. (1994a ). Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci. Lett. 180 147–150.
Not in our library10.1016/0304-3940(94)90508-8
150.
Mogi M. Harada M. Riederer P. Narabayashi H. Fujita K. Nagatsu T. (1994b ). Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 165 208–210.
Not in our library10.1016/0304-3940(94)90746-3
151.
Mogi M. Harada M. Narabayashi H. Inagaki H. Minami M. Nagatsu T. (1996 ). Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci. Lett. 211 13–16.
Not in our library10.1016/0304-3940(96)12706-3
152.
Moon M. Kim H. G. Hwang L. Seo J. H. Kim S. Hwang S. (2009 ). Neuroprotective effect of ghrelin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease by blocking microglial activation. Neurotox. Res. 15 332–347.
Not in our library10.1007/s12640-009-9037-x
153.
Call Off the Dog(ma): M1/M2 Polarization Is Concurrent following Traumatic Brain Injury · 2016
No notice
154.
Myeku N. Clelland C. L. Emrani S. Kukushkin N. V. Yu W. H. Goldberg A. L. (2016 ). Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat. Med. 22 46–53.
Not in our library10.1038/nm.4011
155.
Nagatsu T. Mogi M. Ichinose H. Togari A. (2000 ). Changes in cytokines and neurotrophins in Parkinson’s disease. J. Neural Transm. Suppl. 2000 277–290.
Not in our library10.1007/978-3-7091-6301-6_19
156.
Nalls M. A. Plagnol V. Hernandez D. G. Sharma M. Sheerin U. M. Saad M. (2011 ). Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet 377 641–649.
Not in our library10.1016/s0140-6736(10)62345-8
157.
Navarrete F. Garcia-Gutierrez M. S. Aracil-Fernandez A. Lanciego J. L. Manzanares J. (2018 ). Cannabinoid CB1 and CB2 receptors, and monoacylglycerol lipase gene expression alterations in the basal ganglia of patients with parkinson’s disease. Neurotherapeutics 15 459–469.
Not in our library10.1007/s13311-018-0603-x
158.
Navarro G. Borroto-Escuela D. Angelats E. Etayo I. Reyes-Resina I. Pulido-Salgado M. (2018 ). Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia. Brain Behav. Immun. 67 139–151.
Not in our library10.1016/j.bbi.2017.08.015
159.
Neumann H. Kotter M. R. Franklin R. J. (2009 ). Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132 288–295.
Not in our library10.1093/brain/awn109
160.
Nimmerjahn A. Kirchhoff F. Helmchen F. (2005 ). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308 1314–1318.
Not in our library10.1126/science.1110647
161.
Ninds Exploratory Trials in Parkinson Disease (Net-Pd) Fs-Zone Investigators. (2015 ). Pioglitazone in early Parkinson’s disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 14 795–803.
Not in our library10.1016/s1474-4422(15)00144-1
162.
Ojha S. Javed H. Azimullah S. Haque M. E. (2016 ). beta-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Mol. Cell. Biochem. 418 59–70.
Not in our library10.1007/s11010-016-2733-y
163.
Olanow C. W. Savolainen M. Chu Y. Halliday G. M. Kordower J. H. (2019 ). Temporal evolution of microglia and alpha-synuclein accumulation following foetal grafting in Parkinson’s disease. Brain 142 1690–1700.
Not in our library10.1093/brain/awz104
164.
Orihuela R. McPherson C. A. Harry G. J. (2016 ). Microglial M1/M2 polarization and metabolic states. Br. J. Pharmacol. 173 649–665.
Not in our library10.1111/bph.13139
165.
Ouchi Y. Yoshikawa E. Sekine Y. Futatsubashi M. Kanno T. Ogusu T. (2005 ). Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann. Neurol. 57 168–175.
Not in our library10.1002/ana.20338
166.
CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease · 2011
No notice
167.
Pais T. F. Figueiredo C. Peixoto R. Braz M. H. Chatterjee S. (2008 ). Necrotic neurons enhance microglial neurotoxicity through induction of glutaminase by a MyD88-dependent pathway. J. Neuroinflamm. 5:43.
Not in our library10.1186/1742-2094-5-43
168.
Paolicelli R. C. Bolasco G. Pagani F. Maggi L. Scianni M. Panzanelli P. (2011 ). Synaptic pruning by microglia is necessary for normal brain development. Science 333 1456–1458.
Not in our library10.1126/science.1202529
169.
Pietrzak A. Wierzbicki M. Wiktorska M. Brzezinska-Blaszczyk E. (2011 ). Surface TLR2 and TLR4 expression on mature rat mast cells can be affected by some bacterial components and proinflammatory cytokines. Mediators Inflamm. 2011:427473.
Not in our library10.1155/2011/427473
170.
Pifarre P. Prado J. Baltrons M. A. Giralt M. Gabarro P. Feinstein D. L. (2011 ). Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis. Acta Neuropathol. 121 499–508.
Not in our library10.1007/s00401-010-0795-6
171.
Pisanu A. Lecca D. Mulas G. Wardas J. Simbula G. Spiga S. (2014 ). Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol. Dis. 71 280–291.
Not in our library10.1016/j.nbd.2014.08.011
172.
Pluvinage J. V. Haney M. S. Smith B. A. H. Sun J. Iram T. Bonanno L. (2019 ). CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568 187–192.
Not in our library10.1038/s41586-019-1088-4
173.
Poly T. N. Islam M. M. R. Yang H. C. Li Y. J. (2019 ). Non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease in the elderly population: a meta-analysis. Eur. J. Clin. Pharmacol. 75 99–108.
Not in our library10.1007/s00228-018-2561-y
174.
Porro C. Panaro M. A. Lofrumento D. D. Hasalla E. Trotta T. (2019 ). The multiple roles of exosomes in Parkinson’s disease: an overview. Immunopharmacol. Immunotoxicol. 41 469–476.
Not in our library10.1080/08923973.2019.1650371
175.
Prots I. Grosch J. Brazdis R. M. Simmnacher K. Veber V. Havlicek S. (2018 ). alpha-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. Proc. Natl. Acad. Sci. U.S.A. 115 7813–7818.
Not in our library10.1073/pnas.1713129115
176.
Rabal O. Sanchez-Arias J. A. Cuadrado-Tejedor M. de Miguel I. Perez-Gonzalez M. Garcia-Barroso C. (2018 ). Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer’s disease. Eur. J. Med. Chem. 150 506–524.
Not in our library10.1016/j.ejmech.2018.03.005
177.
Ramazani E. Tayarani-Najaran Z. Fereidoni M. (2019 ). Celecoxib, indomethacin, and ibuprofen prevent 6-hydroxydopamine-induced PC12 cell death through the inhibition of NFkappaB and SAPK/JNK pathways. Iran. J. Basic Med. Sci. 22 477–484.
Not in our library10.22038/ijbms.2019.34011.8091
178.
Ransohoff R. M. (2016 ). A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19 987–991.
Not in our library10.1038/nn.4338
179.
Ransohoff R. M. Perry V. H. (2009 ). Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27 119–145.
Not in our library10.1146/annurev.immunol.021908.132528
180.
TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease · 2013
No notice
181.
Rees K. Stowe R. Patel S. Ives N. Breen K. Clarke C. E. (2011 ). Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson’s disease: evidence from observational studies. Cochrane Database Syst. Rev. 87:CD008454.
Not in our library10.1002/14651858.cd008454.pub2
182.
Ren M. Guo Y. Wei X. Yan S. Qin Y. Zhang X. (2018 ). TREM2 overexpression attenuates neuroinflammation and protects dopaminergic neurons in experimental models of Parkinson’s disease. Exp. Neurol. 302 205–213.
Not in our library10.1016/j.expneurol.2018.01.016
183.
Riederer P. Sofic E. Rausch W. D. Schmidt B. Reynolds G. P. Jellinger K. (1989 ). Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52 515–520.
Not in our library10.1111/j.1471-4159.1989.tb09150.x
184.
Rothhammer V. Borucki D. M. Tjon E. C. Takenaka M. C. Chao C. C. Ardura-Fabregat A. (2018 ). Microglial control of astrocytes in response to microbial metabolites. Nature 557 724–728.
Not in our library10.1038/s41586-018-0119-x
185.
Ruano D. Revilla E. Gavilan M. P. Vizuete M. L. Pintado C. Vitorica J. (2006 ). Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells’ degeneration induced by inflammatory processes after lipopolysaccharide injection. Neuroscience 140 1157–1168.
Not in our library10.1016/j.neuroscience.2006.02.073
186.
Sacino A. N. Brooks M. McKinney A. B. Thomas M. A. Shaw G. Golde T. E. (2014 ). Brain injection of alpha-synuclein induces multiple proteinopathies, gliosis, and a neuronal injury marker. J. Neurosci. 34 12368–12378.
Not in our library10.1523/jneurosci.2102-14.2014
187.
Samii A. Etminan M. Wiens M. O. Jafari S. (2009 ). NSAID use and the risk of Parkinson’s disease: systematic review and meta-analysis of observational studies. Drugs Aging 26 769–779.
Not in our library10.2165/11316780-000000000-00000
188.
Sasso V. Bisicchia E. Latini L. Ghiglieri V. Cacace F. Carola V. (2016 ). Repetitive transcranial magnetic stimulation reduces remote apoptotic cell death and inflammation after focal brain injury. J. Neuroinflamm. 13:150.
Not in our library10.1186/s12974-016-0616-5
189.
CD4+ Regulatory and Effector/Memory T Cell Subsets Profile Motor Dysfunction in Parkinson’s Disease · 2012
No notice
190.
Schafer D. P. Lehrman E. K. Kautzman A. G. Koyama R. Mardinly A. R. Yamasaki R. (2012 ). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74 691–705.
Not in our library10.1016/j.neuron.2012.03.026
191.
Schwenkgrub J. Joniec-Maciejak I. Sznejder-Pacholek A. Wawer A. Ciesielska A. Bankiewicz K. (2013 ). Effect of human interleukin-10 on the expression of nitric oxide synthases in the MPTP-based model of Parkinson’s disease. Pharmacol. Rep. 65 44–49.
Not in our library10.1016/s1734-1140(13)70962-9
192.
Schwenkgrub J. Zaremba M. Joniec-Maciejak I. Cudna A. Mirowska-Guzel D. Kurkowska-Jastrzebska I. (2017 ). The phosphodiesterase inhibitor, ibudilast, attenuates neuroinflammation in the MPTP model of Parkinson’s disease. PLoS One 12:e0182019.
Not in our library10.1371/journal.pone.0182019
193.
Sharma N. Nehru B. (2016 ). Apocyanin, a microglial NADPH oxidase inhibitor prevents dopaminergic neuronal degeneration in lipopolysaccharide-induced parkinson’s disease model. Mol. Neurobiol. 53 3326–3337.
Not in our library10.1007/s12035-015-9267-2
194.
Neuron–glia crosstalk in health and disease: fractalkine and CX 3 CR1 take centre stage · 2013
No notice
195.
Sierra A. Encinas J. M. Deudero J. J. Chancey J. H. Enikolopov G. Overstreet-Wadiche L. S. (2010 ). Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell. 7 483–495.
Not in our library10.1016/j.stem.2010.08.014
196.
Skaper S. D. Facci L. Zusso M. Giusti P. (2017 ). Neuroinflammation. Mast cells, and glia: dangerous liaisons. Neuroscientist 23 478–498.
Not in our library10.1177/1073858416687249
197.
An Inflammation-Centric View of Neurological Disease: Beyond the Neuron · 2018
Corrected
198.
Sofic E. Riederer P. Heinsen H. Beckmann H. Reynolds G. P. Hebenstreit G. (1988 ). Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J. Neural Transm. 74 199–205.
Not in our library10.1007/bf01244786
199.
Song G. J. Nam Y. Jo M. Jung M. Koo J. Y. Cho W. (2016 ). A novel small-molecule agonist of PPAR-gamma potentiates an anti-inflammatory M2 glial phenotype. Neuropharmacology 109 159–169.
Not in our library10.1016/j.neuropharm.2016.06.009
200.
Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases · 2017
No notice
201.
Song N. Wang J. Jiang H. Xie J. (2018 ). Astroglial and microglial contributions to iron metabolism disturbance in Parkinson’s disease. Biochim. Biophys. Acta Mol. Basis Dis. 1864 967–973.
Not in our library10.1016/j.bbadis.2018.01.008
202.
Stefanova N. Fellner L. Reindl M. Masliah E. Poewe W. Wenning G. K. (2011 ). Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 179 954–963.
Not in our library10.1016/j.ajpath.2011.04.013
203.
Stein M. Keshav S. Harris N. Gordon S. (1992 ). Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176 287–292.
Not in our library10.1084/jem.176.1.287
204.
Su X. Federoff H. J. Maguire-Zeiss K. A. (2009 ). Mutant alpha-synuclein overexpression mediates early proinflammatory activity. Neurotox. Res. 16 238–254.
Not in our library10.1007/s12640-009-9053-x
205.
Su X. Maguire-Zeiss K. A. Giuliano R. Prifti L. Venkatesh K. Federoff H. J. (2008 ). Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol. Aging 29 1690–1701.
Not in our library10.1016/j.neurobiolaging.2007.04.006
206.
Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease · 2017
No notice
207.
The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys · 2011
No notice
208.
Swiatkiewicz M. Zaremba M. Joniec I. Czlonkowski A. Kurkowska-Jastrzebska I. (2013 ). Potential neuroprotective effect of ibuprofen, insights from the mice model of Parkinson’s disease. Pharmacol. Rep. 65 1227–1236.
Not in our library10.1016/s1734-1140(13)71480-4
209.
Symons A. Beinke S. Ley S. C. (2006 ). MAP kinase kinase kinases and innate immunity. Trends Immunol. 27 40–48.
Not in our library10.1016/j.it.2005.11.007
210.
Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke · 2016
No notice
211.
Glioma-Associated Microglia/Macrophages Display an Expression Profile Different from M1 and M2 Polarization and Highly Express Gpnmb and Spp1 · 2015
No notice
212.
TREM2-Transduced Myeloid Precursors Mediate Nervous Tissue Debris Clearance and Facilitate Recovery in an Animal Model of Multiple Sclerosis · 2007
No notice
213.
Takahashi K. Rochford C. D. Neumann H. (2005 ). Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201 647–657.
Not in our library10.1084/jem.20041611
214.
Takeda K. Akira S. (2004 ). TLR signaling pathways. Semin. Immunol. 16 3–9.
Not in our library10.1016/j.smim.2003.10.003
215.
Tansey M. G. Goldberg M. S. (2010 ). Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 37 510–518.
Not in our library10.1016/j.nbd.2009.11.004
216.
Taylor J. M. Main B. S. Crack P. J. (2013 ). Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem. Int. 62 803–819.
Not in our library10.1016/j.neuint.2012.12.016
217.
Theillet F. X. Binolfi A. Bekei B. Martorana A. Rose H. M. Stuiver M. (2016 ). Structural disorder of monomeric alpha-synuclein persists in mammalian cells. Nature 530 45–50.
Not in our library10.1038/nature16531
218.
Theodore S. Cao S. McLean P. J. Standaert D. G. (2008 ). Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol. 67 1149–1158.
Not in our library10.1097/nen.0b013e31818e5e99
219.
Toshchakov V. Jones B. W. Perera P. Y. Thomas K. Cody M. J. Zhang S. (2002 ). TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat. Immunol. 3 392–398.
Not in our library10.1038/ni774
220.
Ueno M. Fujita Y. Tanaka T. Nakamura Y. Kikuta J. Ishii M. (2013 ). Layer V cortical neurons require microglial support for survival during postnatal development. Nat. Neurosci. 16 543–551.
Not in our library10.1038/nn.3358
221.
Urrutia P. Aguirre P. Esparza A. Tapia V. Mena N. P. Arredondo M. (2013 ). Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells. J. Neurochem. 126 541–549.
Not in our library10.1111/jnc.12244
222.
Valera E. Mante M. Anderson S. Rockenstein E. Masliah E. (2015 ). Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson’s disease. J. Neuroinflamm. 12:93.
Not in our library10.1186/s12974-015-0320-x
223.
Vay S. U. Flitsch L. J. Rabenstein M. Rogall R. Blaschke S. Kleinhaus J. (2018 ). The plasticity of primary microglia and their multifaceted effects on endogenous neural stem cells in vitro and in vivo. J. Neuroinflamm. 15:226.
Not in our library10.1186/s12974-018-1261-y
224.
Verma R. Kim J. Y. (2016 ). 1,25-Dihydroxyvitamin D3 Facilitates M2 Polarization and Upregulates TLR10 Expression on Human Microglial Cells. Neuroimmunomodulation 23 75–80.
Not in our library10.1159/000444300
225.
Wahner A. D. Bronstein J. M. Bordelon Y. M. Ritz B. (2007 ). Nonsteroidal anti-inflammatory drugs may protect against Parkinson disease. Neurology 69 1836–1842.
Not in our library10.1212/01.wnl.0000279519.99344.ad
226.
Wake H. Moorhouse A. J. Jinno S. Kohsaka S. Nabekura J. (2009 ). Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29 3974–3980.
Not in our library10.1523/jneurosci.4363-08.2009
227.
Wakselman S. Bechade C. Roumier A. Bernard D. Triller A. Bessis A. (2008 ). Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J. Neurosci. 28 8138–8143.
Not in our library10.1523/jneurosci.1006-08.2008
228.
Wang C. Fan G. Xu K. Wang S. (2013 ). Quantitative assessment of iron deposition in the midbrain using 3D-enhanced T2 star weighted angiography (ESWAN): a preliminary cross-sectional study of 20 Parkinson’s disease patients. Magn. Reson. Imaging 31 1068–1073.
Not in our library10.1016/j.mri.2013.04.015
229.
Wang J. Song N. Jiang H. Wang J. Xie J. (2013 ). Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons. Biochim. Biophys. Acta 1832 618–625.
Not in our library10.1016/j.bbadis.2013.01.021
230.
Wang Q. Chu C. H. Oyarzabal E. Jiang L. Chen S. H. Wilson B. (2014 ). Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases. Glia 62 2034–2043.
Not in our library10.1002/glia.22724
231.
Wang S. Chu C. H. Stewart T. Ginghina C. Wang Y. Nie H. (2015a ). alpha-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 112 E1926–E1935.
Not in our library10.1073/pnas.1417883112
232.
Wang S. Jing H. Yang H. Liu Z. Guo H. Chai L. (2015b ). Tanshinone I selectively suppresses pro-inflammatory genes expression in activated microglia and prevents nigrostriatal dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. J. Ethnopharmacol. 164 247–255.
Not in our library10.1016/j.jep.2015.01.042
233.
Neuroinflammation in Parkinson’s disease and its potential as therapeutic target · 2015
No notice
234.
Wang Q. Qian L. Chen S. H. Chu C. H. Wilson B. Oyarzabal E. (2015d ). Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson’s disease models. Brain 138 1247–1262.
Not in our library10.1093/brain/awv034
235.
Wang X. J. Zhang S. Yan Z. Q. Zhao Y. X. Zhou H. Y. Wang Y. (2011 ). Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK. Free Radic. Biol. Med. 50 1094–1106.
Not in our library10.1016/j.freeradbiomed.2011.01.032
236.
Ward R. J. Zucca F. A. Duyn J. H. Crichton R. R. Zecca L. (2014 ). The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 13 1045–1060.
Not in our library10.1016/s1474-4422(14)70117-6
237.
Whitton P. S. (2007 ). Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br. J. Pharmacol. 150 963–976.
Not in our library10.1038/sj.bjp.0707167
238.
Wolf S. A. Boddeke H. W. Kettenmann H. (2017 ). Microglia in physiology and disease. Annu. Rev. Physiol. 79 619–643.
Not in our library10.1146/annurev-physiol-022516-034406
239.
Wu D. C. Jackson-Lewis V. Vila M. Tieu K. Teismann P. Vadseth C. (2002 ). Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci. 22 1763–1771.
Not in our library10.1523/jneurosci.22-05-01763.2002
240.
Microglia as modulators of exosomal alpha-synuclein transmission · 2019
No notice
241.
Xu Y. Zhu N. Xu W. Ye H. Liu K. Wu F. (2018 ). Inhibition of phosphodiesterase-4 reverses abeta-induced memory impairment by regulation of HPA axis related cAMP signaling. Front. Aging Neurosci. 10:204
Not in our library10.3389/fnagi.2018.00204
242.
Yang W. Chen Y. H. Liu H. Qu H. D. (2015 ). Neuroprotective effects of piperine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease mouse model. Int. J. Mol. Med. 36 1369–1376.
Not in our library10.3892/ijmm.2015.2356
243.
Yao K. Zhao Y. F. (2018 ). Aging modulates microglia phenotypes in neuroinflammation of MPTP-PD mice. Exp. Gerontol. 111 86–93.
Not in our library10.1016/j.exger.2018.07.010
244.
Zecca L. Berg D. Arzberger T. Ruprecht P. Rausch W. D. Musicco M. (2005 ). In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage. Mov. Disord. 20 1278–1285.
Not in our library10.1002/mds.20550
245.
Zeng K. W. Zhao M. B. Ma Z. Z. Jiang Y. Tu P. F. (2012 ). Protosappanin A inhibits oxidative and nitrative stress via interfering the interaction of transmembrane protein CD14 with Toll-like receptor-4 in lipopolysaccharide-induced BV-2 microglia. Int. Immunopharmacol. 14 558–569.
Not in our library10.1016/j.intimp.2012.09.004
246.
Zhang F. Shi J. S. Zhou H. Wilson B. Hong J. S. Gao H. M. (2010 ). Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Mol. Pharmacol. 78 466–477.
Not in our library10.1124/mol.110.064535
247.
Zhang J. Zhang Y. Wang J. Cai P. Luo C. Qian Z. (2010 ). Characterizing iron deposition in Parkinson’s disease using susceptibility-weighted imaging: an in vivo MR study. Brain Res. 1330 124–130.
Not in our library10.1016/j.brainres.2010.03.036
248.
Zhang Q. S. Heng Y. Yuan Y. H. Chen N. H. (2017 ). Pathological alpha-synuclein exacerbates the progression of Parkinson’s disease through microglial activation. Toxicol. Lett. 265 30–37.
Not in our library10.1016/j.toxlet.2016.11.002
249.
CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease · 2011
No notice
250.
Zhang W. Wang T. Pei Z. Miller D. S. Wu X. Block M. L. (2005 ). Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 19 533–542.
Not in our library10.1096/fj.04-2751com
251.
Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis · 2016
No notice
252.
Zhang Y. Feng S. Nie K. Li Y. Gao Y. Gan R. (2018 ). TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson’s disease. Biochem. Biophys. Res. Commun. 499 797–802.
Not in our library10.1016/j.bbrc.2018.03.226
253.
Zhao S. Yang J. Wang L. Peng S. Yin J. Jia L. (2016 ). NF-kappab upregulates type 5 phosphodiesterase in N9 microglial cells: inhibition by sildenafil and yonkenafil. Mol. Neurobiol. 53 2647–2658.
Not in our library10.1007/s12035-015-9293-0
254.
Zhou P. Homberg J. R. Fang Q. Wang J. Li W. Meng X. (2019 ). Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model. Brain Behav. Immun. 76 61–73.
Not in our library10.1016/j.bbi.2018.11.006
255.
Zhou T. T. Zu G. Wang X. Zhang X. G. Li S. Liang Z. H. (2015 ). Immunomodulatory and neuroprotective effects of ginsenoside Rg1 in the MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) -induced mouse model of Parkinson’s disease. Int. Immunopharmacol. 29 334–343.
Not in our library10.1016/j.intimp.2015.10.032
256.
Zhu Y. L. Sun M. F. Jia X. B. Cheng K. Xu Y. D. Zhou Z. L. (2019 ). Neuroprotective effects of astilbin on MPTP-induced Parkinson’s disease mice: glial reaction, alpha-synuclein expression and oxidative stress. Int. Immunopharmacol. 66 19–27.
Not in our library10.1016/j.intimp.2018.11.004

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