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The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases

Fangzhou Jiao, Zuojiong Gong

Oxidative Medicine and Cellular Longevity · 2020 · Review

doi:10.1155/2020/6782872

Abstract

Sirtuins are the class III of histone deacetylases whose deacetylate of histones is dependent on nicotinamide adenine dinucleotide (NAD+). Among seven sirtuins, SIRT1 plays a critical role in modulating a wide range of physiological processes, including apoptosis, DNA repair, inflammatory response, metabolism, cancer, and stress. Neuroinflammation is associated with many neurological diseases, including ischemic stroke, bacterial infections, traumatic brain injury, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Recently, numerous studies indicate the protective effects of SIRT1 in neuroinflammation-related diseases. Here, we review the latest progress regarding the anti-inflammatory and neuroprotective effects of SIRT1. First, we introduce the structure, catalytic mechanism, and functions of SIRT1. Next, we discuss the molecular mechanisms of SIRT1 in the regulation of neuroinflammation. Finally, we analyze the mechanisms and effects of SIRT1 in several common neuroinflammation-associated diseases, such as cerebral ischemia, traumatic brain injury, spinal cord injury, AD, and PD. Taken together, this information implies that SIRT1 may serve as a promising therapeutic target for the treatment of neuroinflammation-associated disorders.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1Inflammation is a physiological response of the immune system to harmful infectious and noninfectious stimuli. In response to such stimuli, macrophages, immune cells, and vascular cells take concerted reactions to maintain or restore the integrity of tissue. However, a sustained inflammatory response can be harmful to the body. Inflammatory responses that are centralized in the central nervous system (CNS) are referred to as neuroinflammation. Neuroinflammation has been implicated as the pathogenesis in multiple neurological diseases, including ischemic stroke, bacterial infections, traumatic brain injury, and neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), age-related dementia, and Huntington's disease (HD).

2Due to the existence of the blood-brain barrier (BBB), the peripheral immune cells and molecules have difficulty entering the CNS. Hence, resident innate immune cells of the CNS need to deal directly with various toxins, pathogens, and tissue damage. Pattern recognition receptors (PRRs) have an essential effect on the recognition of pathogen-associated molecular patterns (PAMPs) and derived danger-associated molecular patterns (DAMPs) during inflammatory conditions. There are four families of PRRs, namely, Toll-like receptors (TLRs), NOD-like receptors (NLRs), retinoid acid-inducible gene-1- (RIG-1-) like receptors (RLRs), and C-type lectin receptors (CLRs). In CNS, these PRRs are mainly expressed in microglia, astrocytes, endothelial cells, dendritic cells (DCs), and oligodendrocytes. There are several innate immune cells in the brain, including astrocytes, microglia, macrophages, natural killer (NK) cells, mast cells, and oligodendrocytes. Among these cells, microglia are the primary innate immune cells, and they constitute 10-15% of all the glial cells. Under pathological conditions, microglia are activated by PAMPs and characterized by rapid proliferation and production of proinflammatory cytokines. Acute neuroinflammation is a key response to clear pathogens and to repair tissue damage. However, if acute neuroinflammation remains unresolved, it can lead to chronic inflammation and neurodegeneration.

3Sirtuins are the class III of histone deacetylases and are nicotinamide adenine dinucleotide- (NAD+-) dependent enzymes. The family consists of seven members in mammals, namely, silent information regulator 1 (SIRT1), SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7. The sirtuins are epigenetic modulators involved in many physiologic activities, such as genomic stabilization, cancer, stress response, apoptosis, metabolism, senescence, proliferation, and inflammation. Among all sirtuins, SIRT1 is the first sirtuin to be recognized and is well studied. Many studies have indicated that SIRT1 could regulate the inflammation response in multiple tissues and cells. An increasing number of studies have reported that SIRT1 was closely linked with neuroinflammation. However, the mechanistic pathways involving SIRT1 and neuroinflammation remain poorly defined. Hence, the focus of this review is to summarize the latest advances regarding the potential beneficial roles of SIRT1 in the regulation of neuroinflammation. This study may serve as a useful foundation for the design of a drug for future neuroinflammation and neurodegenerative disease treatments.

2. SIRT1 Structure

4Sirtuins contain a conserved catalytic domain, NAD+ binding domains, and flanking variable NH2- and COOH-terminal regions (Figure 1). The diversity of sirtuin amino acid sequences contribute to their cellular localization, catalysis activity, and function. The human sirtuins are divided into four classes. SIRT1, SIRT2, and SIRT3 are class I showing close homology to yeast Sir2. SIRT4 is class II, and SIRT5 is class III. SIRT6 and SIRT7 belong to class IV sirtuins Among sirtuins, SIRT1 has the largest extensions of terminal regions. The SIRT1 protein (747 amino acids) is made up of the conserved catalytic core (244–512 residues), the COOH-terminal region (1–180 residues), and the NH2-terminal region (513–747 residues). SIRT1 protein contains the nuclear localization signal (KRKKRK) in 41-46 residues. Thus, it is easy to understand that SIRT1 is identified as a nuclear protein. However, numerous evidences indicated that SIRT1 is localized in both the nucleus and cytoplasm in several cells. Under certain conditions, SIRT1 can shuttle between the nucleus and cytoplasm. The nuclear import and export sequences in the NH2-terminal region of SIRT1 have been identified as a regulatory mechanism of nucleocytoplasmic shuttling of SIRT1. Aside from SIRT1, the other six sirtuins have distinct subcellular localizations. SIRT2 is primarily located in the cytoplasm, but it can shuttle from the cytoplasm to the nucleus. SIRT3, SIRT4, and SIRT5 are generally identified as mitochondrial proteins. Recent studies indicated that SIRT3 is not exclusive in mitochondria. SIRT3 primarily localizes in the nucleus and translates to the mitochondria after ultraviolet radiation or etoposide treatment. Apart from SIRT1, SIRT6 and SIRT7 also show nuclear localization. SIRT6 is a chromatin-bound protein, whereas SIRT7 is concentrated in the nucleolus.

3. Catalytic Mechanism of SIRT1

5As the histone deacetylases, mammalian sirtuins share a conserved catalytic domain. For human SIRT1, the catalytic core consists of two domains. The larger NAD+-binding domain composes of a Rossmann fold, and the smaller domain consists of a helical (269–324 residues) and a zinc-binding module (362–419 residues). On the basis of the three-dimensional crystal structures of a sirtuin protein, the catalytic pocket between large and small domains is frequently divided into three active sites: the site A is involved in binding of the adenine-ribose part of NAD, the site B is involved in binding of the nicotinamide-ribose portion, and the site C is the deep location of the NAD-binding pocket. The molecular mechanism of the deacetylation reaction is complicated. Several studies have reported the possible mechanism of the reaction. Briefly, the catalytic reaction begins with forming the ternary complex, which is mediated by NAD+, and an acetylated substrate both binds to the sirtuin enzyme. In this deacetylation process, the glycosidic bond of NAD+-linking nicotinamide and ADP-ribose moiety is cleaved, and the free nicotinamide is released. Then, the acetyl moiety is transferred to ADP-ribose and produces acetyl-ADP-ribose (2′-O-acetyl-ADP-ribose, AADPR) and deacetylated protein (Figure 2). Although human sirtuins belong to histone deacetylases, it should be pointed out that SIRT1, SIRT2, SIRT3, and SIRT7 display deacetylase activity, whereas the deacetylase activities of SIRT4–6 are considered to be weak. SIRT4 has ADP-ribosyltransferase and lipoamidase activity. SIRT5 possesses strong desuccinylation and depropanediylation activity. SIRT6 was initially reported to have deacetylase activity on specific histone acetyl peptides H3 K9 and H3 K56. A recent study found that SIRT6 has demyristoylation activity by regulating the hydrolysis of fatty acylation of lysine residues.

4. SIRT1 Substrates and Function

6SIRT1 is the most well-studied member of the sirtuin family. As a deacetylate histone, it is easy to understand that SIRT1 can regulate the deacetylation of the acetyl-lysine of histone substrate. A previous study confirmed that SIRT1 deacetylates histone H4 at lysine 16 (K16), histone H3 at lysine 9 (K9), and histone H1 at lysine 26 (K26). In addition to the deacetylate of histones, SIRT1 could catalyze the deacetylation of many nonhistone substrates. A growing number of evidence indicate that SIRT1 can deacetylate the lysine residues of a variety of substrates, such as p53, nuclear factor kappa B (NF-κB), Ku70, FOXO1, FOXO3, FOXO4, hypoxia-inducible factor-1a (HIF-1α), HIF-2α, proliferator activated receptor γ coactivator 1α (PGC-1α), and signal transducer and activator of transcription 3 (STAT3) (Table 1). Thus, this wide range of targets reflects that SIRT1 has a strong capacity to regulate multiple physiological functions.

7p53 is the first nonhistone target of SIRT1; deacetylation of p53 at lysine 382 (K382) results in the repression of p53-dependent apoptosis in H1299 cells in response to DNA damage. As a tumor suppressor, the functional and transcriptional activities of p53 are blocked by the deacetylation of SIRT1. Thus, SIRT1 provides a prosurvival response following DNA damage. NF-κB is an important transcription factor that regulates the transcription of many genes. SIRT1 can deacetylate the p65 subunit of NF-κB at lysine 310. It is interesting that deacetylation of p65 augments TNFα-induced apoptosis in non-small-cell lung cancer (NSCLC) cells. A possible hypothesis is the different apoptotic signaling and stimulations. In addition to the apoptosis role, the deacetylation of p65 has been shown to regulate the inflammation response. Ku70 is a DNA repair protein; SIRT1 can deacetylate and activate Ku70 by direct interaction. The deacetylation of Ku70 increases the DNA repair capacity. The Forkhead box O (FOXO) transcription factor family is a subclass of Forkhead transcription factors, including four members FOXO1, FOXO3, FOXO4, and FOXO6. Many evidences suggest that the deacetylation of FOXO1, FOXO3, and FOXO4 can be mediated by SIRT1. For example, the activation of FOXO1 mediated by SIRT1 induces the apoptosis of prostate cancer cells. Deacetylation of FOXO3 by SIRT1 potentiates the ability of FOXO3-induced cell cycle arrest and inhibits cell apoptosis mediated by FOXO3 in response to oxidative stress. In addition, the hyperacetylation and transcriptional activity of FOXO4 can be mediated by peroxide stress, while deacetylation of FOXO4 by SIRT1 enhances the protective effect against oxidative stress. Hypoxia-inducible factors are transcription factors that are critical in the regulation of metabolism under hypoxia. Previous studies have found that both HIF-1α and HIF-2α can be deacetylated by SIRT1. The deacetylation of HIF-1α by SIRT1 enhances the expression of HIF-1α target genes (VEGF, GLUT1, and MMP2) and then results in the promotion of cell invasion. SIRT1 augments the expression of HIF-2α target gene erythropoietin (prosurvival factor) by deacetylation of HIF-2α. PGC-1α is a transcriptional coactivator with multiple functions, including mitochondrial biogenesis and glucose and fatty acid metabolism. Deacetylation of PGC-1α by SIRT1 enhances the effects of PGC-1α on fatty acid oxidation and gluconeogenesis genes in response to caloric restriction. STAT3 is a cellular signal transcription factor that mediates many cellular functions. SIRT1-mediated deacetylation of STAT3 is involved in the regulation of gluconeogenic genes and cell proliferation. In addition to these highlighted substrates, numerous SIRT1 substrates have been discovered. Taken together, these multiple substrates indicate that SIRT1 participates in the regulation of multiple physiological functions, including apoptosis, DNA repair, inflammatory response, metabolism, cancer, and stress.

5. SIRT1 Activator Resveratrol

8Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural polyphenol found in a variety of plant species, which is a natural antibiotic compound synthesized by plants. Numerous studies have shown that resveratrol has many functions, including antioxidant capacity, anti-inflammation, neuroprotection, and anticancer. Many studies confirm that resveratrol is a natural activator of SIRT1. Previous experiments have shown that resveratrol doubled the catalytic rate of SIRT1 at about 11 μM. Dozens of studies report that the anti-inflammatory effects of resveratrol are dependent on SIRT1. However, recent evidence shows that resveratrol may activate SIRT1 activity indirectly. One mechanism in which resveratrol activates SIRT1 involves cAMP and AMPK. Another mechanism is that resveratrol activates Lamin A, which is a protein activator of SIRT1. Several studies have shown that resveratrol regulated neuroinflammation through SIRT1. A recent study indicated that resveratrol inhibits neuroinflammatory response in aged rats after anesthesia and surgery by activation of SIRT1. Similarly, resveratrol inhibited the expressions of inflammatory factors in LPS-induced activation of microglia cells by upregulation of SIRT1.

6. SIRT1 Distribution in CNS

9Previous studies have confirmed the distribution of SIRT1 in a wide variety of mouse organs, including the brain, spinal cord, eyes, heart, liver, kidney, lung, and testis. It is also widely expressed in several human tissues and organ, including the brain, liver, heart, skeletal muscle, pancreas, and adipose tissue. It is interesting that the high levels of SIRT1 expression are observed in the embryonic brain, spinal cord, and heart. An anatomical study of the rodent and human nervous systems indicated that the distribution of SIRT1 is localized in the areas of the hippocampus, prefrontal cortex, and basal ganglia. In addition to these regions, a mouse anatomical study revealed that SIRT1 is also expressed in the hypothalamus and cerebellum. Moreover, this study also indicated that SIRT1 mRNA is mainly expressed in neurons. Recent studies had reported that several cellular types (mouse astrocyte, microglia, and oligodendrocytes) express SIRT1 proteins. Taken together, these studies suggest that SIRT1 is widely expressed in CNS.

7. SIRT1 and Neuroinflammation

10The innate immune system is the first line of defense against infection and injury and plays critical roles in the maintenance of brain homeostasis. It has been shown that astrocytes, microglia, macrophages, NK cells, mast cells, and oligodendrocytes serve as the innate immune cells of the brain. Among these cells, microglia are mainly innate immune cells that are derived from the embryonic yolk sac. Under physiological conditions, microglia constantly survey their microenvironments and present in the resting state with small cellular bodies and slender branching. Under pathological conditions, microglia are activated and converted into amoeboid reactive cells, with the production of proinflammatory factors. Overactivation of microglia has been implicated to the development of neuroinflammation. In addition to microglia, astrocytes also are key innate immune cells involved in the regulation of neuroinflammation. Astrocytes became reactive astrocytes with significant changes in morphology, function, and gene expression in response to CNS injuries and diseases. A previous study suggests that the increase of inflammatory factor (TNF-α, IL-1β, and iNOS) gene expression is observed in both primary microglia and astrocytes after treatment with LPS. Growing evidence supports a role for SIRT1 in the regulation of inflammatory responses in CNS. For example, the SIRT1 activator decreases the secretion of TNF-α and IL-6 in microglial BV2 cells by LPS stimulation, while the SIRT1 inhibitor increases the inflammatory factors release. Another study found that SIRT1 inhibition upregulates the gene expression levels of TNF-α and IL-1β and ROS production in astrocytes after stimulation with LPS. However, the molecular mechanisms involving SIRT1 and neuroinflammation are still unclear. Emerging potential regulatory mechanisms of SIRT1 in the process of neuroinflammation may involve the NF-κB pathway, Toll-like receptor pathway, NLRP3 inflammasome pathway, and MAPK signal pathway (Figure 3). These signal pathways will be discussed in the following paragraphs.

7.1. SIRT1 and NF-κB

11The transcription factor NF-κB family regulates the expression of multiple genes involved in the inflammatory process. It has been shown that the NF-κB family has five subunits: p65 (also RelA), p50, p52, c-Rel, and RelB. The relative pathway mediated by NF-κB complex p65/p50 is commonly defined as the canonical NF-κB pathway. Generally, NF-κB complexes are sequestered by NF-κB inhibitory proteins (IκBs) in the cytoplasm. Once the pathway is activated, the IκB proteins are activated by phosphorylation and its subsequent degradation, resulting in the nuclear translocation of NF-κB complexes and then regulation of target gene expression. A growing number of studies have shown that SIRT1-mediated NF-κB participates in the regulation of inflammation response and diseases. As described previously, SIRT1 has demonstrated the capacity of the deacetylating p65 subunit. Thus, it is easy to understand that SIRT1 mediates the inflammation process by directly regulating the NF-κB pathway. Bone marrow-derived macrophages (BMDMs) from myeloid cell-specific SIRT1 knockout mice result in the hyperacetylation of NF-κB and the increase of proinflammatory cytokines. Activation of SIRT1 by resveratrol inhibits TNF-α-induced inflammation responses in 3T3 fibroblasts by deacetylating the Lys310 residue of the p65 subunit. Similarly, resveratrol decreases the TNF-α-mediated inflammation responses in human chondrocytes by deacetylating NF-κB p65.

12A number of studies demonstrated that the SIRT1 and NF-κB pathways are involved in neuroinflammation. Accumulating studies indicate that the decrease of SIRT1 and the activation of the NF-κB pathway participate in the progress of neuroinflammation and diseases. A recent study found that microglial SIRT1 deficiency aggravates memory deficits and increases IL-1β transcription in aging mice. High levels of acetylation of NF-κB/RelA in primary cortical neurons following oxygen-glucose deprivation (OGD) have been found. Moreover, several neural cell experiments have demonstrated that SIRT1 activator resveratrol suppresses inflammatory cytokines via inhibition of NF-κB transcriptional activity. Furthermore, many animal models indicated that SIRT1 activator resveratrol inhibits the inflammatory cytokines and improves the survival of the neuronal cell by regulating the acetylation of NF-κB p65 (Table 2). In addition to the direct regulation of the NF-κB pathway by deacetylating the p65 subunit, some studies demonstrated that SIRT1 could indirectly regulate the NF-κB pathway by other targets, such as PPARα. Taken together, SIRT1 can suppress the neuroinflammation involved in regulating NF-κB signaling by deacetylation of the p65 subunit and inhibition of NF-κB transcriptional activity.

7.2. SIRT1 and Toll-Like Receptors

13Several toll-like receptors (TLRs) are widely expressed in the immune system of the brain, including microglia, astrocytes, and neurons. As membrane receptors, TLRs recognize several molecules, such as lipopolysaccharide (LPS), heat shock proteins, high-mobility group protein B1 (HMGB1), and peptidoglycan. After activation, TLRs recruit the various downstream molecules, such as myeloid differentiation factor-88 (MyD88), TIR-domain-containing adaptor protein (TIRAP), TNFR-associated factor 6 (TRAF6), and subsequent regulation of activation of NF-κB, leading to the transcription of inflammatory cytokines. It has been confirmed that the TLR pathway is involved in the inflammation response and diseases of CNS. TLR4 knockout inhibits the expression of inflammatory factors IL-1β and TNF-α and improves the survival rate after induction of intracerebral hemorrhage (ICH) compared with wild-type (WT) mice. TLR4 deficiency suppresses the inflammatory factors IL-1β and TNF-α and improves cognitive dysfunction in β2-microglobulin- (B2M-) induced age-related cognitive decline compared with WT mice. Moreover, several studies have demonstrated that SIRT1 regulates neuroinflammation via inhibition of the TLR pathway. There is a recent study of neuroinflammation induced by excessive ethanol (EtOH), and the study found that the SIRT1 activator resveratrol decreases the inflammatory cytokines IL-1β and TNF-α and improves the spatial reference memory by inhibition of the TLR2-MyD88-NF-κB signal pathway. Similarly, resveratrol suppresses the proinflammatory cytokines IL-1β and TNF-α, inhibiting the activation of matrix metalloproteinase-9 (MMP-9) and MMP-2 by downregulation of the TLR-4-NF-κB signaling pathway in trigeminal neuralgia mice. Another study has shown that resveratrol attenuates the cytokines IL-1β, IL-6, and TNF-α by the TLR4-MyD88-NF-κB pathway in hypoxic-ischemic brain injury mice. An experimental subarachnoid hemorrhage model has shown that resveratrol inhibits the proinflammatory cytokines IL-1β, IL-6, and TNF-α and ameliorates neurological behavior impairment by the TLR4-MyD88-NF-κB pathway.

7.3. SIRT1 and NLRP3 Inflammasome

14Inflammasomes are cytosolic molecular complexes that sense a variety of stimuli and subsequently trigger and activate inflammatory events to participate in innate immune defenses. Generally, inflammasome complexes consist of a cytosolic sensor (NLR protein or AIM2-like receptor), an apoptosis-associated speck-like protein containing CARD (ASC), and a pro-caspase-1. Once the cytosolic sensor NLR is in response to intracellular signals, this leads to the formation of the inflammasome complex, regulation of activation of caspase-1 and subsequently activated caspase-1 cleavage pro-IL-1β and pro-IL-18, and release of the proinflammatory cytokines IL-1β and IL-18. To date, five inflammasome complexes have been found: NLRP1, NLRP3, NLRC4, AIM2, and pyrin inflammasome. In CNS, several cells have been found in the expression of inflammasome components, including microglia, neurons, and astrocytes. Accumulating evidence indicates that activation of the NLRP3 inflammasome is involved in neuroinflammation and neurodegenerative pathologies, and the SIRT1 activator resveratrol can regulate neuroinflammation via inhibition of this pathway. In a cell experiment, resveratrol suppresses the release of inflammatory cytokines IL-1β, IL-6, and TNF-α in amyloid-beta- (Aβ-) induced BV2 microglial cells by inhibition of the NLRP3 and NF-κB signaling pathways. Similarly, another study found that resveratrol attenuates ATP and LPS-induced NLRP3 inflammasome activation in BV2 microglial cells. The animal experiment of this study also showed that resveratrol suppresses the inflammatory cytokine IL-1β and activation of microglia in the hippocampus of the sepsis-associated encephalopathy mice by the NLRP3 signaling pathway. Furthermore, many researchers put their interests in the investigation between SIRT1 activator resveratrol and several animal models of brain injury, including subarachnoid hemorrhage, traumatic brain injury, middle cerebral artery occlusion, and cognitive impairment model. All these studies suggest that the SIRT1 activator resveratrol inhibits the inflammatory cytokines IL-1β, IL-18, and TNF-α by inhibiting the NLRP3 inflammasome signaling pathway (Table 3).

7.4. SIRT1 and Mitogen-Activated Protein Kinase

15The activation of the mitogen-activated protein kinase (MAPK) pathway in the innate immune response has been widely studied. The stimulation of PRRs on the cell surface can activate the members of MAPK subfamilies, including p38 kinase, Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK), in conjunction with the NF-κB pathway and many transcription factors of proinflammatory cytokines. It has been found that MAPK pathways contribute to the pathology of several CNS diseases. A growing body of evidence suggests that SIRT1 regulates neuroinflammation involved in MAPK pathways, especially the p38 MAPK pathway. In the study of primary cortical astrocytes, upregulation of SIRT1 by resveratrol or adenoviral vectors inhibits the astrocyte activation after stimulation of IL-1β via inhibition of the MAPK signaling pathway. Another study showed that resveratrol suppresses the inflammatory cytokines IL-1β and TNF-α in hypoxia-induced cytotoxicity in BV2 microglial cells by inhibition of the MAPK and NF-κB signaling pathways. Similarly, resveratrol-enriched rice attenuates several inflammatory cytokines in LPS-activated BV2 microglial cells by suppression of MAPK signaling pathways and NF-κB translocation. There is a study on the neuron cells that found that resveratrol decreases the inflammatory cytokine TNF-α and neuron damage in the hippocampus of an alcohol-induced neurodegeneration rat through the p38 MAPK pathway. Moreover, the SIRT1 inhibitor sirtinol promotes the neuronal apoptosis in injured-side cortexes of a traumatic brain injury rat model by the activation of the p38 MAPK pathway. However, there is an opposite conclusion that the SIRT1 inhibitor salermide or SIRT1 siRNA promotes apoptotic neuronal death by inhibition of the ERK1/2 MAPK pathway (Table 4).

8. SIRT1 and CNS Diseases

16Numerous studies have shown that SIRT1 was implicated in a variety of CNS diseases. The pharmacological SIRT1 activator or inhibitor participant in the regulation of neuroinflammation and neurodegenerative diseases has been reported. Moreover, accumulating studies indicate that synthetic drugs and natural compounds mediate CNS diseases by regulating SIRT1. The following sections discuss the effect of SIRT1 on CNS disorders, including cerebral ischemia, traumatic brain injury, spinal cord injury, AD, and PD.

8.1. Cerebral Ischemia

17Cerebral ischemia is the most common neurological disease due to the sudden reduction or cessation of blood flow to the brain, which leads to infarction and neuronal dysfunction. Increasing evidence suggests that SIRT1 is a promising target for the treatment of cerebral ischemia injury. In an animal model study, several studies have shown that the SIRT1 activator resveratrol provides a neuroprotective effect in the middle cerebral artery occlusion model. One of these studies suggested that SIRT1 exerts the anti-inflammatory and antiapoptotic effects on cerebral ischemic injury by inhibition of acetylation of p53 and NF-κB. Apart from resveratrol, a large number of natural compounds have reported the neuroprotective benefits for cerebral ischemic by activation of SIRT1, while the mechanisms of these compounds that regulate cerebral ischemic are different. The mainly regulatory mechanisms include anti-inflammatory, antiapoptotic, and antioxidative effects (Table 5). For example, rosuvastatin was found to provide a neuroprotective effect against ischemic stroke by inhibiting the NF-κB signaling pathway through the activation of SIRT1. Salvianolic acid B derived from danshen has a protective effect against ischemic stroke through the activation of SIRT1, leads to an increase of Bcl-2 and a decrease of Bax expression by inhibiting the acetylation of FOXO1, and finally inhibits the apoptosis. Another study has shown that alpha-lipoic acid reduced the ischemic brain damage by the improvement of oxidative damage through the SIRT1/PGC-1α pathway.

8.2. Traumatic Brain Injury

18Traumatic brain injury (TBI) is the neurological dysfunction caused by physical force. In addition to this direct insult, secondary injury is driven by a cascade of the inflammatory response, BBB disruption, and metabolic changes. Currently, several studies have demonstrated that the activator of SIRT1 contributes to the improvement of TBI animal models by the involvement of NLRP3 inflammasome and MAPK pathways. Similarly, some studies have shown that an inhibitor of SIRT1 exacerbated the brain damage of TBI models by activation of p38 and ERK1/2 MAPK pathways. Besides, several studies have demonstrated that natural compounds protect against TBI by activation of SIRT1. For example, berberine has reported the neuroprotective effect in a severe TBI mouse model by inhibition of the p38 MAPK pathway through the activation of SIRT1. Polydatin derived from Polygonum cuspidatum ameliorated the damage of TBI through SIRT1-mediated improvement of endoplasmic reticulum stress and mitochondrial injury. Another study has demonstrated that omega-3 polyunsaturated fatty acids (ω-3 PUFA) reduced the neuronal apoptosis in TBI rats through the promotion of autophagy by SIRT1-mediated deacetylation of beclin-1. They also found that ω-3 PUFA could inhibit the inflammatory response in the TBI model by SIRT1-mediated deacetylation of HMGB1 and NF-κB (Table 6).

8.3. Spinal Cord Injury

19Spinal cord injury (SCI) is a devastating neurological disorder which leads not only to motor and sensory deficits but also to a wide range of other organ dysfunctions, such as respiratory and bowel issues, bladder dysfunction, and osteoporosis. Posttraumatic inflammation plays a critical role in the pathogenesis of SCI. Numerous studies have shown that SIRT1 exerts a neuroprotective effect in the animal model of SCI. For instance, SIRT1 agonist CAY10602 inhibited cell apoptosis through the p53 signaling pathway in the SCI rat model. Pretreatment of resveratrol had a neuroprotective effect on spinal cord neuron apoptosis by regulating autophagy via the activation of the SIRT1/AMPK pathway. A study has found that the SIRT1 activator of SRT1720 ameliorated inflammatory response and microglial activation through regulation of the Wnt/β-catenin pathway. Consistent with this study, another study had confirmed that SRT1720 suppressed the inflammatory reactions. In addition, SIRT1 knockout mice led to severe motor function, neuronal survival, and inflammatory response than WT mice after SCI.

8.4. Alzheimer's Disease (AD)

20Alzheimer's disease (AD) is the most common neurodegenerative disease that leads to the decline of cognitive function and memory. AD is characterized by the pathological accumulation of amyloid-β (Aβ), neurofibrillary tangles (NFTs), and phosphorylated tau protein. In addition, inflammation is thought to exacerbate the pathology of AD. One study has reported that resveratrol provides a beneficial effect on AD rats by downregulation of NF-κB p65, Aβ, and MMP-9. Another study has shown that resveratrol ameliorated the Aβ-induced cognitive deficits in AD mice by upregulation of SIRT1 and downregulation of NF-κB/IL-1β/NLRP3. However, numerous evidences indicated the beneficial effects of SIRT1 in AD by regulating the expression of Aβ and tau protein. Some research has suggested that resveratrol suppressed the Aβ-induced neuronal apoptosis by activation of SIRT1 pathways. Moreover, a recent study has reported that the upregulation of SIRT1 promoted the degradation of Aβ in primary astrocytes. In addition, a study suggested that SIRT1 could suppress the spread of pathogenic tau by deacetylation of tau in tauP301S transgenic mice. Furthermore, accumulating evidence has demonstrated that the SIRT1 agonist resveratrol has a protective effect on multiple animal models of AD. For example, the treatment of resveratrol improved learning and memory and suppressed neural apoptosis in the Tg2576 mouse model of AD. Similarly, resveratrol has been found to decrease Aβ levels and improve learning and memory in APP/PS1 AD mice. In addition, another AD model study was induced by Aβ1–42, and this study has shown that resveratrol ameliorated the spatial, learning, and memory deficits by regulating SIRT1 signaling pathways. Furthermore, overexpression of SIRT1 in the hippocampus improved learning and memory and reduced the expression of Aβ and tau in the 3xTg AD mouse model. Apart from resveratrol, several natural compounds have reported the beneficial effects of the regulation of SIRT1 in AD animal studies (Table 7).

8.5. Parkinson's Disease (PD)

21Parkinson's disease (PD) is the second most common neurological disorder and is characterized by the loss of dopaminergic (DA) neurons. Aggregation of alpha-synuclein (α-syn) of neurons is another pathological feature of PD. Increasing evidence supports the important role of neuroinflammation in the pathogenesis of PD. Accumulating evidence supports the hypothesis that SIRT1 has beneficial effects on different models of PD. Three neurotoxins, including rotenone, 6-hydroxydopamine (6-OHDA), and 1-methyl-4-phenylpyridinium (MPP+), are extensively used in cellular models of PD. Several in vitro studies have found that resveratrol ameliorated neuronal apoptosis in the rotenone-induced SH-SY5Y cell model of PD by regulation of SIRT1 pathways. A recent study has reported that the upregulation of SIRT1 protected SH-SY5Y cells from rotenone by inhibition of NF-κB. In addition, some natural compounds, including epigallocatechin-3-gallate (EGCG), echinacoside (ECH), and salidroside, have reported the neuroprotective effects on MPP+-treated cellular models of PD by regulating SIRT1 pathways. Furthermore, some recent studies indicate that the neuroprotective role of SIRT1 in the animal model of PD. For example, activation SIRT1 by resveratrol alleviated the loss of dopaminergic neurons and promoted the degradation of α-synuclein by deacetylation of LC3 in the MPTP-induced mouse model. SIRT1 knockout worsens movement function in a mouse PD model induced by MPTP. However, a recent study suggested that SIRT1-transgenic mice fail to alleviate the loss of nigrostriatal dopamine neurons in the MPTP-induced mouse model. A list of studies of treatments for PD that target SIRT1 is shown in Table 8.

9. SIRT1 and Brain Aging

22Aging is a physiological phenomenon in which the body function declines in a time-dependent fashion. It has been widely reported that brain aging is characterized by the presence of cognitive changes. Aging is a major risk factor for some neurodegenerative diseases, such as AD and PD. Some studies have shown that the inflammatory process and oxidative stress contribute to the cognitive changes in aged brains. Gene expression studies have shown the age-related gene expression changes in the human brain. The downregulation genes which include those related to memory and learning, calcium signaling, and mitochondrial function are downregulated. In addition, the upregulation genes include DNA repair, oxidative stress, and inflammatory response. The chronic inflammatory status was shown to link with aging and age-related diseases closely. The major characteristics of the aging process are a progressive increase in proinflammatory status. This phenomenon was firstly called “inflamm-aging”. As discussed in the previous section, SIRT1 plays an important role in the progression of neurodegenerative diseases, such as AD and PD. Increasing evidence shows that SIRT1 is involved in the regulation of aging and lifespan. Brain-specific Sirt1-overexpressing (BRASTO) transgenic mice were shown to have increased lifespans, and pharmacologic SIRT1 activator SRT1720 was shown to have lifespan benefits in mice. Growing evidence indicates that SIRT1 can be a connecting link among inflammatory response, oxidative stress, and aging. A recent study has shown that SIRT1-knockout zebrafish resulted in chronic inflammation, oxidative injury, and decreased lifespan. In addition, SIRT1 can regulate oxidative stress, inflammation, and senescence in the progression of COPD. These studies suggest that SIRT1 may be a potential target for aging-associated disorders.

10. SIRT1 and Clinical Study

23On the basis of the above research, a large body of cellular and animal studies indicates the neuroprotective effect of SIRT1 in neuroinflammation and neurodegenerative diseases. In addition, there are an increasing number of clinical studies to explore the effect of SIRT1 on inflammatory diseases. For example, treating ulcerative colitis subjects with resveratrol for six weeks decreased serum inflammatory markers TNF-α and hs-CRP compared to placebo. Another randomized controlled clinical trial demonstrated that treatment with resveratrol for 12 weeks led to the reduction of serum ALT, TNF-α, IL-6, and hs-CRP in nonalcoholic fatty liver disease patients. Moreover, there are several clinical trials in the area of CNS diseases. AD subjects who received resveratrol for 52 weeks were able to decrease the expression of cerebrospinal fluid MMP-9 and modulate the inflammatory markers and adaptive immunity. However, another clinical trial of AD indicates that resveratrol has no beneficial effects. In addition, treatment with resveratrol for 26weeks improved memory performance and hippocampal functional connectivity in healthy older adults. In contrast, one recent clinical trial indicates that resveratrol fails to improve verbal memory in older adults. A randomized interventional study showed that resveratrol improved the resting-state functional connectivity (RSFC) of the hippocampus and reduced the serum glycated hemoglobin A1c (HbA1c) in patients with mild cognitive impairment (MCI). These findings suggest that SIRT1 may be the potential target treatment of neuroinflammation and neurodegenerative disorders. However, in order to explore the therapeutic benefit of SIRT1 on CNS diseases, larger sample clinical trials with longer duration need to be performed in the future.

11. Conclusions and Perspectives

24In this review, we summarized the latest evidence of the beneficial roles of SIRT1 in the regulation of neuroinflammation and neurodegenerative diseases. As one of the most well-studied sirtuins, SIRT1 can regulate multiple biological functions, including apoptosis, DNA repair, inflammatory response, metabolism, cancer, and stress. We focused on the regulatory effect of SIRT1 in the inflammation response of CNS. Numerous researches indicate that mechanisms of SIRT1 modulate inflammatory reactions in CNS by many different molecules and pathways. Several potential modulatory pathways were summarized in this text, including NF-κB, TLRs, NLRP3 inflammasome, and MAPK pathways. The neuroprotective effects of SIRT1 activation have been reported in in vivo and in vitro models of neuroinflammation-associated diseases. Moreover, some clinical trials have reported the neuroprotective effects of the SIRT1 activator resveratrol. Although a large number of studies demonstrated the benefic effects of the pharmacological activator of SIRT1 in neurological disorders. Some questions still need to be answered. For example, the biological functions of SIRT1 are complex and wide. The precise mechanisms of SIRT1 by deacetylation, which targets the inflammatory process of CNS diseases, are unclear. In addition, the evidence of anti-inflammatory and neuroprotective effects of SIRT1 from clinical studies is not enough. Therefore, further investigations are needed in the precise targets of SIRT1, which will contribute to developing treatment strategies for neuroinflammation-related diseases.

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98.
Moon M. H., Jeong J. K., Lee Y. J., Seol J. W., Jackson C. J., Park S. Y. SIRT1, a class III histone deacetylase, regulates TNF-α-induced inflammation in human chondrocytes. Osteoarthritis Cartilage. 2013;21(3):470-480.
Not in our library10.1016/j.joca.2012.11.017
99.
Cho S. H., Chen J. A., Sayed F., et al. SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β. Journal Neuroscience. 2015;35(2):807-818.
Not in our library10.1523/jneurosci.2939-14.2015
100.
Lanzillotta A., Pignataro G., Branca C., et al. Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window. Neurobiology Disease. 2013;49:177-189.
Not in our library10.1016/j.nbd.2012.08.018
101.
Zhao H., Wang Q., Cheng X., et al. Inhibitive effect of resveratrol on the inflammation in cultured astrocytes and microglia induced by Aβ1–42. Neuroscience. 2018;379:390-404.
Not in our library10.1016/j.neuroscience.2018.03.047
102.
Chen J., Zhou Y., Mueller-Steiner S., et al. SIRT1 protects against microglia-dependent Amyloid-β toxicity through inhibiting NF-κB signaling. Journal Biological Chemistry. 2005;280(48):40364-40374.
Not in our library10.1074/jbc.m509329200
103.
Lanzillotta A., Sarnico I., Ingrassia R., et al. The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury. Cell Death Disease. 2010;1(11):p. e96.
Not in our library10.1038/cddis.2010.76
104.
Liu L., Zhang Q., Cai Y., et al. Resveratrol counteracts lipopolysaccharide-induced depressive-like behaviors via enhanced hippocampal neurogenesis. Oncotarget. 2016;7(35):56045-56059.
Not in our library10.18632/oncotarget.11178
105.
Zhao H. F., Li N., Wang Q., Cheng X. J., Li X. M., Liu T. T. Resveratrol decreases the insoluble Aβ1-42 level in hippocampus and protects the integrity of the blood-brain barrier in AD rats. Neuroscience. 2015;310:641-649.
Not in our library10.1016/j.neuroscience.2015.10.006
106.
Planavila A., Iglesias R., Giralt M., Villarroya F. Sirt1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. Cardiovascular Research. 2011;90(2):276-284.
Not in our library10.1093/cvr/cvq376
107.
Kay E., Scotland R. S., Whiteford J. R. Toll-like receptors: role in inflammation and therapeutic potential. Biofactors. 2014;40(3):284-294.
Not in our library10.1002/biof.1156
108.
Fei X., He Y., Chen J., et al. The role of Toll-like receptor 4 in apoptosis of brain tissue after induction of intracerebral hemorrhage. Journal Neuroinflammation. 2019;16(1):p. 234.
Not in our library10.1186/s12974-019-1634-x
109.
Zhong Q., Zou Y., Liu H., et al. Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice. Molecular Brain. 2020;13(1):p. 20.
Not in our library10.1186/s13041-020-0559-8
110.
Qi B., Shi C., Meng J., Xu S., Liu J. Resveratrol alleviates ethanol-induced neuroinflammation in vivo and in vitro: Involvement of TLR2-MyD88-NF-κB pathway. International Journal Biochemistry Cell Biology. 2018;103:56-64.
Not in our library10.1016/j.biocel.2018.07.007
111.
Yin Y., Guo R., Shao Y., et al. Pretreatment with resveratrol ameliorate trigeminal neuralgia by suppressing matrix metalloproteinase-9/2 in trigeminal ganglion. International Immunopharmacology. 2019;72:339-347.
Not in our library10.1016/j.intimp.2019.04.014
112.
Le K., Daliv E. C., Wu S., et al. SIRT1-regulated HMGB1 release is partially involved in TLR4 signal transduction: a possible anti-neuroinflammatory mechanism of resveratrol in neonatal hypoxic-ischemic brain injury. International Immunopharmacology. 2019;75, article 105779.
Not in our library10.1016/j.intimp.2019.105779
113.
Zhang X.-S., Li W., Wu Q., et al. Resveratrol attenuates acute inflammatory injury in experimental subarachnoid hemorrhage in rats via inhibition of TLR4 pathway. International Journal Molecular Sciences. 2016;17(8):p. 1331.
Not in our library10.3390/ijms17081331
114.
Rathinam V. A., Fitzgerald K. A. Inflammasome complexes: emerging mechanisms and effector functions. Cell. 2016;165(4):792-800.
Not in our library10.1016/j.cell.2016.03.046
115.
Kanneganti T. D. The inflammasome: firing up innate immunity. Immunological Reviews. 2015;265(1):1-5.
Not in our library10.1111/imr.12297
116.
Albornoz E. A., Woodruff T. M., Gordon R. Inflammasomes in CNS diseases. Experientia Supplementum. 2018;108:41-60.
Not in our library10.1007/978-3-319-89390-7_3
117.
Feng L., Zhang L. Resveratrol suppresses Aβ-induced microglial activation through the TXNIP/TRX/NLRP3 signaling pathway. DNA Cell Biology. 2019;38(8):874-879.
Not in our library10.1089/dna.2018.4308
118.
Sui D.-M., Xie Q., Yi W.-J., et al. Resveratrol protects against sepsis-associated encephalopathy and inhibits the NLRP3/IL-1β axis in microglia. Mediators Inflammation. 2016;2016, article 1045657:1-10.
Not in our library10.1155/2016/1045657
119.
Liu T., Ma Y., Zhang R., et al. Resveratrol ameliorates estrogen deficiency-induced depression- and anxiety-like behaviors and hippocampal inflammation in mice. Psychopharmacology. 2019;236(4):1385-1399.
Not in our library10.1007/s00213-018-5148-5
120.
Zhang X., Wu Q., Zhang Q., et al. Resveratrol attenuates early brain injury after experimental subarachnoid hemorrhage via inhibition of NLRP3 inflammasome activation. Frontiers Neuroscience. 2017;11:p. 611.
Not in our library10.3389/fnins.2017.00611
121.
Li X. M., Zhou M. T., Wang X. M., Ji M. H., Zhou Z. Q., Yang J. J. Resveratrol pretreatment attenuates the isoflurane-induced cognitive impairment through its anti-inflammation and -apoptosis actions in aged mice. Journal Molecular Neuroscience. 2014;52(2):286-293.
Not in our library10.1007/s12031-013-0141-2
122.
Zou P., Liu X., Li G., Wang Y. Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1. Molecular Medicine Reports. 2018;17(2):3212-3217.
Not in our library10.3892/mmr.2017.8241
123.
He Q., Li Z., Wang Y., Hou Y., Li L., Zhao J. Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. International Immunopharmacology. 2017;50:208-215.
Not in our library10.1016/j.intimp.2017.06.029
124.
Arthur J. S., Ley S. C. Mitogen-activated protein kinases in innate immunity. Nature Reviews Immunology. 2013;13(9):679-692.
Not in our library10.1038/nri3495
125.
Kim E. K., Choi E.-J. Compromised MAPK signaling in human diseases: an update. Archives Toxicology. 2015;89(6):867-882.
Not in our library10.1007/s00204-015-1472-2
126.
Interactions between Sirt1 and MAPKs regulate astrocyte activation induced by brain injury in vitro and in vivo · 2017
Not checked
127.
Zhang Q., Yuan L., Zhang Q., et al. Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation. International Immunopharmacology. 2015;28(1):578-587.
Not in our library10.1016/j.intimp.2015.07.027
128.
Subedi L., Baek S.-H., Kim S. Y. Genetically engineered resveratrol-enriched rice inhibits neuroinflammation in lipopolysaccharide-activated BV2 microglia via downregulating mitogen-activated protein kinase-nuclear factor kappa B signaling pathway. Oxidative Medicine Cellular Longevity. 2018;2018, article 8092713:1-14.
Not in our library10.1155/2018/8092713
129.
Gu X., Cai Z., Cai M., et al. AMPK/SIRT1/p38 MAPK signaling pathway regulates alcohol-induced neurodegeneration by resveratrol. Molecular Medicine Reports. 2018;17(4):5402-5408.
Not in our library10.3892/mmr.2018.8482
130.
Yang H., Gu Z. T., Li L., et al. SIRT1 plays a neuroprotective role in traumatic brain injury in rats via inhibiting the p38 MAPK pathway. Acta Pharmacologica Sinica. 2017;38(2):168-181.
Not in our library10.1038/aps.2016.130
131.
Zhao Y., Luo P., Guo Q., et al. Interactions between SIRT1 and MAPK/ERK regulate neuronal apoptosis induced by traumatic brain injury in vitro and in vivo. Experimental Neurology. 2012;237(2):489-498.
Not in our library10.1016/j.expneurol.2012.07.004
132.
Shin J. A., Lee K. E., Kim H. S., Park E. M. Acute resveratrol treatment modulates multiple signaling pathways in the ischemic brain. Neurochemical Research. 2012;37(12):2686-2696.
Not in our library10.1007/s11064-012-0858-2
133.
Hernandez-Jimenez M., Hurtado O., Cuartero M. I., et al. Silent information regulator 1 protects the brain against cerebral ischemic damage. Stroke. 2013;44(8):2333-2337.
Not in our library10.1161/strokeaha.113.001715
134.
Hermann D. M., Zechariah A., Kaltwasser B., et al. Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia. Neurobiology Disease. 2015;83:16-25.
Not in our library10.1016/j.nbd.2015.08.018
135.
Koronowski K. B., Dave K. R., Saul I., et al. Resveratrol preconditioning induces a novel extended window of ischemic tolerance in the mouse brain. Stroke. 2015;46(8):2293-2298.
Not in our library10.1161/strokeaha.115.009876
136.
Wan D., Zhou Y., Wang K., Hou Y., Hou R., Ye X. Resveratrol provides neuroprotection by inhibiting phosphodiesterases and regulating the cAMP/AMPK/SIRT1 pathway after stroke in rats. Brain Research Bulletin. 2016;121:255-262.
Not in our library10.1016/j.brainresbull.2016.02.011
137.
Kou D. Q., Jiang Y. L., Qin J. H., Huang Y. H. Magnolol attenuates the inflammation and apoptosis through the activation of SIRT1 in experimental stroke rats. Pharmacological Reports. 2017;69(4):642-647.
Not in our library10.1016/j.pharep.2016.12.012
138.
Wang P., Xu T. Y., Guan Y. F., et al. Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1-dependent adenosine monophosphate-activated kinase pathway. Annals Neurology. 2011;69(2):360-374.
Not in our library10.1002/ana.22236
139.
Yan L., Zhu T. Effects of rosuvastatin on neuronal apoptosis in cerebral ischemic stroke rats via Sirt1/NF-kappa B signaling pathway. European Review Medical Pharmacological Sciences. 2019;23(12):5449-5455.
Not in our library10.26355/eurrev_201906_18214
140.
Lv H., Wang L., Shen J., et al. Salvianolic acid B attenuates apoptosis and inflammation via SIRT1 activation in experimental stroke rats. Brain Research Bulletin. 2015;115:30-36.
Not in our library10.1016/j.brainresbull.2015.05.002
141.
Fu B., Zhang J., Zhang X., et al. Alpha-lipoic acid upregulates SIRT1-dependent PGC-1α expression and protects mouse brain against focal ischemia. Neuroscience. 2014;281:251-257.
Not in our library10.1016/j.neuroscience.2014.09.058
142.
Needham E. J., Helmy A., Zanier E. R., Jones J. L., Coles A. J., Menon D. K. The immunological response to traumatic brain injury. Journal Neuroimmunology. 2019;332:112-125.
Not in our library10.1016/j.jneuroim.2019.04.005
143.
Zhang Z., Li D., Xu L., Li H. P. Sirt1 improves functional recovery by regulating autophagy of astrocyte and neuron after brain injury. Brain Research Bulletin. 2019;150:42-49.
Not in our library10.1016/j.brainresbull.2019.05.005
144.
Wang J., Zhang Y. Neuroprotective effect of berberine agonist against impairment of learning and memory skills in severe traumatic brain injury via Sirt1/p38 MAPK expression. Molecular Medicine Reports. 2018;17(5):6881-6886.
Not in our library10.3892/mmr.2018.8674
145.
Polydatin prevents the induction of secondary brain injury after traumatic brain injury by protecting neuronal mitochondria · 2019
Not checked
146.
Omega-3 polyunsaturated fatty acid attenuates traumatic brain injury-induced neuronal apoptosis by inducing autophagy through the upregulation of SIRT1-mediated deacetylation of Beclin-1 · 2018
Not checked
147.
Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury · 2018
No notice
148.
Bloom O., Herman P. E., Spungen A. M. Systemic inflammation in traumatic spinal cord injury. Experimental Neurology. 2020;325, article 113143.
Not in our library10.1016/j.expneurol.2019.113143
149.
Wang S., Smith G. M., Selzer M. E., Li S. Emerging molecular therapeutic targets for spinal cord injury. Expert Opinion Therapeutic Targets. 2019;23(9):787-803.
Not in our library10.1080/14728222.2019.1661381
150.
Yu X., Zhang S., Zhao D., et al. SIRT1 inhibits apoptosis in in vivo and in vitro models of spinal cord injury via microRNA-494. Journal Molecular Medicine. 2019;43(4):1758-1768.
Not in our library10.3892/ijmm.2019.4106
151.
Yan P., Bai L., Lu W., Gao Y., Bi Y., Lv G. Regulation of autophagy by AMP-activated protein kinase/sirtuin 1 pathway reduces spinal cord neurons damage. Iranian Journal Basic Medical Sciences. 2017;20(9):1029-1036.
Not in our library10.22038/ijbms.2017.9272
152.
Zhao H., Chen S., Gao K., et al. Resveratrol protects against spinal cord injury by activating autophagy and inhibiting apoptosis mediated by the SIRT1/AMPK signaling pathway. Neuroscience. 2017;348:241-251.
Not in our library10.1016/j.neuroscience.2017.02.027
153.
Lu P., Han D., Zhu K., Jin M., Mei X., Lu H. Effects of sirtuin 1 on microglia in spinal cord injury: involvement of Wnt/β-catenin signaling pathway. Neuroreport. 2019;30(13):867-874.
Not in our library10.1097/wnr.0000000000001293
154.
Chen H., Ji H., Zhang M., et al. An agonist of the protective factor SIRT1 improves functional recovery and promotes neuronal survival by attenuating inflammation after spinal cord injury. Journal Neuroscience. 2017;37(11):2916-2930.
Not in our library10.1523/jneurosci.3046-16.2017
155.
Yan Y., Yang H., Xie Y., Ding Y., Kong D., Yu H. Research progress on Alzheimer's disease and resveratrol. Neurochemical Research. 2020;45(5):989-1006.
Not in our library10.1007/s11064-020-03007-0
156.
Heppner F. L., Ransohoff R. M., Becher B. Immune attack: the role of inflammation in Alzheimer disease. Neuroscience. 2015;16(6):358-372.
Not in our library10.1038/nrn3880
157.
Qi Y., Shang L., Liao Z., et al. Intracerebroventricular injection of resveratrol ameliorated Aβ-induced learning and cognitive decline in mice. Metabolic Brain Disease. 2019;34(1):257-266.
Not in our library10.1007/s11011-018-0348-6
158.
Resveratrol Inhibits β-Amyloid-Induced Neuronal Apoptosis through Regulation of SIRT1-ROCK1 Signaling Pathway · 2013
No notice
159.
Ai Z., Li C., Li L., He G. Resveratrol inhibits β-amyloid-induced neuronal apoptosis via regulation of p53 acetylation in PC12 cells. Molecular Medicine Reports. 2015;11(4):2429-2434.
Not in our library10.3892/mmr.2014.3034
160.
Zhang J., Feng X., Wu J., et al. Neuroprotective effects of resveratrol on damages of mouse cortical neurons induced by β-amyloid through activation of SIRT1/Akt1 pathway. Biofactors. 2014;40(2):258-267.
Not in our library10.1002/biof.1149
161.
Li M. Z., Zheng L. J., Shen J., et al. SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes. Neural Regeneration Research. 2018;13(11):2005-2013.
Not in our library10.4103/1673-5374.239449
162.
Min S.-W., Sohn P. D., Li Y., et al. SIRT1 deacetylates tau and reduces pathogenic tau spread in a mouse model of tauopathy. Journal Neuroscience. 2018;38(15):3680-3688.
Not in our library10.1523/jneurosci.2369-17.2018
163.
Wang X., Ma S., Yang B., et al. Resveratrol promotes hUC-MSCs engraftment and neural repair in a mouse model of Alzheimer's disease. Behavioural Brain Research. 2018;339:297-304.
Not in our library10.1016/j.bbr.2017.10.032
164.
Ma X. R., Sun Z. K., Han X., et al. Neuroprotective effect of resveratrol via activation of Sirt1 signaling in a rat model of combined diabetes and Alzheimer's disease. Frontiers Neuroscience. 2020;13:p. 1400.
Not in our library10.3389/fnins.2019.01400
165.
Dong Y.-T., Cao K., Tan L.-C., et al. Stimulation of SIRT1 attenuates the level of oxidative stress in the brains of APP/PS1 double transgenic mice and in primary neurons exposed to oligomers of the amyloid-β peptide. Journal Alzheimers Disease. 2018;63(1):283-301.
Not in our library10.3233/jad-171020
166.
Cao K., Dong Y. T., Xiang J., et al. The neuroprotective effects of SIRT1 in mice carrying the APP/PS1 double-transgenic mutation and in SH-SY5Y cells over-expressing human APP670/671 may involve elevated levels of α7 nicotinic acetylcholine receptors. Aging. 2020;12(2):1792-1807.
Not in our library10.18632/aging.102713
167.
Porquet D., Griñán-Ferré C., Ferrer I., et al. Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer's disease. Journal Alzheimers Disease. 2014;42(4):1209-1220.
Not in our library10.3233/jad-140444
168.
Wang R., Zhang Y., Li J., Zhang C. Resveratrol ameliorates spatial learning memory impairment induced by Aβ 1–42 in rats. Neuroscience. 2017;344:39-47.
Not in our library10.1016/j.neuroscience.2016.08.051
169.
Corpas R., Revilla S., Ursulet S., et al. SIRT1 overexpression in mouse hippocampus induces cognitive enhancement through proteostatic and neurotrophic mechanisms. Molecular Neurobiology. 2017;54(7):5604-5619.
Not in our library10.1007/s12035-016-0087-9
170.
SLAB51 Probiotic Formulation Activates SIRT1 Pathway Promoting Antioxidant and Neuroprotective Effects in an AD Mouse Model · 2018
No notice
171.
Testa G., Staurenghi E., Giannelli S., et al. A silver lining for 24-hydroxycholesterol in Alzheimer's disease: the involvement of the neuroprotective enzyme sirtuin 1. Redox Biology. 2018;17:423-431.
Not in our library10.1016/j.redox.2018.05.009
172.
Li Q., Zeng J., Su M., He Y., Zhu B. Acetylshikonin from Zicao attenuates cognitive impairment and hippocampus senescence in d-galactose-induced aging mouse model via upregulating the expression of SIRT1. Brain Research Bulletin. 2018;137:311-318.
Not in our library10.1016/j.brainresbull.2018.01.007
173.
Ansari Dezfouli M., Zahmatkesh M., Farahmandfar M., Khodagholi F. Melatonin protective effect against amyloid β-induced neurotoxicity mediated by mitochondrial biogenesis; involvement of hippocampal sirtuin-1 signaling pathway. Physiology Behavior. 2019;204:65-75.
Not in our library10.1016/j.physbeh.2019.02.016
174.
Sun P., Yin J.-B., Liu L.-H., et al. Protective role of dihydromyricetin in Alzheimer's disease rat model associated with activating AMPK/SIRT1 signaling pathway. Bioscience Reports. 2019;39(1).
Not in our library10.1042/bsr20180902
175.
Gao J., Zhou R., You X., et al. Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer's disease via SIRT1/NF-κB pathway. Metabolic Brain Disease. 2016;31(4):771-778.
Not in our library10.1007/s11011-016-9813-2
176.
Kalampokini S., Becker A., Fassbender K., Lyros E., Unger M. M. Nonpharmacological modulation of chronic inflammation in Parkinson's disease: role of diet interventions. Parkinsons Disease. 2019;2019, article 7535472:1-12.
Not in our library10.1155/2019/7535472
177.
Hirsch E. C., Vyas S., Hunot S. Neuroinflammation in Parkinson's disease. Parkinsonism related disorders. 2012;18(Supplement 1):S210-S212.
Not in our library10.1016/s1353-8020(11)70065-7
178.
Falkenburger B. H., Saridaki T., Dinter E. Cellular models for Parkinson's disease. Journal Neurochemistry. 2016;139:121-130.
Not in our library10.1111/jnc.13618
179.
Wang Y., Lv D., Liu W., et al. Disruption of the circadian clock alters antioxidative defense via the SIRT1-BMAL1 pathway in 6-OHDA-induced models of Parkinson's disease. Oxidative Medicine and Cellular Longevity. 2018;2018:11.
Not in our library10.1155/2018/4854732
180.
Feng Y., Liu T., Dong S. Y., et al. Rotenone affects p53 transcriptional activity and apoptosis via targeting SIRT1 and H3K9 acetylation in SH-SY5Y cells. Journal Neurochemistry. 2015;134(4):668-676.
Not in our library10.1111/jnc.13172
181.
Wu Y., Li X., Zhu J. X., et al. Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson's disease. Neurosignals. 2011;19(3):163-174.
Not in our library10.1159/000328516
182.
SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson’s disease · 2017
No notice
183.
Ye Q., Ye L., Xu X., et al. Epigallocatechin-3-gallate suppresses 1-methyl-4-phenyl-pyridine-induced oxidative stress in PC12 cells via the SIRT1/PGC-1α signaling pathway. BMC Complementary Medicine Therapies. 2012;12(1):p. 82.
Not in our library10.1186/1472-6882-12-82
184.
Chen C., Xia B., Tang L., et al. Echinacoside protects against MPTP/MPP (+)-induced neurotoxicity via regulating autophagy pathway mediated by Sirt1. Metabolic Brain Disease. 2019;34(1):203-212.
Not in our library10.1007/s11011-018-0330-3
185.
Wang C. Y., Sun Z. N., Wang M. X., Zhang C. SIRT1 mediates salidroside-elicited protective effects against MPP (+) -induced apoptosis and oxidative stress in SH-SY5Y cells: involvement in suppressing MAPK pathways. Cell Biology International. 2018;42(1):84-94.
Not in our library10.1002/cbin.10864
186.
Guo Y.-J., Dong S.-Y., Cui X.-X., et al. Resveratrol alleviates MPTP-induced motor impairments and pathological changes by autophagic degradation of α-synuclein via SIRT1-deacetylated LC3. Molecular Nutrition Food Research. 2016;60(10):2161-2175.
Not in our library10.1002/mnfr.201600111
187.
Zhang Q., Zhang P., Qi G. J., et al. Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models. Biochimica Biophysica Acta General Subjects. 2018;1862(6):1443-1451.
Not in our library10.1016/j.bbagen.2018.03.021
188.
Kitao Y., Ageta-Ishihara N., Takahashi R., Kinoshita M., Hori O. Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism. F1000Res. 2015;4:p. 130.
Not in our library10.12688/f1000research.6386.1
189.
Erdő F., Denes L., de Lange E. Age-associated physiological and pathological changes at the blood-brain barrier: a review. Journal Cerebral Blood Flow Metabolism. 2016;37(1):4-24.
Not in our library10.1177/0271678x16679420
190.
Friedrich M. J. Researchers probe the aging brain in health and disease. JAMA. 2014;311(3):231-232.
Not in our library10.1001/jama.2013.284609
191.
Aging and Parkinson's disease: Different sides of the same coin? · 2017
No notice
192.
Microglial cell dysregulation in brain aging and neurodegeneration · 2015
No notice
193.
Berr C., Balansard B., Arnaud J., Roussel A. M., Alpérovitch A. Cognitive decline is associated with systemic oxidative stress: the EVA Study. Journal American Geriatrics Society. 2000;48(10):1285-1291.
Not in our library10.1111/j.1532-5415.2000.tb02603.x
194.
Erraji-Benchekroun L., Underwood M. D., Arango V., et al. Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biological Psychiatry. 2005;57(5):549-558.
Not in our library10.1016/j.biopsych.2004.10.034
195.
Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study · 2012
No notice
196.
Cornejo F., von Bernhardi R. Age-dependent changes in the activation and regulation of microglia. Advances Experimental Medicine Biology. 2016;949:205-226.
Not in our library10.1007/978-3-319-40764-7_10
197.
Bektas A., Schurman S. H., Sen R., Ferrucci L. Aging, inflammation and the environment. Experimental Gerontology. 2018;105:10-18.
Not in our library10.1016/j.exger.2017.12.015
198.
An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment · 2016
No notice
199.
Franceschi C., Bonafè M., Valensin S., et al. Inflamm-aging: an evolutionary perspective on immunosenescence. Annals New York Academy Sciences. 2000;908:244-254.
Not in our library10.1111/j.1749-6632.2000.tb06651.x
200.
Satoh A., Brace C. S., Rensing N., et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metabolism. 2013;18(3):416-430.
Not in our library10.1016/j.cmet.2013.07.013
201.
Mitchell S. J., Martin-Montalvo A., Mercken E. M., et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Reports. 2014;6(5):836-843.
Not in our library10.1016/j.celrep.2014.01.031
202.
Knockout of longevity gene Sirt1 in zebrafish leads to oxidative injury, chronic inflammation, and reduced life span. · 2019
Not checked
203.
Conti V., Corbi G., Manzo V., Pelaia G., Filippelli A., Vatrella A. Sirtuin 1 and aging theory for chronic obstructive pulmonary disease. Analytical Cellular Pathology. 2015;2015:8.
Not in our library10.1155/2015/897327
204.
Samsami-Kor M., Daryani N. E., Asl P. R., Hekmatdoost A. Anti-inflammatory effects of resveratrol in patients with ulcerative colitis: a randomized, double-blind, placebo-controlled pilot study. Archives Medical Research. 2015;46(4):280-285.
Not in our library10.1016/j.arcmed.2015.05.005
205.
Faghihzadeh F., Adibi P., Rafiei R., Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutrition Research. 2014;34(10):837-843.
Not in our library10.1016/j.nutres.2014.09.005
206.
Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease · 2017
No notice
207.
Turner R. S., Thomas R. G., Craft S., et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383-1391.
Not in our library10.1212/wnl.0000000000002035
208.
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Zhang S., Jiang L., Che F., Lu Y., Xie Z., Wang H. Arctigenin attenuates ischemic stroke via SIRT1-dependent inhibition of NLRP3 inflammasome. Biochemical Biophysical Research Communications. 2017;493(1):821-826.
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Not in our library10.1007/s00018-011-0850-z

Cited by papers we hold 3

The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing · 2024
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Novel Role of the SIRT1 in Endocrine and Metabolic Diseases · 2023
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Neuroinflammation in Alzheimer’s Disease · 2021
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