Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review

Abstract

Glaucoma, an irreversible optic neuropathy, primarily affects retinal ganglion cells (RGC) and causes vision loss and blindness. The damage to RGCs in glaucoma occurs by various mechanisms, including elevated intraocular pressure, oxidative stress, inflammation, and other neurodegenerative processes. As the disease progresses, the loss of RGCs leads to vision loss. Therefore, protecting RGCs from damage and promoting their survival are important goals in managing glaucoma. In this regard, resveratrol (RES), a polyphenolic phytoalexin, exerts antioxidant effects and slows down the evolution and progression of glaucoma. The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina. Additionally, RES plays protective roles in RGCs by promoting cell growth, reducing apoptosis, and decreasing oxidative stress in H₂O₂-exposed RGCs. RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways. RES could alleviate retinal function impairment by suppressing the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway. Therefore, RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.

Keywords

glaucoma / ischemic-reperfusion injury / oxidative stress / resveratrol / retinal ganglion cells

References

[1] Alkhatib AW. Glaucoma: types, risk factors, detection, and management. Sch Acad J Biosci. 2023;6:207-211.

[2] Vijaya L, Manish P, Ronnie G, Shantha B. Management of complications in glaucoma surgery. Indian J Ophthalmol. 2011;59(suppl 1):S131.

[3] Senjam SS. Glaucoma blindness-a rapidly emerging non-communicable ocular disease in India: addressing the issue with advocacy. J Family Med Prim Care. 2020;9(5):2200-2206.

[4] Laroche D, Rickford K, Sinon J, Brown A, Ng C, Sakkari S. Preventing blindness from glaucoma with patient education, the NIDEK GS-1 gonioscope, lensectomy and microinvasive glaucoma surgery. J Natl Med Assoc. 2023;115(2):175-185.

[5] Młynarczyk M, Falkowska M, Micun Z, et al. Diet, oxidative stress, and blood serum nutrients in various types of glaucoma: a systematic review. Nutrients. 2022;14(7):1421.

[6] Lee Y-H, Kim C-S, Hong S-p. Rate of visual field progression in primary open-angle glaucoma and primary angle-closure glaucoma. Korean J Ophthalmol. 2004;18(2):106-115.

[7] Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;295(5557):1077-1079.

[8] Janssen SF, Gorgels TG, Ramdas WD, et al. The vast complexity of primary open angle glaucoma: disease genes, risks, molecular mechanisms and pathobiology. Prog Retin Eye res. 2013;37:31-67.

[9] Sun X, Dai Y, Chen Y, et al. Primary angle closure glaucoma: what we know and what we don’t know. Prog Retin Eye res. 2017;57:26-45.

[10] Liu L, Sha X-Y, Wu Y-N, Chen M-T, Zhong J-X. Lycium barbarum polysaccharides protects retinal ganglion cells against oxidative stress injury. Neural Regen res. 2020;15(8):1526-1531.

[11] Mead B, Tomarev S. Evaluating retinal ganglion cell loss and dysfunction. Exp Eye res. 2016;151:96-106.

[12] Dhande OS, Huberman AD. Retinal ganglion cell maps in the brain: implications for visual processing. Curr Opin Neurobiol. 2014;24:133-142.

[13] Dhande OS, Stafford BK, Lim J-HA, Huberman AD. Contributions of retinal ganglion cells to subcortical visual processing and behaviors. Annu Rev Vis Sci. 2015;1:291-328.

[14] Chen H-Y, Ho Y-J, Chou H-C, et al. TGF-β1 signaling protects retinal ganglion cells from oxidative stress via modulation of the HO-1/Nrf2 pathway. Chem Biol Interact. 2020;331:109249.

[15] Agarwal P, Agarwal R. Tackling retinal ganglion cell apoptosis in glaucoma: role of adenosine receptors. Expert Opin Ther Targets. 2021;25(7):585-596.

[16] Zamanian M, Shamsizadeh A, Esmaeili Nadimi A, et al. Short-term effects of troxerutin (vitamin P4) on muscle fatigue and gene expression of Bcl-2 and Bax in the hepatic tissue of rats. Can J Physiol Pharmacol. 2017;95(6):708-713.

[17] Kumar DM, Agarwal N. Oxidative stress in glaucoma: a burden of evidence. J Glaucoma. 2007;16(3):334-343.

[18] Ye M-j, Meng N. Resveratrol acts via the mitogen-activated protein kinase (MAPK) pathway to protect retinal ganglion cells from apoptosis induced by hydrogen peroxide. Bioengineered. 2021;12(1):4878-4886.

[19] Robin AL, Muir KW. Medication adherence in patients with ocular hypertension or glaucoma. Expert Rev Ophthalmol. 2019;14(4-5):199-210.

[20] Friedman DS, Quigley HA, Gelb L, et al. Using pharmacy claims data to study adherence to glaucoma medications: methodology and findings of the Glaucoma Adherence and Persistency Study (GAPS). Invest Ophthalmol Vis Sci. 2007;48(11):5052-5057.

[21] Wong TY, Sun J, Kawasaki R, et al. Guidelines on diabetic eye care: the international council of ophthalmology recommendations for screening, follow-up, referral, and treatment based on resource settings. Ophthalmology. 2018;125(10):1608-1622.

[22] Pescosolido N, Gatto V, Stefanucci A, Rusciano D. Oral treatment with the melatonin agonist agomelatine lowers the intraocular pressure of glaucoma patients. Ophthalmic Physiol Opt. 2015;35(2):201-205.

[23] Koucheki B, Hashemi H. Selective laser trabeculoplasty in the treatment of open-angle glaucoma. J Glaucoma. 2012;21(1):65-70.

[24] Fingeret M, Dickerson JE Jr. The role of minimally invasive glaucoma surgery devices in the management of glaucoma. Optom Vis Sci. 2018;95(2):155-162.

[25] Garcia-Medina JJ, Rubio-Velazquez E, Lopez-Bernal MD, et al. Glaucoma and antioxidants: review and update. Antioxidants. 2020;9(11):1031.

[26] Dziedziak J, Kasarełło K, Cudnoch-Jędrzejewska A. Dietary antioxidants in age-related macular degeneration and glaucoma. Antioxidants. 2021;10(11):1743.

[27] Burugula B, Ganesh BS, Chintala SK. Curcumin attenuates staurosporine-mediated death of retinal ganglion cells. Invest Ophthalmol Vis Sci. 2011;52(7):4263-4273.

[28] Li S, Jakobs TC. Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage. Life Sci Alliance. 2023;6(8):e202301976.

[29] Ko M-L, Peng P-H, Hsu S-Y, Chen C-F. Dietary deficiency of vitamin E aggravates retinal ganglion cell death in experimental glaucoma of rats. Curr Eye res. 2010;35(9):842-849.

[30] Li S-Y, Lo AC. Lutein protects RGC-5 cells against hypoxia and oxidative stress. Int J Mol Sci. 2010;11(5):2109-2117.

[31] Pang Y, Qin M, Hu P, et al. Resveratrol protects retinal ganglion cells against ischemia induced damage by increasing Opa1 expression. Int J Mol Med. 2020;46(5):1707-1720.

[32] Chupradit S, Bokov D, Zamanian MY, Heidari M, Hakimizadeh E. Hepatoprotective and therapeutic effects of resveratrol: a focus on anti-inflammatory and antioxidative activities. Fundam Clin Pharmacol. 2022;36(3):468-485.

[33] Zamanian MY, Parra RMR, Soltani A, et al. Targeting Nrf2 signaling pathway and oxidative stress by resveratrol for Parkinson’s disease: an overview and update on new developments. Mol Biol Rep. 2023;1-10:5455-5464.

[34] Wu Y, Pang Y, Wei W, et al. Resveratrol protects retinal ganglion cell axons through regulation of the SIRT1-JNK pathway. Exp Eye res. 2020;200:108249.

[35] Seong H, Jeong JY, Ryu J, et al. Resveratrol prevents hypoxia-induced retinal ganglion cell death related with ErbB2. Int J Ophthalmol. 2022;15(3):394-400.

[36] Tan M, Yu D. Molecular mechanisms of erbB2-mediated breast cancer chemoresistance. Breast Cancer Chemosensitivity; 2007:119-129.

[37] Pezzuto JM. Resveratrol: twenty years of growth, development and controversy. Biomol Ther. 2019;27(1):1-14.

[38] Kobylka P, Kucinska M, Kujawski J, Lazewski D, Wierzchowski M, Murias M. Resveratrol analogues as selective estrogen signaling pathway modulators: structure-activity relationship. Molecules. 2022;27(20):6973.

[39] Chan EWC, Wong CW, Tan YH, Foo JPY, Wong SK, Chan HT. Resveratrol and pterostilbene: a comparative overview of their chemistry, biosynthesis, plant sources and pharmacological properties. J Appl Pharm Sci. 2019;9(7):124-129.

[40] Mlakić M, Fodor L, Odak I, et al. Resveratrol-maltol and resveratrol-thiophene hybrids as cholinesterase inhibitors and antioxidants: synthesis, biometal chelating capability and crystal structure. Molecules. 2022;27(19):6379.

[41] Wang F, Chatterjee S. Dominant carbons in trans-and cis-resveratrol isomerization. J Phys Chem B. 2017;121(18):4745-4755.

[42] Loureiro JA, Andrade S, Duarte A, et al. Resveratrol and grape extract-loaded solid lipid nanoparticles for the treatment of Alzheimer’s disease. Molecules. 2017;22(2):277.

[43] Hasan MM, Bae H. An overview of stress-induced resveratrol synthesis in grapes: perspectives for resveratrol-enriched grape products. Molecules. 2017;22(2):294.

[44] Bavaresco L, Mattivi F, De Rosso M, Flamini R. Effects of elicitors, viticultural factors, and enological practices on resveratrol and stilbenes in grapevine and wine. Mini Rev Med Chem. 2012;12(13):1366-1381.

[45] Rudolf J, Resurreccion A. Optimization of trans-resveratrol concentration and sensory properties of peanut kernels by slicing and ultrasound treatment, using response surface methodology. J Food Sci. 2007;72(7):S450-S462.

[46] Toniolo L, Concato M, Giacomello E. Resveratrol, a multitasking molecule that improves skeletal muscle health. Nutrients. 2023;15(15):3413.

[47] Sergides C, Chirilă M, Silvestro L, Pitta D, Pittas A. Bioavailability and safety study of resveratrol 500 mg tablets in healthy male and female volunteers. Exp Ther Med. 2016;11(1):164-170.

[48] Jannin B, Menzel M, Berlot J-P, Delmas D, Lançon A, Latruffe N. Transport of resveratrol, a cancer chemopreventive agent, to cellular targets: plasmatic protein binding and cell uptake. Biochem Pharmacol. 2004;68(6):1113-1118.

[49] Davidov-Pardo G, McClements DJ. Resveratrol encapsulation: designing delivery systems to overcome solubility, stability and bioavailability issues. Trends Food Sci Technol. 2014;38(2):88-103.

[50] Wenzel E, Soldo T, Erbersdobler H, Somoza V. Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Mol Nutr Food res. 2005;49(5):482-494.

[51] Wang P, Gao J, Ke W, et al. Resveratrol reduces obesity in high-fat diet-fed mice via modulating the composition and metabolic function of the gut microbiota. Free Radic Biol Med. 2020;156:83-98.

[52] Henry C, Vitrac X, Decendit A, Ennamany R, Krisa S, Mérillon J-M. Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells. J Agric Food Chem. 2005;53(3):798-803.

[53] Truong VL, Jun M, Jeong WS. Role of resveratrol in regulation of cellular defense systems against oxidative stress. Biofactors. 2018;44(1):36-49.

[54] Briskey D, Rao A. Trans-resveratrol oral bioavailability in humans using LipiSperse™ dispersion technology. Pharmaceutics. 2020;12(12):1190.

[55] Shi Y, Zhou J, Jiang B, Miao M. Resveratrol and inflammatory bowel disease. Ann N Y Acad Sci. 2017;1403(1):38-47.

[56] Decui L, Garbinato CLL, Schneider SE, et al. Micronized resveratrol shows promising effects in a seizure model in zebrafish and signalizes an important advance in epilepsy treatment. Epilepsy res. 2020;159:106243.

[57] Lasa A, Churruca I, Eseberri I, Andrés-Lacueva C, Portillo MP. Delipidating effect of resveratrol metabolites in 3 T 3-L 1 adipocytes. Mol Nutr Food res. 2012;56(10):1559-1568.

[58] Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food res. 2005;49(5):472-481.

[59] Andres-Lacueva C, Urpi-Sarda M, Zamora-Ros R, Lamuela-Raventos RM. Bioavailability and metabolism of resveratrol. Plant Phenolics and Human Health: Biochemistry, Nutrition, and Pharmacology; 2009:265-297.

[60] Frombaum M, Le Clanche S, Bonnefont-Rousselot D, Borderie D. Antioxidant effects of resveratrol and other stilbene derivatives on oxidative stress and NO bioavailability: potential benefits to cardiovascular diseases. Biochimie. 2012;94(2):269-276.

[61] Zhang L, Li Y, Gu Z, et al. Resveratrol inhibits enterovirus 71 replication and pro-inflammatory cytokine secretion in rhabdosarcoma cells through blocking IKKs/NF-κB signaling pathway. PLoS ONE. 2015;10(2):e0116879.

[62] Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell. 2006;127(6):1109-1122.

[63] Sung MM, Byrne NJ, Robertson IM, et al. Resveratrol improves exercise performance and skeletal muscle oxidative capacity in heart failure. Am J Physiol Heart Circ Physiol. 2017;312(4):H842-H853.

[64] Dos Santos MG, Schimith LE, André-Miral C, Muccillo-Baisch AL, Arbo BD, Hort MA. Neuroprotective effects of resveratrol in in vivo and in vitro experimental models of Parkinson’s disease: a systematic review. Neurotox res. 2022;1-27:319-345.

[65] Thakkar S, Anklam E, Xu A, et al. Regulatory landscape of dietary supplements and herbal medicines from a global perspective. Regul Toxicol Pharmacol. 2020;114:104647.

[66] Timmers S, Hesselink MK, Schrauwen P. Therapeutic potential of resveratrol in obesity and type 2 diabetes: new avenues for health benefits? Ann N Y Acad Sci. 2013;1290(1):83-89.

[67] Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health-a comprehensive review of human clinical trials. Mol Nutr Food res. 2011;55(8):1129-1141.

[68] Espinoza JL, Trung LQ, Inaoka PT, et al. The repeated administration of resveratrol has measurable effects on circulating T-cell subsets in humans. Oxid Med Cell Longev. 2017;2017:6781872.

[69] Cottart CH, Nivet-Antoine V, Beaudeux JL. Review of recent data on the metabolism, biological effects, and toxicity of resveratrol in humans. Mol Nutr Food res. 2014;58(1):7-21.

[70] Salehi B, Mishra AP, Nigam M, et al. Resveratrol: a double-edged sword in health benefits. Biomedicine. 2018;6(3):91.

[71] Shaito A, Posadino AM, Younes N, et al. Potential adverse effects of resveratrol: a literature review. Int J Mol Sci. 2020;21(6):2084.

[72] Quarta A, Gaballo A, Pradhan B, Patra S, Jena M, Ragusa A. Beneficial oxidative stress-related trans-resveratrol effects in the treatment and prevention of breast cancer. Appl Sci. 2021;11(22):11041.

[73] Rafati A, Hoseini L, Babai A, Noorafshan A, Haghbin H, Karbalay-Doust S. Mitigating effect of resveratrol on the structural changes of mice liver and kidney induced by cadmium;a stereological study. Prev Nutr Food Sci. 2015;20(4):266-275.

[74] Gadacha W, Ben-Attia M, Bonnefont-Rousselot D, Aouani E, Ghanem-Boughanmi N, Touitou Y. Resveratrol opposite effects on rat tissue lipoperoxidation: pro-oxidant during day-time and antioxidant at night. Redox Rep. 2009;14(4):154-158.

[75] Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet. 2019;393(10180):1505-1516.

[76] Anderson DR, Drance SM, Schulzer M. Factors that predict the benefit of lowering intraocular pressure in normal tension glaucoma. Am J Ophthalmol. 2003;136(5):820-829.

[77] Marquis RE, Whitson JT. Management of glaucoma: focus on pharmacological therapy. Drugs Aging. 2005;22:1-21.

[78] Llobet A, Gasull X, Gual A. Understanding trabecular meshwork physiology: a key to the control of intraocular pressure? Phys Ther. 2003;18(5):205-209.

[79] Kurysheva NI, Lepeshkina LV. Selective laser trabeculoplasty protects glaucoma progression in the initial primary open-angle glaucoma and angle-closure glaucoma after laser peripheral iridotomy in the long term. Biomed res Int. 2019;2019:1-10.

[80] Melamed S, Pei J, Epstein DL. Delayed response to argon laser trabeculoplasty in monkeys: morphological and morphometric analysis. Arch Ophthalmol. 1986;104(7):1078-1083.

[81] Cai J-C, Chen Y-L, Cao Y-H, Babenko A, Chen X. Numerical study of aqueous humor flow and iris deformation with pupillary block and the efficacy of laser peripheral iridotomy. Clin Biomech. 2022;92:105579.

[82] Razeghinejad MR, Spaeth GL. A history of the surgical management of glaucoma. Optom Vis Sci. 2011;88(1):E39-E47.

[83] Panarelli JF, Nayak NV, Sidoti PA. Postoperative management of trabeculectomy and glaucoma drainage implant surgery. Curr Opin Ophthalmol. 2016;27(2):170-176.

[84] Pillunat LE, Erb C, Jünemann AG, Kimmich F. Micro-invasive glaucoma surgery (MIGS): a review of surgical procedures using stents. Clin Ophthalmol. 2017;11:1583-1600.

[85] Pereira IC, van de Wijdeven R, Wyss HM, Beckers HJ, den Toonder JM. Conventional glaucoma implants and the new MIGS devices: a comprehensive review of current options and future directions. Eye. 2021;35(12):3202-3221.

[86] Fan Gaskin JC, Shah MH, Chan EC. Oxidative stress and the role of NADPH oxidase in glaucoma. Antioxidants. 2021;10(2):238.

[87] Duarte JN. Neuroinflammatory mechanisms of mitochondrial dysfunction and neurodegeneration in glaucoma. J Ophthalmol. 2021;2021:4581909.

[88] Hurley DJ, Normile C, Irnaten M, O’Brien C. The intertwined roles of oxidative stress and endoplasmic reticulum stress in glaucoma. Antioxidants. 2022;11(5):886.

[89] Harada C, Noro T, Kimura A, et al. Suppression of oxidative stress as potential therapeutic approach for normal tension glaucoma. Antioxidants. 2020;9(9):874.

[90] Doucette LP, Rasnitsyn A, Seifi M, Walter MA. The interactions of genes, age, and environment in glaucoma pathogenesis. Surv Ophthalmol. 2015;60(4):310-326.

[91] Kuang G, Halimitabrizi M, Edziah A-A, Salowe R, O’Brien JM. The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review. Front Physiol. 2023;14:1184060.

[92] Chrysostomou V, Rezania F, Trounce IA, Crowston JG. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol. 2013;13(1):12-15.

[93] Brown EE, DeWeerd AJ, Ildefonso CJ, Lewin AS, Ash JD. Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors. Redox Biol. 2019;24:101201.

[94] Chen K, Zhang Q, Wang J, et al. Taurine protects transformed rat retinal ganglion cells from hypoxia-induced apoptosis by preventing mitochondrial dysfunction. Brain res. 2009;1279:131-138.

[95] Huang C, Xie L, Wu Z, et al. Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing. Sci Rep. 2018;8(1):4498.

[96] Kumar A, Basavaraj MG, Gupta SK, et al. Role of CYP1B1, MYOC, OPTN and OPTC genes in adult-onset primary open-angle glaucoma: predominance of CYP1B1 mutations in Indian patients. Mol Vis. 2007;13:667-676.

[97] Hirooka K, Yamamoto T, Kiuchi Y. Dysfunction of axonal transport in normal-tension glaucoma: a biomarker of disease progression and a potential therapeutic target. Neural Regen res. 2021;16(3):506-507.

[98] Hartsock MJ, Cho H, Wu L, Chen W-J, Gong J, Duh EJ. A mouse model of retinal ischemia-reperfusion injury through elevation of intraocular pressure. J Vis Exp. 2016;113:e54065.

[99] Ji K, Li Z, Lei Y, et al. Resveratrol attenuates retinal ganglion cell loss in a mouse model of retinal ischemia reperfusion injury via multiple pathways. Exp Eye res. 2021;209:108683.

[100] Luo J, He T, Yang J, Yang N, Li Z, Xing Y. SIRT1 is required for the neuroprotection of resveratrol on retinal ganglion cells after retinal ischemia-reperfusion injury in mice. Graefes Arch Clin Exp Ophthalmol. 2020;258:335-344.

[101] Wang N, Cao Y, Si C, et al. Emerging role of ERBB2 in targeted therapy for metastatic colorectal cancer: signaling pathways to therapeutic strategies. Cancer. 2022;14(20):5160.

[102] Andrechek ER, Hardy WR, Girgis-Gabardo AA, et al. ErbB2 is required for muscle spindle and myoblast cell survival. Mol Cell Biol. 2002;22(13):4714-4722.

[103] Marchionni MA, Goodearl AD, Su Chen M, et al. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature. 1993;362(6418):312-318.

[104] Garratt AN, Özcelik C, Birchmeier C. ErbB2 pathways in heart and neural diseases. Trends Cardiovasc Med. 2003;13(2):80-86.

[105] Jackson-Fisher AJ, Bellinger G, Ramabhadran R, Morris JK, Lee K-F, Stern DF. ErbB2 is required for ductal morphogenesis of the mammary gland. Proc Natl Acad Sci U S A. 2004;101(49):17138-17143.

[106] Araya LE, Soni IV, Hardy JA, Julien O. Deorphanizing caspase-3 and caspase-9 substrates in and out of apoptosis with deep substrate profiling. ACS Chem Biol. 2021;16(11):2280-2296.

[107] Robinson N, Ganesan R, Hegedűs C, Kovács K, Kufer TA, Virág L. Programmed necrotic cell death of macrophages: focus on pyroptosis, necroptosis, and parthanatos. Redox Biol. 2019;26:101239.

[108] Asadi M, Taghizadeh S, Kaviani E, et al. Caspase-3: structure, function, and biotechnological aspects. Biotechnol Appl Biochem. 2022;69(4):1633-1645.

[109] Zhao X, Bausano B, Pike BR, et al. TNF-αstimulates caspase-3 activation and apoptotic cell death in primary septo-hippocampal cultures. J Neurosci res. 2001;64(2):121-131.

[110] Nakanishi K, Maruyama M, Shibata T, Morishima N. Identification of a caspase-9 substrate and detection of its cleavage in programmed cell death during mouse development. J Biol Chem. 2001;276(44):41237-41244.

[111] Tripathi SK, Rengasamy KR, Biswal BK. Plumbagin engenders apoptosis in lung cancer cells via caspase-9 activation and targeting mitochondrial-mediated ROS induction. Arch Pharm res. 2020;43:242-256.

[112] Li P, Zhou L, Zhao T, et al. Caspase-9: structure, mechanisms and clinical application. Oncotarget. 2017;8(14):23996-24008.

[113] Zhang T-M. TRIAP1 inhibition activates the cytochrome c/Apaf-1/caspase-9 signaling pathway to enhance human ovarian cancer sensitivity to cisplatin. Chemotherapy. 2019;64(3):119-128.

[114] Park H-B, Baek K-H. E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. Biochim Biophys Acta Rev Cancer. 2022;1877(3):188736.

[115] Katz M, Amit I, Yarden Y. Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys Acta Mol Cell Res. 2007;1773(8):1161-1176.

[116] Clerk A, Kemp TJ, Harrison JG, Mullen AJ, Barton PJ, Sugden PH. Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Ju. N-terminal kinases are required for efficient up-regulation of c-Jun protein. Biochem J. 2002;368(1):101-110.

[117] Rorbach-Dolata A, Piwowar A. Extracellular signal-regulated kinases, P38 and c-Jun N-terminal kinases phosphorylation changes in PC12 cells with diabetic disturbances and comorbid excitotoxicity-a preliminary report. J Physiol Pharmacol. 2020;71(5):625-633.

[118] Yuan J, Dong X, Yap J, Hu J. The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol. 2020;13(1):1-19.

[119] Lavoie H, Gagnon J, Therrien M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol. 2020;21(10):607-632.

[120] Florio T, Yao H, Carey KD, Dillon TJ, Stork PJ. Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1). Mol Endocrinol. 1999;13(1):24-37.

[121] Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002;12(6):258-266.

[122] Tarantino G, Caputi A. JNKs, insulin resistance and inflammation: a possible link between NAFLD and coronary artery disease. World J Gastroenterol. 2011;17(33):3785-3794.

[123] Bogoyevitch MA. The isoform-specific functions of the c-Jun N-terminal kinases (JNKs): differences revealed by gene targeting. Bioessays. 2006;28(9):923-934.

[124] Park C-H, Lee MJ, Ahn J, et al. Heat shock-induced matrix metalloproteinase (MMP)-1 and MMP-3 are mediated through ERK and JNK activation and via an autocrine interleukin-6 loop. J Invest Dermatol. 2004;123(6):1012-1019.

[125] Nebreda AR, Porras A. p38 MAP kinases: beyond the stress response. Trends Biochem Sci. 2000;25(6):257-260.

[126] Yong H-Y, Koh M-S, Moon A. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs. 2009;18(12):1893-1905.

[127] Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta Mol Cell Res. 2007;1773(8):1358-1375.

[128] Lim CS, Kiriakidis S, Sandison A, Paleolog EM, Davies AH. Hypoxia-inducible factor pathway and diseases of the vascular wall. J Vasc Surg. 2013;58(1):219-230.

[129] Wan L, Huang J, Chen J, et al. Expression and significance of FOXP1, HIF-1a and VEGF in renal clear cell carcinoma. J BUON. 2015;20(1):188-195.

[130] Firdaus R, Prijanti AR. Control of HIF-1αlevels potentially promotes the tissue repair in various conditions through target gene expression. BioSci Med J Biomed Transl Res. 2022;6(1):1266-1274.

[131] Minet E, Michel G, Remacle J, Michiels C. Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis. Int J Mol Med. 2000;5(3):253-262.

[132] Elebiyo TC, Rotimi D, Evbuomwan IO, et al. Reassessing vascular endothelial growth factor (VEGF) in anti-angiogenic cancer therapy. Cancer Treat Res Commun. 2022;32:100620.

[133] Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int. 2004;65(6):2003-2017.

[134] Velazquez OC. Angiogenesis and vasculogenesis: inducing the growth of new blood vessels and wound healing by stimulation of bone marrow-derived progenitor cell mobilization and homing. J Vasc Surg. 2007;45(6):A39-A47.

[135] Bai Y, Jx M, Guo J, et al. Müller cell-derived VEGF is a significant contributor to retinal neovascularization. J Pathol. 2009;219(4):446-454.

[136] Yang Y, Liu Y, Wang Y, et al. Regulation of SIRT1 and its roles in inflammation. Front Immunol. 2022;13:831168.

[137] Kim E-J, Um S-J. SIRT1: roles in aging and cancer. BMB Rep. 2008;41(11):751-756.

[138] Yu A, Dang W. Regulation of stem cell aging by SIRT1-linking metabolic signaling to epigenetic modifications. Mol Cell Endocrinol. 2017;455:75-82.

[139] Albani D, Polito L, Batelli S, et al. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by α-synuclein or amyloid-β(1-42) peptide. J Neurochem. 2009;110(5):1445-1456.

[140] Pallàs M, Casadesús G, Smith MA, et al. Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res. 2009;6(1):70-81.

[141] Antonsson B. Bax and other pro-apoptotic Bcl-2 family “killer-proteins”and their victim the mitochondrion. Cell Tissue res. 2001;306:347-361.

[142] Sitarek P, Skała E, Toma M, et al. A preliminary study of apoptosis induction in glioma cells via alteration of the Bax/Bcl-2-p53 axis by transformed and non-transformed root extracts of Leonurus sibiricus L. Tumor Biol. 2016;37:8753-8764.

[143] Maes ME, Schlamp CL, Nickells RW. BAX to basics: how the BCL2 gene family controls the death of retinal ganglion cells. Prog Retin Eye res. 2017;57:1-25.

[144] Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169(3):381-405.

[145] Gan Y, Shi C, Inge L, Hibner M, Balducci J, Huang Y. Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells. Oncogene. 2010;29(35):4947-4958.

[146] Abeyrathna P, Su Y. The critical role of Akt in cardiovascular function. Vascul Pharmacol. 2015;74:38-48.

[147] Hopkins N, Goldsmith ZK, Jablonski MM, Wilson MW, Seigel GM, Morales VM. In search for the RGC lineage: characterization of R28 cells and the expression of RGC markers. Invest Ophthalmol Vis Sci. 2019;60(9):4861.

[148] Wang C, An Y, Xia Z, et al. The neuroprotective effect of melatonin in glutamate excitotoxicity of R28 cells and mouse retinal ganglion cells. Front Endocrinol. 2022;13:986131.

[149] Frezza C, Cipolat S, De Brito OM, et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006;126(1):177-189.

[150] Palmer CS, Osellame LD, Stojanovski D, Ryan MT. The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery. Cell Signal. 2011;23(10):1534-1545.

[151] Quintana-Cabrera R, Quirin C, Glytsou C, et al. The cristae modulator optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function. Nat Commun. 2018;9(1):3399.

[152] Broxton CN, Culotta VC. SOD enzymes and microbial pathogens: surviving the oxidative storm of infection. PLoS Pathog. 2016;12(1):e1005295.

[153] Spirina LV, Yunusova NV, Kondakova IV, Tarasenko NV. Transcription factors Brn-3αand TRIM16 in cancers, association with hormone reception. Heliyon. 2019;5(8):e02090.

[154] Nadal-Nicolás FM, Jiménez-López M, Sobrado-Calvo P, et al. Brn3a as a marker of retinal ganglion cells: qualitative and quantitative time course studies in naive and optic nerve-injured retinas. Invest Ophthalmol Vis Sci. 2009;50(8):3860-3868.

[155] Kogan CS, Zangenehpour S, Chaudhuri A. Developmental profiles of SMI-32 immunoreactivity in monkey striate cortex. Dev Brain Res. 2000;119(1):85-95.

[156] Tan H, Li X, Huang K, Luo M, Wang L. Morphological and distributional properties of SMI-32 immunoreactive ganglion cells in the rat retina. J Comp Neurol. 2022;530(8):1276-1287.

[157] Seifer DB, Lambert-Messerlian G, Schneyer AL. Ovarian brain-derived neurotrophic factor is present in follicular fluid from normally cycling women. Fertil Steril. 2003;79(2):451-452.

[158] Balaratnasingam S, Janca A. Brain derived neurotrophic factor: a novel neurotrophin involved in psychiatric and neurological disorders. Pharmacol Ther. 2012;134(1):116-124.

[159] Zhang F, Kang Z, Li W, Xiao Z, Zhou X. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer’s disease. J Clin Neurosci. 2012;19(7):946-949.

[160] Hannan MA, Dash R, Sohag AAM, Haque MN, Moon IS. Neuroprotection against oxidative stress: phytochemicals targeting TrkB signaling and the Nrf2-ARE antioxidant system. Front Mol Neurosci. 2020;13:116.

[161] Cao K, Ishida T, Fang Y, et al. Protection of the retinal ganglion cells: intravitreal injection of resveratrol in mouse model of ocular hypertension. Invest Ophthalmol Vis Sci. 2020;61(3):13.

[162] Baudouin C, Kolko M, Melik-Parsadaniantz S, Messmer EM. Inflammation in glaucoma: from the back to the front of the eye, and beyond. Prog Retin Eye res. 2021;83:100916.

[163] Vohra R, Tsai JC, Kolko M. The role of inflammation in the pathogenesis of glaucoma. Surv Ophthalmol. 2013;58(4):311-320.

[164] Wei X, Cho KS, Thee EF, Jager MJ, Chen DF. Neuroinflammation and microglia in glaucoma: time for a paradigm shift. J Neurosci res. 2019;97(1):70-76.

[165] Malvitte L, Montange T, Vejux A, et al. Measurement of inflammatory cytokines by multicytokine assay in tears of patients with glaucoma topically treated with chronic drugs. Br J Ophthalmol. 2007;91(1):29-32.

[166] Adornetto A, Russo R, Parisi V. Neuroinflammation as a target for glaucoma therapy. Neural Regen res. 2019;14(3):391-394.

[167] Morgan MJ, Liu Z-g. Crosstalk of reactive oxygen species and NF-κB signaling. Cell res. 2011;21(1):103-115.

[168] Mahaling B, Low SW, Beck M, et al. Damage-associated molecular patterns (DAMPs) in retinal disorders. Int J Mol Sci. 2022;23(5):2591.

[169] Schmidt RL, Lenz LL. Distinct licensing of IL-18 and IL-1βsecretion in response to NLRP3 inflammasome activation. PLoS ONE. 2012;7(9):e45186.

[170] Shinozaki Y, Koizumi S. Potential roles of astrocytes and Müller cells in the pathogenesis of glaucoma. J Pharmacol Sci. 2021;145(3):262-267.

[171] Inman DM, Horner PJ. Reactive nonproliferative gliosis predominates in a chronic mouse model of glaucoma. Glia. 2007;55(9):942-953.

[172] Mehta A, Prabhakar M, Kumar P, Deshmukh R, Sharma P. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Eur J Pharmacol. 2013;698(1-3):6-18.

[173] Casson RJ. Possible role of excitotoxicity in the pathogenesis of glaucoma. Clin Exp Ophthalmol. 2006;34(1):54-63.

[174] Luo H, Zhuang J, Hu P, et al. Resveratrol delays retinal ganglion cell loss and attenuates gliosis-related inflammation from ischemia-reperfusion injury. Invest Ophthalmol Vis Sci. 2018;59(10):3879-3888.

[175] Naidoo N. Cellular stress/the unfolded protein response: relevance to sleep and sleep disorders. Sleep Med Rev. 2009;13(3):195-204.

[176] Arensdorf AM, Diedrichs D, Rutkowski DT. Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences. Front Genet. 2013;4:256.

[177] Direito I, Gomes D, Monteiro FL, et al. The clinicopathological significance of BiP/GRP-78 in breast cancer: a meta-analysis of public datasets and immunohistochemical detection. Curr Oncol. 2022;29(12):9066-9087.

[178] Shima K, Klinger M, Schütze S, et al. The role of endoplasmic reticulum-related BiP/GRP 78 in interferon gamma-induced persistent C hlamydia pneumoniae infection. Cell Microbiol. 2015;17(7):923-934.

[179] Hu Y, Park KK, Yang L, et al. Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron. 2012;73(3):445-452.

[180] Vannuvel K, Renard P, Raes M, Arnould T. Functional and morphological impact of ER stress on mitochondria. J Cell Physiol. 2013;228(9):1802-1818.

[181] Xu W, Wang C, Hua J. X-box binding protein 1 (XBP1) function in diseases. Cell Biol Int. 2021;45(4):731-739.

[182] Lindsey JD, Duong-Polk KX, Hammond D, Leung CK-s, Weinreb RN. Protection of injured retinal ganglion cell dendrites and unfolded protein response resolution after long-term dietary resveratrol. Neurobiol Aging. 2015;36(5):1969-1981.

[183] Bai Y, Xu J, Brahimi F, Zhuo Y, Sarunic MV, Saragovi HU. An agonistic TrkB mAb causes sustained TrkB activation, delays RGC death, and protects the retinal structure in optic nerve axotomy and in glaucoma. Invest Ophthalmol Vis Sci. 2010;51(9):4722-4731.

[184] King CE, Rodger J, Bartlett C, Esmaili T, Dunlop SA, Beazley LD. Erythropoietin is both neuroprotective and neuroregenerative following optic nerve transection. Exp Neurol. 2007;205(1):48-55.

[185] Kim SH, Park JH, Kim YJ, Park KH. The neuroprotective effect of resveratrol on retinal ganglion cells after optic nerve transection. Mol Vis. 2013;19:1667-1676.

[186] Khan AJ, LaCava S, Mehta M, et al. The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo. Oncotarget. 2019;10(29):2824-2834.

[187] Hascup KN, Findley CA, Britz J, et al. Riluzole attenuates glutamatergic tone and cognitive decline in AβPP/PS1 mice. J Neurochem. 2021;156(4):513-523.

[188] Pirhan D, Yüksel N, Emre E, Cengiz A, Kürşat YD. Riluzole-and resveratrol-induced delay of retinal ganglion cell death in an experimental model of glaucoma. Curr Eye res. 2016;41(1):59-69.

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