Preventive Effects of Crocin, a Key Carotenoid Component in Saffron, Against Nicotine‑Triggered Neurodegeneration in Rat Hippocampus: Possible Role of Autophagy and Apoptosis

Mina Gholami, Daniel J. Klionsky, Majid Motaghinejad

Abstract


Background: Nicotine is a behavioral stimulant that in high doses, through the neuro‑inflammatory and oxidative stress pathway, can induce apoptosis and autophagy leading to cell death. Previous data indicate that crocin has neuroprotective properties. The aim of the current study is to investigate crocin’s neuroprotective effects against nicotine‑triggered neuro‑inflammation, apoptosis, and autophagy in rat hippocampus. Methods: Seventy adult male Wistar rats were divided into the following seven groups: Group one received normal saline (0.2 ml/rat), group two was treated with nicotine 10 mg/kg intraperitoneally, groups 3 to 6 were treated simultaneously with nicotine and crocin (10, 20, 40, and 80 mg/kg, intraperitoneally), group 7 was treated with crocin‑alone (80 mg/kg, intraperitoneally). The period of the mentioned agent administration was 21 days. On the 22nd day, an open field test (OFT) was used for evaluation of anxiety and motor activity changes. Inflammatory and oxidative stress factors and also apoptosis and autophagy biomarkers were evaluated. Results: All mentioned doses of crocin could decrease the nicotine‑induced OFT behavioral changes. Crocin also could decrease levels of hippocampal TNF/TNF‑α (tumor necrosis factor), IL1B/IL‑1β (interleukin 1 beta), oxidized glutathione (GSSG), unphosphorylated and phosphorylated forms of JNK, BECN1 (beclin 1), BAX (BCL2 associated X, apoptosis regulator), and phosphorylated/inactive forms of BCL2 (BCL2 apoptosis regulator) in nicotine‑dependent rats. Crocin treatments also caused increases in the reduced form of glutathione (GSH) content and activity of CAT (catalase) and mitochondrial complex enzymes in nicotine‑addicted subjects. Conclusions: Crocin can modulate JNK‑BCL2‑BECN1 or JNK‑BCL2‑BAX signaling pathways and reduce neuronal oxidative stress, neuro‑inflammation, and mitochondrial respiratory chain enzymes and exert neuroprotective effects against nicotine‑induced neurodegeneration.

Keywords


Apoptosis; autophagy; crocin; nicotine

Full Text:

PDF

References


Cross SJ, Lotfipour S, Leslie FM. Mechanisms and genetic factors underlying co use of nicotine and alcohol or other drugs of abuse. Am J Drug Alcohol Abuse 2017;43:171 85.

Siqueira LM, Ryan SA, Gonzalez PK, Patrick SW, Quigley J, Walker LR. Nicotine and tobacco as substances of abuse in children and adolescents. Pediatrics 2017;139:e20163436. doi: 10.1542/peds.2016 3436.

Jarvik ME. The role of nicotine in the smoking habit. Learning Mechanisms in Smoking. Routledge; Tailor and Francis group;2017. p.15590.

Selya AS, Dierker L, Rose JS, Hedeker D, Mermelstein RJ. The role of nicotine dependence in e cigarettes’ potential for smoking reduction. Nicotine Tob Res 2018;20:1272 7.

Laviolette SR. Molecular and neuronal mechanisms underlying the effects of adolescent nicotine exposure on anxiety and mood disorders. Neuropharmacology 2021;184:108411. doi: 10.1016/j. neuropharm.2020.108411.

Besson M, Forget B. Cognitive dysfunction, affective states, and vulnerability to nicotine addiction: A multifactorial perspective. Front Psychiatry 2016;7:160. doi: 10.3389/fpsyt.2016.00160.

Motaghinejad M, Motevalian M, Fatima S, Faraji F, Mozaffari S. The neuroprotective effect of curcumin against nicotine induced neurotoxicity is mediated by CREB–BDNF signaling pathway. Neurochem Res 2017;42:2921 32.

Motaghinejad M, Fatima S, Karimian M, Ganji S. Protective effects of forced exercise against nicotine induced anxiety, depression and cognition impairment in rat. J Basic Clin Physiol Pharm 2016;27:19 27.

Motaghinejad M, Farokhi N, Motevalian M, Safari S. Molecular, histological and behavioral evidences for neuroprotective effects of minocycline against nicotine induced neurodegeneration and cognition impairment: Possible role of CREB BDNF signaling pathway. Behav Brain Res 2020;386:112597. doi: 10.1016/j.bbr. 2020.112597.

Yu R, Deochand C, Krotow A, Leão R, Tong M, Agarwal AR, et al. Tobacco smoke induced brain white matter myelin dysfunction: Potential co factor role of smoking in neurodegeneration. J Alzheimers Dis 2016;50:133 48.

Deochand C, Tong M, Agarwal AR, Cadenas E, de la Monte SM. Tobacco smoke exposure impairs brain insulin/IGF signaling: Potential co factor role in neurodegeneration. J Alzheimers Dis 2016;50:373 86.

Xue R, Wan Y, Sun X, Zhang X, Gao W, Wu W. Nicotinic mitigation of neuroinflammation and oxidative stress after chronic sleep deprivation. Front Immunol 2019;10:2546. doi: 10.3389/fimmu.2019.02546.

Oliveira da Silva A, Manhaes A, Cristina Rodrigues F, Filgueiras C, Abreu Villaca Y. Hippocampal increased cell death and decreased cell density elicited by nicotine and/or ethanol during adolescence are reversed during drug withdrawal. Neuroscience 2010;167:163 73.

Wei J, Wang J, Dwyer JB, Mangold J, Cao J, Leslie FM, et al. Gestational nicotine treatment modulates cell death/ survival related pathways in the brains of adolescent female rats. Int J Neuropsychopharmacol 2011;14:91 106.

Ijomone OM, Olaibi OK, Nwoha PU. Effects of chronic nicotine administration on body weight, food intake and nitric oxide concentration in female and male rats. Pathophysiology 2014;21:185 90.

Gauthier AC, Liu J. Focus: The aging brain: Neurodegeneration and neuroprotection in glaucoma. Yale J Biol Med 2016;89:73.

Salahshoor MR, Abdolmaleki A, Roshankhah S, Jalali A, Jalili C. Curcumin recovers the toxic effects of nicotine on hippocampus cornu ammonis 1 in rats. J Pharmacol Pharmacother 2019;10:85.

Al Malki AL, Moselhy SS. Protective effect of vitamin E and epicatechin against nicotine induced oxidative stress in rats. Toxicol Indus Health 2013;29:202 8.

Bhattacharjee A, Prasad SK, Pal S, Maji B, Syamal AK, Mukherjee S. Synergistic protective effect of folic acid and vitamin B12 against nicotine induced oxidative stress and apoptosis in pancreatic islets of the rat. Pharm Biol 2016;54:433 44.

Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000;1:120 30.

Frake RA, Ricketts T, Menzies FM, Rubinsztein DC. Autophagy and neurodegeneration. J Clin Invest 2015;125:65 74.

Chen L, Qi Y, Yang X. Neuroprotective effects of crocin against oxidative stress induced by ischemia/reperfusion injury in rat retina. Ophthal Res 2015;54:157 68.

Soeda S, Aritake K, Urade Y, Sato H, Shoyama Y. Neuroprotective activities of saffron and crocin. The Benefits of Natural Products for Neurodegenerative Diseases. Springer; 2016. p. 27592.

Kermanshahi S, Ghanavati G, Abbasi Mesrabadi M, Gholami M, Ulloa L, Motaghinejad M, et al. Novel neuroprotective potential of crocin in neurodegenerative disorders: An illustrated mechanistic review. Neurochem Res 2020;45:2573 85.

Mozaffari S, Yasuj SR, Motaghinejad M, Motevalian M, Kheiri R. Crocin acting as a neuroprotective agent against methamphetamine induced neurodegeneration via CREB BDNF signaling pathway. Iran J Pharm Res 2019;18:745 58.

Ahmed S, Hasan MM, Heydari M, Rauf A, Bawazeer S, Abu Izneid T, et al. Therapeutic potentials of crocin in medication of neurological disorders. Food Chem Toxicol 2020;145:111739. doi: 10.1016/j.fct.2020.111739.

Gholami M, Nozarnezhad R, Motaghinejad M. Hypothetical protective effects of crocin carotenoid against coronavirus induced organ damage: The possible role of the NF κB signaling pathway. Iran J Med Sci 2021;46:228 9.

Wang K, Zhang L, Rao W, Su N, Hui H, Wang L, et al. Neuroprotective effects of crocin against traumatic brain injury in mice: Involvement of notch signaling pathway. Neurosci Lett 2015;591:53 8.

Nam KN, Park Y M, Jung H J, Lee JY, Min BD, Park S U, et al. Anti inflammatory effects of crocin and crocetin in rat brain microglial cells. Eur J Pharmacol 2010;648:110 6.

Bathaie SZ, Farajzade A, Hoshyar R. A review of the chemistry and uses of crocins and crocetin, the carotenoid natural dyes in saffron, with particular emphasis on applications as colorants including their use as biological stains. Biotech Histochem 2014;89:401 11.

Xi L, Qian Z, Du P, Fu J. Pharmacokinetic properties of crocin (crocetin digentiobiose ester) following oral administration in rats. Phytomedicine 2007;14:633 6.

Soeda S, Ochiai T, Shimeno H, Saito H, Abe K, Tanaka H, et al. Pharmacological activities of crocin in saffron. J Nat Med 2007;61:102 11.

Krishnaswamy V, Alugoju P, Periyasamy L. Effect of short term oral supplementation of crocin on age related oxidative stress, cholinergic, and mitochondrial dysfunction in rat cerebral cortex. Life Sci 2020;263:118545. doi: 10.1016/j.lfs.2020.118545.

Yousefsani BS, Mehri S, Pourahmad J, Hosseinzadeh H. Protective effect of crocin against mitochondrial damage and memory deficit induced by beta amyloid in the hippocampus of rats. Iran J Pharmac Res 2021;20:79 94.

Talaei A, Moghadam MH, Tabassi SAS, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: A randomized, double blind, placebo controlled, pilot clinical trial. J Affect Disord 2015;174:51 6.

Khani F, Radahmadi M, Alaei H, Jafari E. Effects of crocin on cognitive and spatial memories in rats under chronic isolation stress. Physiol Pharmacol 2018;22:254 68.

Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR, et al. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology 2007;190:269 319.

Motaghinejad M, Safari S, Feizipour S, Sadr S. Crocin may be useful to prevent or treatment of alcohol induced neurodegeneration and neurobehavioral sequels via modulation of CREB/BDNF and Akt/GSK signaling pathway. Med Hypotheses 2019;124:21 5.

Ebrahimzadeh A, Moghadam SY, Rahimi H, Motaghinejad M, Motevalian M, Safari S, et al. Crocin acts as a neuroprotective mediator against methylphenidateinduced neurobehavioral and neurochemical sequelae: Possible role of the CREB BDNF signaling pathway. Acta Neurobiol Exp 2019;79:352 66.

Vakili A, Einali MR, Bandegi AR. Protective effect of crocin against cerebral ischemia in a dose dependent manner in a rat model of ischemic stroke. Stroke Cerebrovasc Dis 2014;23:106 13.

Khalili M, Hamzeh F. Effects of active constituents of crocus sativus L., crocin on streptozocin induced model of sporadic Alzheimer’s disease in male rats. Iran Biomed J 2010;14:59 65.

Le Foll B, Goldberg SR. Nicotine induces conditioned place preferences over a large range of doses in rats. Psychopharmacology 2005;178:481 92.

Mehri S, Abnous K, Khooei A, Mousavi SH, Shariaty VM, Hosseinzadeh H. Crocin reduced acrylamide induced neurotoxicity in Wistar rat through inhibition of oxidative stress. Iran J Basic Med Sci 2015;18:902.

Gould TD, Dao DT, Kovacsics CE. The open field test. Mood and Anxiety Related Phenotypes in Mice. Springer; 2009. p. 1 20.

Ghafarimoghadam M, Mashayekh R, Gholami M, Fereydani P, Shelley Tremblay J, Kandezi N, et al. A review of behavioral methods for the evaluation of cognitive performance in animal models: Current techniques and links to human cognition. Physiol Behav 2022;244:113652. doi: 10.1016/j.physbeh. 2021.113652.

Davis JA. Mouse and rat anesthesia and analgesia. Curr Protoc Neurosci 2008;42:A.4B.1 A.4B.21. doi: 10.1002/0471142301. nsa04bs42.

Luca C, Salvatore F, Vincenzo DP, Giovanni C, Attilio ILM. Anesthesia protocols in laboratory animals used for scientific purposes. Acta Biomed 2018;89:337 42.

Motaghinejad M, Seyedjavadein Z, Motevalian M, Asadi M. The neuroprotective effect of lithium against high dose methylphenidate: Possible role of BDNF. Neurotoxicology 2016;56:40 54.

Dave KR, Saul I, Busto R, Ginsberg MD, Sick TJ, Pérez Pinzón MA. Ischemic preconditioning preserves mitochondrial function after global cerebral ischemia in rat hippocampus. J Cereb Blood Flow Metab 2001;21:1401 10.

Vahdati Hassani F, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H. Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. DARU J Pharm Sci 2014;22:1 9. doi: 10.1186/2008 2231 22 16.

Kipp JL, Ramirez VD. Effect of estradiol, diethylstilbestrol, and resveratrol on F0F1 ATPase activity from mitochondrial preparations of rat heart, liver, and brain. Endocrine 2001;15:165 75.

Zadali R, Ghareghozloo ER, Ramezani M, Hassani V, Rafiei Y, Chiyaneh SM, et al. Interactions with and membrane permeabilization of brain mitochondria by amyloid fibrils. J Vis Exp 2019:e59883.

Redmile Gordon M, Armenise E, White RP, Hirsch P, Goulding K. A comparison of two colorimetric assays, based upon lowry and bradford techniques, to estimate total protein in soil extracts. Soil Biol Biochem 2013;67:166 73.

Mæhre HK, Dalheim L, Edvinsen GK, Elvevoll EO, Jensen I J. Protein determination—method matters. Foods 2018;7:5.

Motaghinejad M, Motevalian M, Shabab B. Possible involvements of glutamate and adrenergic receptors on acute toxicity of methylphenidate in isolated hippocampus and cerebral cortex of adult rats. Fundam Clin Pharmacol 2017;31:208 25.

Motaghinejad M, Motevalian M, Fatima S, Hashemi H, Gholami M. Curcumin confers neuroprotection against alcohol induced hippocampal neurodegeneration via CREB BDNF pathway in rats. Biomed Pharmacother 2017;87:721 40.

Motaghinejad M, Motevalian M. Involvement of AMPA/kainate and GABA A receptors in topiramate neuroprotective effects against methylphenidate abuse sequels involving oxidative stress and inflammation in rat isolated hippocampus. Eur J Pharmacol 2016;784:181 91.

Qiao H, Dong L, Zhang X, Zhu C, Zhang X, Wang L, et al. Protective effect of luteolin in experimental ischemic stroke: Upregulated SOD1, CAT, Bcl 2 and claudin 5, down regulated MDA and Bax expression. Neurochem Res 2012;37:2014 24.

Vekaria RH, Patel MN, Bhalodiya PN, Patel V, Desai TR, Tirgar PR. Evaluation of neuroprotective effect of coriandrum sativum linn. against ischemicreperfusion insult in brain. Int J Phytopharmacol 2012;2:186 93.

Motaghinejad M, Mashayekh R, Motevalian M, Safari S. The possible role of CREBBDNF signaling pathway in neuroprotective effects of minocycline against alcoholinduced neurodegeneration: Molecular and behavioral evidences. Fundam Clin Pharmacol 2021;35:113 30.

Hnasko R. Elisa. Springer; 2015.

Crowther JR. The ELISA Guidebook. Springer Science & Business Media; 2008.

Kirby DM, Thorburn DR, Turnbull DM, Taylor RW. Biochemical assays of respiratory chain complex activity. Methods Cell Biol 2007;80:93 119.

Bénit P, Goncalves S, Dassa EP, Brière J J, Martin G, Rustin P. Three spectrophotometric assays for the measurement of the five respiratory chain complexes in minuscule biological samples. Clin Chim Acta 2006;374:81 6.

Benowitz NL. Nicotine addiction. N Engl J Med 2010;362:2295 303.

Changeux J P. Nicotine addiction and nicotinic receptors: Lessons from genetically modified mice. Nat Rev Neurosci 2010;11:389 401.

Dome P, Lazary J, Kalapos MP, Rihmer Z. Smoking, nicotine and neuropsychiatric disorders. Neurosci Biobehav Rev 2010;34:295 342.

Watterson E, Daniels CW, Watterson LR, Mazur GJ, Brackney RJ, Olive MF, et al. Nicotine induced place conditioning and locomotor activity in an adolescent animal model of attention deficit/hyperactivity disorder (ADHD). Behav Brain Res 2015;291:184 8.

Heishman SJ, Kleykamp BA, Singleton EG. Meta analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology 2010;210:453 69.

Razavi BM, Sadeghi M, Abnous K, Hasani FV, Hosseinzadeh H. Study of the role of CREB, BDNF, and VGF neuropeptide in long term antidepressant activity of crocin in the rat cerebellum. Iran J Pharm Res 2017;16:1452 62.

Dastgerdi AH, Radahmadi M, Pourshanazari AA, Dastgerdi HH. Effects of crocin on learning and memory in rats under chronic restraint stress with special focus on the hippocampal and frontal cortex corticosterone levels. Adv Biomed Res 2017;6:157.

Rezai M, Mahmoodi M, Kaeidi A, Karimabad MN, Khoshdel A, Hajizadeh MR. Effect of crocin carotenoid on BDNF and CREB gene expression in brain ventral tegmental area of morphine treated rats. Asian Pac J Trop Biomed 2018;8:387 93.

Hassani FV, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H. Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. Daru 2014;22:16. doi: 10.1186/2008 2231 22 16.

Shafahi M, Vaezi G, Shajiee H, Sharafi S, Khaksari M. Crocin inhibits apoptosis and astrogliosis of hippocampus neurons against methamphetamine neurotoxicity via antioxidant and anti inflammatory mechanisms. Neurochem Res 2018;43:2252 9.

Nunes SOV, Vargas HO, Prado E, Barbosa DS, de Melo LP, Moylan S, et al. The shared role of oxidative stress and inflammation in major depressive disorder and nicotine dependence. Neurosci Biobehav Rev 2013;37:1336 45.

Hritcu L, Ciobica A, Gorgan L. Nicotine induced memory impairment by increasing brain oxidative stress. Cent Eur J Biol 2009;4:335 42.

Saad AB, Rjeibi I, Brahmi N, Elaloui E, Zouari N. Nicotine induced oxidative stress, testis injury, AChE inhibition and brain damage alleviated by Mentha spicata. Inflammopharmacology 2020;28:939 48.

Elsonbaty SM, Ismail AF. Nicotine encourages oxidative stress and impairment of rats’ brain mitigated by Spirulina platensis lipopolysaccharides and low dose ionizing radiation. Arch Biochem Biophys 2020;689:108382. doi: 10.1016/j.abb. 2020.108382.

Cardinale A, Nastrucci C, Cesario A, Russo P. Nicotine: Specific role in angiogenesis, proliferation and apoptosis. Crit Rev Toxicol 2012;42:68 89.

Benowitz NL. Pharmacology of nicotine: Addiction, smoking induced disease, and therapeutics. Ann Rev Pharmacol Toxicol 2009;49:57 71.

Rajaei Z, Hosseini M, Alaei H. Effects of crocin on brain oxidative damage and aversive memory in a 6 OHDA model of Parkinson’s disease. Arq Neuropsiquiatr 2016;74:723 9.

Rao SV, Hemalatha P, Yetish S, Muralidhara M, Rajini PS. Prophylactic neuroprotective propensity of crocin, a carotenoid against rotenone induced neurotoxicity in mice: Behavioural and biochemical evidence. Metab Brain Dis 2019;34:1341 53.

Bradford ST, Stamatovic SM, Dondeti RS, Keep RF, Andjelkovic AV. Nicotine aggravates the brain postischemic inflammatory response. Am J Physiol Heart Circ Physiol 2011;300:H1518 29.

Swan GE, Lessov Schlaggar CN. The effects of tobacco smoke and nicotine on cognition and the brain. Neuropsychol Rev 2007;17:259 73.

Hashemzaei M, Mamoulakis C, Tsarouhas K, Georgiadis G, Lazopoulos G, Tsatsakis A, et al. Crocin: A fighter against inflammation and pain. Food Chem Toxicol 2020;143:111521. doi: 10.1016/j.fct.2020.111521.

Korani S, Korani M, Sathyapalan T, Sahebkar A. Therapeutic effects of crocin in autoimmune diseases: A review. Biofactors 2019;45:835 43.

Farkhondeh T, Samarghandian S, Yazdi HS, Samini F. The protective effects of crocin in the management of neurodegenerative diseases: A review. Am J Neurodegener Dis 2018;7:1 10.

Zhang L, Previn R, Lu L, Liao R F, Jin Y, Wang R K. Crocin, a natural product attenuates lipopolysaccharide induced anxiety and depressive like behaviors through suppressing NF kB and NLRP3 signaling pathway. Brain Res Bull 2018;142:352 9.

Malińska D, Więckowski MR, Michalska B, Drabik K, Prill M, Patalas Krawczyk P, et al. Mitochondria as a possible target for nicotine action. J Bioenerg Biomembr 2019;51:259 76.

Godoy JA, Valdivieso AG, Inestrosa NC. Nicotine modulates mitochondrial dynamics in hippocampal neurons. Mol Neurobiol 2018;55:8965 77.

Benowitz NL. Nicotine addiction. N Engl J Med 2010;362:2295.

Yousefsani BS, Pourahmad J, Hosseinzadeh H. The mechanism of protective effect of crocin against liver mitochondrial toxicity caused by arsenic III. Toxicol Mech Methods 2018;28:105 14.

Okouchi M, Ekshyyan O, Maracine M, Aw TY. Neuronal apoptosis in neurodegeneration. Antioxidants Redox Signal 2007;9:1059 96.

Stefani IC, Wright D, M Polizzi K, Kontoravdi C. The role of ER stress induced apoptosis in neurodegeneration. Curr Alzheimer Res 2012;9:373 87.

Graeber MB, Moran LB. Mechanisms of cell death in neurodegenerative diseases: Fashion, fiction, and facts. Brain Pathol 2002;12:385 90.

Kandezi N, Majdi F, Davoudizadeh R, Motaghinejad M, Safari S. Preventive properties of Ramelteon against cocaine induced autophagia and apoptosis: A hypothetic role of TNF α receptor involvement and JNK/Bcl 2 Beclin1 or Bcl 2/Bax signaling pathway. Int J Prev Med 2020;11:11 36.

Marquez RT, Xu L. Bcl 2: Beclin 1 complex: Multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res 2012;2:214.

Wei Y, Sinha SC, Levine B. Dual role of JNK1 mediated phosphorylation of Bcl 2 in autophagy and apoptosis regulation. Autophagy 2008;4:949 51.

Decuypere J P, Parys JB, Bultynck G. Regulation of the autophagic bcl 2/beclin 1 interaction. Cells 2012;1:284 312.

Ateyya H, Nader MA, Attia GM, El Sherbeeny NA. Influence of alpha lipoic acid on nicotine induced lung and liver damage in experimental rats. Can J Physiol Pharmacol 2017;95:492 500.

Zhou Y, Wang Z X, Tang M P, Yao C J, Xu W J, Wang L Y, et al. Nicotine induces cyclooxygenase 2 and prostaglandin E2 expression in human umbilical vein endothelial cells. Int Immunopharmacol 2010;10:461 6.

Robertson GS, Crocker SJ, Nicholson DW, Schulz JB. Neuroprotection by the inhibition of apoptosis. Brain Pathol 2000;10:283 92.

Zhu H, Zhang Y, Shi Z, Lu D, Li T, Ding Y, et al. The neuroprotection of liraglutide against ischemia induced apoptosis through the activation of the PI3K/AKT and MAPK pathways. Sci Rep 2016;6:26859. doi: 10.1038/srep26859.

Cherra 3Rd SJ, Chu CT. Autophagy in neuroprotection and neurodegeneration: A question of balance. Future Neurol 2008;3:309 323.

Mariño G, Madeo F, Kroemer G. Autophagy for tissue homeostasis and neuroprotection. Curr Opin Cell Biol 2011;23:198 206.