Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction

Abstract

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse models. Supporting this, short-term oral nicotinamide treatment in human glaucoma patients provides a recovery of retinal ganglion cell function implying a protection of visual function. Despite this, the mechanism of neuroprotection and full effects of nicotinamide on retinal ganglion cells is unclear. Glaucoma is a complex neurodegenerative disease in which a mix of healthy, stressed, and degenerating retinal ganglion cells co-exist, and in which retinal ganglion cells display compartmentalized degeneration across their visual trajectory. Therefore, we assess the effects of nicotinamide on retinal ganglion cells in normal physiological conditions and across a range of glaucoma relevant insults. We confirm neuroprotection afforded by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We define a small molecular weight metabolome for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption that can be prevented by nicotinamide. Nicotinamide provides these neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term NAM treatment as a neuroprotective therapy for human glaucoma. One Sentence Summary The NAD precursor nicotinamide has a potent neuroprotective effect in the retina and optic nerve, targeting neuronal function, metabolism, and mitochondrial function.

References 88

1. 1.

   Tham Y.C., Li X., Wong T.Y., Quigley H.A., Aung T., Cheng C.Y. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081-2090.

   Not in our library10.1016/j.ophtha.2014.05.013

2. 2.

   Naik S., Pandey A., Lewis S.A., Rao B.S.S., Mutalik S. Neuroprotection: a versatile approach to combat glaucoma. Eur. J. Pharmacol. 2020;881:173208.

   Not in our library10.1016/j.ejphar.2020.173208

3. 3.

   Peters D., Bengtsson B., Heijl A. Factors associated with lifetime risk of open-angle glaucoma blindness. Acta Ophthalmol. 2014;92(5):421-425.

   Not in our library10.1111/aos.12203

4. 4.

   Tribble J.R., Vasalauskaite A., Redmond T., Young R.D., Hassan S., Fautsch M.P. Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma. Brain Commun. 2019;1(1):fcz035.

   Not in our library10.1093/braincomms/fcz035

5. 5.

   Williams P.A., Harder J.M., Foxworth N.E., Cochran K.E., Philip V.M., Porciatti V. Vitamin B-3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science. 2017;355(6326):756-760.

   Not in our library10.1126/science.aal0092

6. 6.

   Kouassi Nzoughet J., Chao de la Barca J.M., Guehlouz K., Leruez S., Coulbault L., Allouche S. Nicotinamide deficiency in primary open-angle glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(7):2509-2514.

   Not in our library10.1167/iovs.19-27099

7. 7.

   Hui F., Tang J., Williams P.A., McGuinness M.B., Hadoux X., Casson R.J. Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: a crossover randomized clinical trial. Clin. Exp. Ophthalmol. 2020;48(7):903-914.

   Not in our library10.1111/ceo.13818

8. 8.

   Poljsak B., Milisav I. Vitamin B3 forms as precursors to NAD+: are they safe? Trends Food Sci. Technol. 2018;79:198-203.

   Not in our library

9. 9.

   Knip M., Douek I.F., Moore W.P., Gillmor H.A., McLean A.E., Bingley P.J. Safety of high-dose nicotinamide: a review. Diabetologia. 2000;43(11):1337-1345.

   Not in our library10.1007/s001250051536

10. 10.

    Morgan J.E. Retina ganglion cell degeneration in glaucoma: an opportunity missed? A review. Clin. Exp. Ophthalmol. 2012;40(4):364-368.

    Not in our library10.1111/j.1442-9071.2012.02789.x

11. 11.

    Tribble J.R., Otmani A., Kokkali E., Lardner E., Morgan J.E., Williams P.A. Retinal ganglion cell degeneration in a rat magnetic bead model of ocular hypertensive glaucoma. Transl Vis Sci Technol. 2021;10(1):21.

    Not in our library10.1167/tvst.10.1.21

12. 12.

    Bull N.D., Johnson T.V., Welsapar G., DeKorver N.W., Tomarev S.I., Martin K.R. Use of an adult rat retinal explant model for screening of potential retinal ganglion cell neuroprotective therapies. Invest. Ophthalmol. Vis. Sci. 2011;52(6):3309-3320.

    Not in our library10.1167/iovs.10-6873

13. 13.

    Binley K.E., Ng W.S., Barde Y.A., Song B., Morgan J.E. Brain-derived neurotrophic factor prevents dendritic retraction of adult mouse retinal ganglion cells. Eur. J. Neurosci. 2016;44(3):2028-2039.

    Not in our library10.1111/ejn.13295

14. 14.

    Zhang X., Jones D., Gonzalez-Lima F. Neurodegeneration produced by rotenone in the mouse retina: a potential model to investigate environmental pesticide contributions to neurodegenerative diseases. J. Toxicol. Environ. Health. 2006;69(18):1681-1697.

    Not in our library10.1080/15287390600630203

15. 15.

    Cimdins K., Waugh H.S., Chrysostomou V., Lopez Sanchez M.I.G., Johannsen V.A., Cook M.J. Amyloid precursor protein mediates neuronal protection from rotenone toxicity. Mol. Neurobiol. 2019;56(8):5471-5482.

    Not in our library10.1007/s12035-018-1460-7

16. 16.

    Schindelin J., Arganda-Carreras I., Frise E., Kaynig V., Longair M., Pietzsch T. Fiji: an open-source platform for biological-image analysis. Nat. Methods. 2012;9(7):676-682.

    Not in our library10.1038/nmeth.2019

17. 17.

    Wang L., Dong J., Cull G., Fortune B., Cioffi G.A. Varicosities of intraretinal ganglion cell axons in human and nonhuman primates. Invest. Ophthalmol. Vis. Sci. 2003;44(1):2-9.

    Not in our library10.1167/iovs.02-0333

18. 18.
    Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma · 2016

    No notice
19. 19.

    Quiros P.M., Goyal A., Jha P., Auwerx J. Analysis of mtDNA/nDNA ratio in mice. Curr Protoc Mouse Biol. 2017;7(1):47-54.

    Not in our library10.1002/cpmo.21

20. 20.

    Xia J., Psychogios N., Young N., Wishart D.S. MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Res. 2009;37:W652-W660.

    Not in our library10.1093/nar/gkp356

21. 21.

    Xia J., Wishart D.S. Web-based inference of biological patterns, functions and pathways from metabolomic data using MetaboAnalyst. Nat. Protoc. 2011;6(6):743-760.

    Not in our library10.1038/nprot.2011.319

22. 22.
    Centering, scaling, and transformations: improving the biological information content of metabolomics data · 2006

    No notice
23. 23.

    Gu Z., Gu L., Eils R., Schlesner M., Brors B. Circlize Implements and enhances circular visualization in R. Bioinformatics. 2014;30(19):2811-2812.

    Not in our library10.1093/bioinformatics/btu393

24. 24.

    Misgeld T., Kerschensteiner M., Bareyre F.M., Burgess R.W., Lichtman J.W. Imaging axonal transport of mitochondria in vivo. Nat. Methods. 2007;4(7):559-561.

    Not in our library10.1038/nmeth1055

25. 25.

    Burgess R.W., Fuerst P.G. Distinct expression patterns of mitochondrially localized YFP in neuronal subsets in the retina of three transgenic mouse lines. BMC Res. Notes. 2010;3:253.

    Not in our library10.1186/1756-0500-3-253

26. 26.

    Sun S., Erchova I., Sengpiel F., Votruba M. Opa1 deficiency leads to diminished mitochondrial bioenergetics with compensatory increased mitochondrial motility. Invest. Ophthalmol. Vis. Sci. 2020;61(6):42.

    Not in our library10.1167/iovs.61.6.42

27. 27.

    Winzeler A., Wang J.T. Purification and culture of retinal ganglion cells from rodents. Cold Spring Harb. Protoc. 2013;2013(7):643-652.

    Not in our library10.1101/pdb.prot074906

28. 28.

    Neumann S., Chassefeyre R., Campbell G.E., Encalada S.E. KymoAnalyzer: a software tool for the quantitative analysis of intracellular transport in neurons. Traffic. 2017;18(1):71-88.

    Not in our library10.1111/tra.12456

29. 29.

    Skytt D.M., Toft-Kehler A.K., Brændstrup C.T., Cejvanovic S., Gurubaran I.S., Bergersen L.H. Glia-neuron interactions in the retina can Be studied in cocultures of müller cells and retinal ganglion cells. BioMed Res. Int. 2016;2016:1087647.

    Not in our library10.1155/2016/1087647

30. 30.

    Vohra R., Aldana B.I., Bulli G., Skytt D.M., Waagepetersen H., Bergersen L.H. Lactate-mediated protection of retinal ganglion cells. J. Mol. Biol. 2019;431(9):1878-1888.

    Not in our library10.1016/j.jmb.2019.03.005

31. 31.

    Nair A.B., Jacob S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 2016;7(2):27-31.

    Not in our library10.4103/0976-0105.177703

32. 32.

    Kasischke K., Büchner M., Ludolph A.C., Riepe M.W. Nuclear shrinkage in live mouse hippocampal slices. Acta Neuropathol. 2001;101(5):483-490.

    Not in our library10.1007/s004010000317

33. 33.

    Verdin E. NAD⁺ in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208-1213.

    Not in our library10.1126/science.aac4854

34. 34.

    Tribble J.R., Kokkali E., Otmani A., Plastino F., Lardner E., Vohra R. When is a control not a control? Reactive microglia occur throughout the control contralateral pathway of retinal ganglion cell projections in experimental glaucoma. Transl Vis Sci Technol. 2021;10(1):22.

    Not in our library10.1167/tvst.10.1.22

35. 35.

    Coleman M.P., Höke A. Programmed axon degeneration: from mouse to mechanism to medicine. Nat. Rev. Neurosci. 2020;21(4):183-196.

    Not in our library10.1038/s41583-020-0269-3

36. 36.

    Béard E., Braissant O. Synthesis and transport of creatine in the CNS: importance for cerebral functions. J. Neurochem. 2010;115(2):297-313.

    Not in our library10.1111/j.1471-4159.2010.06935.x

37. 37.

    Sia P.I., Wood J.P.M., Chidlow G., Casson R. Creatine is neuroprotective to retinal neurons in vitro but not in vivo. Invest. Ophthalmol. Vis. Sci. 2019;60(13):4360-4377.

    Not in our library10.1167/iovs.18-25858

38. 38.

    Tretter L., Adam-Vizi V. Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2005;360(1464):2335-2345.

    Not in our library10.1098/rstb.2005.1764

39. 39.

    Gibson G.E., Park L.C., Sheu K.F., Blass J.P., Calingasan N.Y. The alpha-ketoglutarate dehydrogenase complex in neurodegeneration. Neurochem. Int. 2000;36(2):97-112.

    Not in our library10.1016/s0197-0186(99)00114-x

40. 40.

    Herrmann W., Obeid R. Homocysteine: a biomarker in neurodegenerative diseases. Clin. Chem. Lab. Med. 2011;49(3):435-441.

    Not in our library10.1515/cclm.2011.084

41. 41.

    Navneet S., Zhao J., Wang J., Mysona B., Barwick S., Ammal Kaidery N. Hyperhomocysteinemia-induced death of retinal ganglion cells: the role of Müller glial cells and NRF2. Redox Biol. 2019;24:101199.

    Not in our library10.1016/j.redox.2019.101199

42. 42.

    Moore P., El-sherbeny A., Roon P., Schoenlein P.V., Ganapathy V., Smith S.B. Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp. Eye Res. 2001;73(1):45-57.

    Not in our library10.1006/exer.2001.1009

43. 43.

    Klein J. Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids. J. Neural. Transm. 2000;107(8–9):1027-1063.

    Not in our library10.1007/s007020070051

44. 44.

    Bonventre J.V., Huang Z., Taheri M.R., O'Leary E., Li E., Moskowitz M.A. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature. 1997;390(6660):622-625.

    Not in our library10.1038/37635

45. 45.

    Qu B., Gong Y., Gill J.M., Kenney K., Diaz-Arrastia R. Heterozygous knockout of cytosolic phospholipase A. Brain Res. 2017;1670:248-252.

    Not in our library10.1016/j.brainres.2017.06.021

46. 46.

    Bárány M., Chang Y.C., Arús C., Rustan T., Frey W.H. Increased glycerol-3-phosphorylcholine in post-mortem Alzheimer's brain. Lancet. 1985;1(8427):517.

    Not in our library10.1016/s0140-6736(85)92114-2

47. 47.

    Walter A., Korth U., Hilgert M., Hartmann J., Weichel O., Fassbender K. Glycerophosphocholine is elevated in cerebrospinal fluid of Alzheimer patients. Neurobiol. Aging. 2004;25(10):1299-1303.

    Not in our library10.1016/j.neurobiolaging.2004.02.016

48. 48.
    NAD+ biosynthesis, aging, and disease · 2018

    No notice
49. 49.

    Baltan S., Inman D.M., Danilov C.A., Morrison R.S., Calkins D.J., Horner P.J. Metabolic vulnerability disposes retinal ganglion cell axons to dysfunction in a model of glaucomatous degeneration. J. Neurosci. 2010;30(16):5644-5652.

    Not in our library10.1523/jneurosci.5956-09.2010

50. 50.

    Crish S.D., Calkins D.J. Neurodegeneration in glaucoma: progression and calcium-dependent intracellular mechanisms. Neuroscience. 2011;176:1-11.

    Not in our library10.1016/j.neuroscience.2010.12.036

51. 51.

    Chrysostomou V., Rezania F., Trounce I.A., Crowston J.G. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr. Opin. Pharmacol. 2013;13(1):12-15.

    Not in our library10.1016/j.coph.2012.09.008

52. 52.

    Hou Y., Lautrup S., Cordonnier S., Wang Y., Croteau D.L., Zavala E. NAD + supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A. 2018;115(8):E1876-E1885.

    Not in our library10.1073/pnas.1718819115

53. 53.

    Gong B., Pan Y., Vempati P., Zhao W., Knable L., Ho L. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol. Aging. 2013;34(6):1581-1588.

    Not in our library10.1016/j.neurobiolaging.2012.12.005

54. 54.
    Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model · 2015

    No notice
55. 55.

    Sorrentino V., Romani M., Mouchiroud L., Beck J.S., Zhang H., D'Amico D. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature. 2017;552(7684):187-193.

    Not in our library10.1038/nature25143

56. 56.

    Lehmann S., Loh S.H., Martins L.M. Enhancing NAD + salvage metabolism is neuroprotective in a PINK1 model of Parkinson’s disease. Biol Open. 2017;6(2):141-147.

    Not in our library10.1242/bio.022186

57. 57.

    Jia H., Li X., Gao H., Feng Z., Zhao L., Jia X. High doses of nicotinamide prevent oxidative mitochondrial dysfunction in a cellular model and improve motor deficit in a Drosophila model of Parkinson's disease. J. Neurosci. Res. 2008;86(9):2083-2090.

    Not in our library10.1002/jnr.21650

58. 58.

    Alisky J.M. Niacin improved rigidity and bradykinesia in a Parkinson's disease patient but also caused unacceptable nightmares and skin rash--a case report. Nutr. Neurosci. 2005;8(5–6):327-329.

    Not in our library10.1080/10284150500484638

59. 59.

    Schöndorf D.C., Ivanyuk D., Baden P., Sanchez-Martinez A., De Cicco S., Yu C. The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson's disease. Cell Rep. 2018;23(10):2976-2988.

    Not in our library10.1016/j.celrep.2018.05.009

60. 60.

    Lin J.B., Kubota S., Ban N., Yoshida M., Santeford A., Sene A. NAMPT-mediated NAD(+) biosynthesis is essential for vision in mice. Cell Rep. 2016;17(1):69-85.

    Not in our library10.1016/j.celrep.2016.08.073

61. 61.

    Liu H.W., Smith C.B., Schmidt M.S., Cambronne X.A., Cohen M.S., Migaud M.E. Pharmacological bypass of NAD + salvage pathway protects neurons from chemotherapy-induced degeneration. Proc. Natl. Acad. Sci. U. S. A. 2018;115(42):10654-10659.

    Not in our library10.1073/pnas.1809392115

62. 62.
    Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 · 2014

    No notice
63. 63.

    Pirinen E., Auranen M., Khan N.A., Brilhante V., Urho N., Pessia A. Niacin Cures Systemic NAD + Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metabol. 2020;31(6):1078-1090.

    Not in our library10.1016/j.cmet.2020.04.008

64. 64.

    Wang J., Zhai Q., Chen Y., Lin E., Gu W., McBurney M.W. A local mechanism mediates NAD-dependent protection of axon degeneration. J. Cell Biol. 2005;170(3):349-355.

    Not in our library10.1083/jcb.200504028

65. 65.

    Araki T., Sasaki Y., Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004;305(5686):1010-1013.

    Not in our library10.1126/science.1098014

66. 66.

    Babetto E., Beirowski B., Janeckova L., Brown R., Gilley J., Thomson D. Targeting NMNAT1 to axons and synapses transforms its neuroprotective potency in vivo. J. Neurosci. 2010;30(40):13291-13304.

    Not in our library10.1523/jneurosci.1189-10.2010

67. 67.

    Feng Y., Yan T., Zheng J., Ge X., Mu Y., Zhang Y. Overexpression of Wld(S) or Nmnat2 in mauthner cells by single-cell electroporation delays axon degeneration in live zebrafish. J. Neurosci. Res. 2010;88(15):3319-3327.

    Not in our library10.1002/jnr.22498

68. 68.

    Williams P.A., Harder J.M., Foxworth N.E., Cardozo B.H., Cochran K.E., John S.W.M. Nicotinamide and WLDS act together to prevent neurodegeneration in glaucoma. Front. Neurosci. 2017;11.

    Not in our library10.3389/fnins.2017.00232

69. 69.

    Di Stefano M., Nascimento-Ferreira I., Orsomando G., Mori V., Gilley J., Brown R. A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ. 2015;22(5):731-742.

    Not in our library10.1038/cdd.2014.164

70. 70.

    Gerdts J., Brace E.J., Sasaki Y., DiAntonio A., Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. Science. 2015;348(6233):453-457.

    Not in our library10.1126/science.1258366

71. 71.
    Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons · 2010

    No notice
72. 72.

    Fry L.E., Fahy E., Chrysostomou V., Hui F., Tang J., van Wijngaarden P. The coma in glaucoma: retinal ganglion cell dysfunction and recovery. Prog. Retin. Eye Res. 2018;65:77-92.

    Not in our library10.1016/j.preteyeres.2018.04.001

73. 73.

    Casson R.J., Chidlow G., Crowston J.G., Williams P.A., Wood J.P.M. Retinal energy metabolism in health and glaucoma. Prog. Retin. Eye Res. 2020;100881.

    Not in our library10.1016/j.preteyeres.2020.100881

74. 74.

    Williams P.A., Harder J.M., John S.W.M. Glaucoma as a metabolic optic neuropathy: making the case for nicotinamide treatment in glaucoma. J. Glaucoma. 2017;26(12):1161-1168.

    Not in our library10.1097/ijg.0000000000000767

75. 75.

    Chen H., Chan D.C. Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum. Mol. Genet. 2009;18(R2):R169-R176.

    Not in our library10.1093/hmg/ddp326

76. 76.

    Milner J. Cellular regulation of SIRT1. Curr. Pharmaceut. Des. 2009;15(1):39-44.

    Not in our library10.2174/138161209787185841

77. 77.

    Brenmoehl J., Hoeflich A. Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3. Mitochondrion. 2013;13(6):755-761.

    Not in our library10.1016/j.mito.2013.04.002

78. 78.

    Benigni A., Perico L., Macconi D. Mitochondrial dynamics is linked to longevity and protects from end-organ injury: the emerging role of sirtuin 3. Antioxidants Redox Signal. 2016;25(4):185-199.

    Not in our library10.1089/ars.2016.6682

79. 79.

    Liang M., Yin X.L., Wang L.Y., Yin W.H., Song N.Y., Shi H.B. NAD+ attenuates bilirubin-induced hyperexcitation in the ventral cochlear nucleus by inhibiting excitatory neurotransmission and neuronal excitability. Front. Cell. Neurosci. 2017;11:21.

    Not in our library10.3389/fncel.2017.00021

80. 80.

    Bold J.M., Gardner C.R., Walker R.J. Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors. Br. J. Pharmacol. 1985;84(3):689-696.

    Not in our library10.1111/j.1476-5381.1985.tb16151.x

81. 81.

    Pustovit K.B., Abramochkin D.V. Effects of nicotinamide adenine dinucleotide (NAD(+)) and diadenosine tetraphosphate (Ap4A) on electrical activity of working and pacemaker atrial myocardium in Guinea pigs. Bull. Exp. Biol. Med. 2016;160(6):733-736.

    Not in our library10.1007/s10517-016-3297-2

82. 82.

    Kuzmin V.S., Pustovit K.B., Abramochkin D.V. Effects of exogenous nicotinamide adenine dinucleotide (NAD+) in the rat heart are mediated by P2 purine receptors. J. Biomed. Sci. 2016;23(1):50.

    Not in our library10.1186/s12929-016-0267-y

83. 83.

    Pustovit K.B., Potekhina V.M., Ivanova A.D., Petrov A.M., Abramochkin D.V., Kuzmin V.S. Extracellular ATP and β-NAD alter electrical properties and cholinergic effects in the rat heart in age-specific manner. Purinergic Signal. 2019;15(1):107-117.

    Not in our library10.1007/s11302-019-09645-6

84. 84.

    Chou T.H., Romano G.L., Amato R., Porciatti V. Nicotinamide-rich diet in DBA/2J mice preserves retinal ganglion cell metabolic function as assessed by PERG adaptation to flicker. Nutrients. 2020;12(7).

    Not in our library10.3390/nu12071910

85. 85.

    Howell G.R., Soto I., Zhu X., Ryan M., Macalinao D.G., Sousa G.L. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J. Clin. Invest. 2012;122(4):1246-1261.

    Not in our library10.1172/jci61135

86. 86.

    Weber A.J., Harman C.D. BDNF preserves the dendritic morphology of alpha and beta ganglion cells in the cat retina after optic nerve injury. Invest. Ophthalmol. Vis. Sci. 2008;49(6):2456-2463.

    Not in our library10.1167/iovs.07-1325

87. 87.

    Agostinone J., Alarcon-Martinez L., Gamlin C., Yu W.Q., Wong R.O.L., Di Polo A. Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury. Brain. 2018;141(7):1963-1980.

    Not in our library10.1093/brain/awy142

88. 88.

    Foxton R.H., Finkelstein A., Vijay S., Dahlmann-Noor A., Khaw P.T., Morgan J.E. VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma. Am. J. Pathol. 2013;182(4):1379-1390.

    Not in our library10.1016/j.ajpath.2012.12.032

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