Abstract
The study investigated the potential neuroprotective effects of metformin (MET) on alcohol-induced neurotoxicity in adult Wistar rats. The animals were randomized in four groups (n = 10): control, alcohol (ALC), ALC + MET, and MET. ALC (2 g/kg b.w.) and MET (200 mg/kg b.w.) were orally administered for 21 days, once daily. For the ALC + MET group, MET was administered 2 h after ALC treatment. On day 22, the open field test (OFT) and elevated plus maze (EPM) were performed. MET improved global activity and increased the time spent in unprotected open arms, decreased oxidative stress, both in the frontal lobe and in the hippocampus, and increased neuroglobin expression in the frontal cortex. Histopathologically, an increased neurosecretory activity in the frontal cortex in the ALC + MET group was noticed. Thus, our findings suggest that metformin has antioxidant and anxiolytic effects and may partially reverse the neurotoxic effects induced by ethanol.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdelsaid M, Prakash R, Li W et al (2015) Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes. Diabetes 64:1804–1817. https://doi.org/10.2337/db14-1423
Ahmed S, Mahmood Z, Javed A, Hashmi SN, Zerr I, Zafar S, Zahid S (2017) Effect of metformin on adult hippocampal neurogenesis: comparison with donepezil and links to cognition. J Mol Neurosci 62:88–98. https://doi.org/10.1007/s12031-017-0915-z
Aksoz E, Gocmez SS, Sahin TD, Aksit D, Aksit H, Utkan T (2019) The protective effect of metformin in scopolamine-induced learning and memory impairment in rats. Pharmacol Rep 71(5):818–825. https://doi.org/10.1016/j.pharep.2019.04.015
Algire C, Moiseeva O, Deschenes-Simard X et al (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila) 5:536–543. https://doi.org/10.1158/1940-6207.Capr-11-0536
Anchan D, Clark S, Pollard K, Vasudevan N (2014) GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice. Brain Behav 4:51–59. https://doi.org/10.1002/brb3.197
Arbelaez-Quintero I, Palacios M (2017) To use or not to use metformin in cerebral ischemia: a review of the application of metformin in stroke rodents. Stroke Res Treat 2017:9756429. https://doi.org/10.1155/2017/9756429
Ashabi G, Khodagholi F, Khalaj L, Goudarzvand M, Nasiri M (2014) Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats: interference of AMPK/PGC-1alpha pathway. Metab Brain Dis 29:47–58. https://doi.org/10.1007/s11011-013-9475-2
Bakhashab S, Ahmed F, Schulten HJ, Ahmed FW, Glanville M, Al-Qahtani MH, Weaver JU (2018) Proangiogenic effect of metformin in endothelial cells is via upregulation of VEGFR1/2 and their signaling under hyperglycemia-hypoxia. Int J Mol Sci 19. https://doi.org/10.3390/ijms19010293
Balen AH, Morley LC, Misso M et al (2016) The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update 22:687–708. https://doi.org/10.1093/humupd/dmw025
Belenichev IF, Pavlyuk IV, Kucherenko LI (2018) Antioxidant modulation of NO-dependent mechanisms of oxidative stress initiation in brain of rats subjected to chronic alcohol intoxication. https://doi.org/10.12988/bmgt.2016.6617
Belovicova K, Bogi E, Csatlosova K, Dubovicky M (2017) Animal tests for anxiety-like and depression-like behavior in rats. Interdiscip Toxicol 10:40–43. https://doi.org/10.1515/intox-2017-0006
Brynildsen JK, Lee BG, Perron IJ, Jin S, Kim SF, Blendy JA (2018) Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal. Proc Natl Acad Sci U S A 115:4282–4287. https://doi.org/10.1073/pnas.1707047115
Butterfield DA, Reed TT, Perluigi M et al (2007) Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer’s disease. Brain Res 1148:243–248. https://doi.org/10.1016/j.brainres.2007.02.084
Carrey N, McFadyen MP, Brown RE (2000) Effects of subchronic methylphenidate hydrochloride administration on the locomotor and exploratory behavior of prepubertal mice. J Child Adolesc Psychopharmacol 10:277–286. https://doi.org/10.1089/cap.2000.10.277
Chen Y, Zhou K, Wang R et al (2009) Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A 106:3907–3912. https://doi.org/10.1073/pnas.0807991106
Clark GJ, Pandya K, Lau-Cam CA (2017) The effect of metformin and taurine, alone and in combination, on the oxidative stress caused by diabetes in the rat brain. Adv Exp Med Biol 975(Pt 1):353–369. https://doi.org/10.1007/978-94-024-1079-2_31
Conti M, Morand PC, Levillain P, Lemonnier A (1991) Improved fluorometric determination of malonaldehyde. Clin Chem 37:1273–1275
Conway KP, Swendsen J, Husky MM, He JP, Merikangas KR (2016) Association of lifetime mental disorders and subsequent alcohol and illicit drug use: results from the National Comorbidity Survey-Adolescent Supplement. J Am Acad Child Adolesc Psychiatry 55:280–288. https://doi.org/10.1016/j.jaac.2016.01.006
Correia S, Carvalho C, Santos MS et al (2008) Metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. Med Chem 4:358–364. https://doi.org/10.2174/157340608784872299
Cui N, Hu M, Khalil RA (2017) Matrix metalloproteinases and tissue remodeling in health and disease: cardiovascular remodeling. In: Matrix metalloproteinases and tissue remodeling in health and disease: cardiovascular Remodeling, vol 147, 1st edn. Academic press, Cambridge, pp 1–73
Dagon Y, Avraham Y, Magen I, Gertler A, Ben-Hur T, Berry EM (2005) Nutritional status, cognition, and survival: a new role for leptin and AMP kinase. J Biol Chem 280:42142–42148. https://doi.org/10.1074/jbc.M507607200
Darwish RS, Amiridze N, Aarabi B (2007) Nitrotyrosine as an oxidative stress marker: evidence for involvement in neurologic outcome in human traumatic brain injury. J Trauma 63:439–442. https://doi.org/10.1097/TA.0b013e318069178a
El-Mir MY, Detaille D, RV G et al (2008) Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 34:77–87. https://doi.org/10.1007/s12031-007-9002-1
Fan J, Li D, Chen HS et al (2019) Metformin produces anxiolytic-like effects in rats by facilitating GABAA receptor trafficking to membrane. Br J Pharmacol 176:297–316. https://doi.org/10.1111/bph.14519
Feng S, Cen J, Huang Y, Shen H, Yao L, Wang Y, Chen Z (2011) Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS One 6:e20599. https://doi.org/10.1371/journal.pone.0020599
Filipovic D, Todorovic N, Bernardi RE, Gass P (2017) Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms. Brain Struct Funct 222:1–20. https://doi.org/10.1007/s00429-016-1218-9
Finnerty N, O'Riordan SL, Klamer D, Lowry J, Palsson E (2015) Increased brain nitric oxide levels following ethanol administration. Nitric Oxide 47:52–57. https://doi.org/10.1016/j.niox.2015.03.002
Fowler AK, Thompson J, Chen L, Dagda M, Dertien J, Dossou KSS, Moaddel R, Bergeson SE, Kruman II (2014) Differential sensitivity of prefrontal cortex and hippocampus to alcohol-induced toxicity. PLoS One 9:e106945. https://doi.org/10.1371/journal.pone.0106945
Gamberini MT, Rodrigues DS, Rodrigues D, Pontes VB (2015) Effects of the aqueous extract of Pimpinella anisum L. seeds on exploratory activity and emotional behavior in rats using the open field and elevated plus maze tests. J Ethnopharmacol 168:45–49. https://doi.org/10.1016/j.jep.2015.03.053
Ghadernezhad N, Khalaj L, Pazoki-Toroudi H, Mirmasoumi M, Ashabi G (2016) Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway. Pharm Biol 54(10):2211–2219. https://doi.org/10.3109/13880209.2016.1150306
Guidolin D, Tortorella C, Marcoli M, Maura G, Agnati LF (2016) Neuroglobin, a factor playing for nerve cell survival. Int J Mol Sci 17. https://doi.org/10.3390/ijms17111817
Guo M, Mi J, Jiang QM, Xu JM, Tang YY, Tian G, Wang B (2014) Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharmacol Physiol 41:650–656. https://doi.org/10.1111/1440-1681.12265
Haorah J, Knipe B, Leibhart J, Ghorpade A, Persidsky Y (2005) Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction. J Leukoc Biol 78:1223–1232. https://doi.org/10.1189/jlb.0605340
Hayes V, Demirkol A, Ridley N, Withall A, Draper B (2016) Alcohol-related cognitive impairment: current trends and future perspectives. Neurodegener Dis Manag 6:509–523. https://doi.org/10.2217/nmt-2016-0030
Hill RL, Singh IN, Wang JA, Hall ED (2017) Time courses of post-injury mitochondrial oxidative damage and respiratory dysfunction and neuronal cytoskeletal degradation in a rat model of focal traumatic brain injury. Neurochem Int 111:45–56. https://doi.org/10.1016/j.neuint.2017.03.015
Jimenez JC, Su K, Goldberg AR et al (2018) Anxiety cells in a hippocampal-hypothalamic circuit. Neuron 97:670–683.e676. https://doi.org/10.1016/j.neuron.2018.01.016
Jung J, Michalak M, Agellon LB (2017) Endoplasmic reticulum malfunction in the nervous system. Front Neurosci 11:220. https://doi.org/10.3389/fnins.2017.00220
Kasdallah-Grissa A, Mornagui B, Aouani E, Hammami M, Gharbi N, Kamoun A, El-Fazaa S (2006) Protective effect of resveratrol on ethanol-induced lipid peroxidation in rats. Alcohol Alcohol 41:236–239. https://doi.org/10.1093/alcalc/agh256
Kushwah N, Jain V, Deep S, Prasad D, Singh SB, Khan N (2016) Neuroprotective role of intermittent hypobaric hypoxia in unpredictable chronic mild stress induced depression in rats. PLoS One 11:e0149309. https://doi.org/10.1371/journal.pone.0149309
Lage R, Dieguez C, Vidal-Puig A, Lopez M (2008) AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 14:539–549. https://doi.org/10.1016/j.molmed.2008.09.007
Lasek AW (2016) Effects of ethanol on brain extracellular matrix: implications for alcohol use disorder. Alcohol Clin Exp Res 40:2030–2042. https://doi.org/10.1111/acer.13200
Lau LW, Cua R, Keough MB, Haylock-Jacobs S, Yong VW (2013) Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat Rev Neurosci 14:722–729. https://doi.org/10.1038/nrn3550
Li J, McCullough LD (2010) Effects of AMP-activated protein kinase in cerebral ischemia. J Cereb Blood Flow Metab 30:480–492. https://doi.org/10.1038/jcbfm.2009.255
Li W, Chaudhari K, Shetty R et al (2019) Metformin alters locomotor and cognitive function and brain metabolism in mormoglycemic mice. Aging Dis 10:949–963. https://doi.org/10.14336/ad.2019.0120
Liu JS, Zhao ML, Brosnan CF, Lee SC (2001) Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 158:2057–2066. https://doi.org/10.1016/s0002-9440(10)64677-9
Luyckx E, Van Acker ZP, Ponsaerts P, Dewilde S (2019) Neuroglobin expression models as a tool to study its function. Oxidative Med Cell Longev 2019:5728129–5728117. https://doi.org/10.1155/2019/5728129
Maniar K, Moideen A, Mittal A, Patil A, Chakrabarti A, Banerjee D (2017) A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: genesis of a wonder drug? Pharmacol Res 117:103–128. https://doi.org/10.1016/j.phrs.2016.12.003
Markowicz-Piasecka M, Sikora J, Szydlowska A, Skupien A, Mikiciuk-Olasik E, Huttunen KM (2017) Metformin - a future therapy for neurodegenerative diseases : theme: drug discovery, development and delivery in Alzheimer’s disease Guest Editor: Davide Brambilla. Pharm Res 34:2614–2627. https://doi.org/10.1007/s11095-017-2199-y
Mash DC, Ffrench-Mullen J, Adi N, Qin Y, Buck A, Pablo J (2007) Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One 2:e1187. https://doi.org/10.1371/journal.pone.0001187
McCreight LJ, Bailey CJ, Pearson ER (2016) Metformin and the gastrointestinal tract. Diabetologia 59:426–435. https://doi.org/10.1007/s00125-015-3844-9
Mizoguchi H, Nakade J, Tachibana M, Ibi D, Someya E, Koike H, Kamei H, Nabeshima T, Itohara S, Takuma K, Sawada M, Sato J, Yamada K (2011) Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. J Neurosci 31(36):12963–12971
Motaghinejad M, Motevalian M, Fatima S, Hashemi H, Gholami M (2017) Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats. Biomed Pharmacother. https://doi.org/10.1016/j.biopha.2016.12.020
Naghdi S, Slovinsky WS, Madesh M, Rubin E, Hajnoczky G (2018) Mitochondrial fusion and Bid-mediated mitochondrial apoptosis are perturbed by alcohol with distinct dependence on its metabolism. Cell Death Dis 9:1028. https://doi.org/10.1038/s41419-018-1070-3
Naseer MI, Lee HY, Ullah N, Ullah I, Park MS, Kim MO (2011) siRNA-mediated GABA(B) receptor at early fetal rat brain upon acute and chronic ethanol exposure: down regulation of PKA and p-CREB expression. Synapse 65:109–118. https://doi.org/10.1002/syn.20824
Olateju OI, Spocter MA, Patzke N, Ihunwo AO, Manger PR (2018) Hippocampal neurogenesis in the C57BL/6J mice at early adulthood following prenatal alcohol exposure. Metab Brain Dis 33:397–410. https://doi.org/10.1007/s11011-017-0156-4
Pippenger CE, Browne RW, Armstrong D (1998) Regulatory antioxidant enzymes. Methods Mol Biol 108:299–313. https://doi.org/10.1385/0-89603-472-0:299
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33. https://doi.org/10.1016/s0014-2999(03)01272-x
Ramos A (2008) Animal models of anxiety: do I need multiple tests? Trends Pharmacol Sci 29:493–498. https://doi.org/10.1016/j.tips.2008.07.005
Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J (2009) Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373:2223–2233. https://doi.org/10.1016/s0140-6736(09)60746-7
Rempe RG, Hartz AMS, Bauer B (2016) Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cereb Blood Flow Metab 36:1481–1507. https://doi.org/10.1177/0271678x16655551
Rocha-Ferreira E, Rudge B, Hughes MP, Rahim AA, Hristova M, Robertson NJ (2016) Immediate remote ischemic postconditioning reduces brain nitrotyrosine formation in a piglet asphyxia model. Oxidative Med Cell Longev 2016:5763743. https://doi.org/10.1155/2016/5763743
Rodriguez D, Morrison CJ, Overall CM (2010) Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta 1803:39–54. https://doi.org/10.1016/j.bbamcr.2009.09.015
Rosso P, Fioramonti M, Fracassi A, Marangoni M, Taglietti V, Siteni S, Segatto M (2016) AMPK in the central nervous system: physiological roles and pathological implications. Research and Reports in Biology 7:1–13. https://doi.org/10.2147/RRB.S90858
Rubio-Araiz A, Porcu F, Perez-Hernandez M et al (2017) Disruption of blood-brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model. Addict Biol 22:1103–1116. https://doi.org/10.1111/adb.12376
Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11:230–241. https://doi.org/10.1016/j.arr.2011.12.005
Samochowiec A, Grzywacz A, Kaczmarek L et al (2010) Functional polymorphism of matrix metalloproteinase-9 (MMP-9) gene in alcohol dependence: family and case control study. Brain Res 1327:103–106. https://doi.org/10.1016/j.brainres.2010.02.072
Saraei P, Asadi I, Kakar MA, Moradi-Kor N (2019) The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res 11:3295–3313. https://doi.org/10.2147/cmar.S200059
Sarkaki A, Farbood Y, Badavi M, Khalaj L, Khodagholi F, Ashabi G (2015) Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia. Metab Brain Dis 30:1139–1150. https://doi.org/10.1007/s11011-015-9677-x
Sevastre-Berghian AC, Fagarasan V, Toma VA et al (2017, 2017) Curcumin reverses the diazepam-induced cognitive impairment by modulation of oxidative stress and ERK 1/2/NF-kappaB pathway in brain. Oxidative Med Cell Longev:3037876. https://doi.org/10.1155/2017/3037876
Smith AM, Zeve DR, Grisel JJ, Chen WJ (2005) Neonatal alcohol exposure increases malondialdehyde (MDA) and glutathione (GSH) levels in the developing cerebellum. Brain Res Dev Brain Res 160:231–238. https://doi.org/10.1016/j.devbrainres.2005.09.004
Smith AW, Nealey KA, Wright JW, Walker BM (2011) Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems. Neurobiol Learn Mem 96:199–206. https://doi.org/10.1016/j.nlm.2011.04.011
Smith AC, Kupchik YM, Scofield MD, Gipson CD, Wiggins A, Thomas CA, Kalivas PW (2014) Synaptic plasticity mediating cocaine relapse requires matrix metalloproteinases. Nat Neurosci 17:1655–1657. https://doi.org/10.1038/nn.3846
Thomas I, Gregg B (2017) Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes 18:10–16. https://doi.org/10.1111/pedi.12473
Titheradge MA (1998) The enzymatic measurement of nitrate and nitrite. In: Titheradge MA (ed) Nitric oxide protocols. Part of the Methods in molecular biology™, book series. MIMB. vol 100. Humana Press, New Jersey, pp 89–91
Toma VA, Farcas AD, Parvu M, Silaghi-Dumitrescu R, Roman I (2017) CA3 hippocampal field: cellular changes and its relation with blood nitro-oxidative stress reveal a balancing function of CA3 area in rats exposed to repetead restraint stress. Brain Res Bull 130:10–17. https://doi.org/10.1016/j.brainresbull.2016.12.012
Tsilibary E, Tzinia A, Radenovic L et al (2014) Neural ECM proteases in learning and synaptic plasticity. Prog Brain Res 214:135–157. https://doi.org/10.1016/b978-0-444-63486-3.00006-2
Ullah I, Ullah N, Naseer MI, Lee HY, Kim MOK (2012) Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons. BMC Neurosci 13:11. https://doi.org/10.1186/1471-2202-13-11
Volkow ND, Wiers CE, Shokri-Kojori E, Tomasi D, Wang GJ, Baler R (2017) Neurochemical and metabolic effects of acute and chronic alcohol in the human brain: Studies with positron emission tomography. Neuropharmacology 122:175–188. https://doi.org/10.1016/j.neuropharm.2017.01.012
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2:322–328. https://doi.org/10.1038/nprot.2007.44
Wang C, Youle RJ (2009) The role of mitochondria in apoptosis*. Annu Rev Genet 43:95–118. https://doi.org/10.1146/annurev-genet-102108-134850
Wang J, Gallagher D, DeVito LM et al (2012) Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 11:23–35. https://doi.org/10.1016/j.stem.2012.03.016
Wright JW, Masino AJ, Reichert JR, Turner GD, Meighan SE, Meighan PC, Harding JW (2003) Ethanol-induced impairment of spatial memory and brain matrix metalloproteinases. Brain Res 963:252–261. https://doi.org/10.1016/s0006-8993(02)04036-2
Wscieklica T, de Barros VM, Le Sueur ML, Pouza KC, Spadari RC, Cespedes IC (2016) Alcohol consumption increases locomotion in an open field and induces Fos-immunoreactivity in reward and approach/withdrawal-related neurocircuitries. Alcohol 50:73–82. https://doi.org/10.1016/j.alcohol.2015.11.005
Yerevanian A, Soukas AA (2019) Metformin: mechanisms in human obesity and weight loss. Curr Obes Rep 8:156–164. https://doi.org/10.1007/s13679-019-00335-3
Yuan J, Amin P, Ofengeim D (2019) Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci 20:19–33. https://doi.org/10.1038/s41583-018-0093-1
Zou MH, Kirkpatrick SS, Davis BJ et al (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem 279:43940–43951. https://doi.org/10.1074/jbc.M404421200
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing Interests
The authors declare that they have no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Highlights
• ALC increased anxiety, nitrotyrosine and MMP-2 levels in both areas of the brain.
• MET improved locomotion and had anxiolytic effect in the EPM test.
• MET reduced partially the ethanol neurotoxicity by lowering the redox imbalance.
• MET diminished MMP-2 levels and increased neuroglobin, especially in the frontal lobe.
Rights and permissions
About this article
Cite this article
Bonea, M., Filip, G.A., Toma, V.A. et al. The Modulatory Effect of Metformin on Ethanol-Induced Anxiety, Redox Imbalance, and Extracellular Matrix Levels in the Brains of Wistar Rats. J Mol Neurosci 70, 1943–1961 (2020). https://doi.org/10.1007/s12031-020-01593-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-020-01593-w