Skip to main content

Anti-inflammatory, Antioxidant, and Antiapoptotic Action of Metformin Attenuates Ethanol Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders

Neurotoxicity Research volume 40, pages 605–613 (2022)Cite this article

Abstract

Fetal alcohol exposure has permanent effects on the brain structure, leading to functional deficits in several aspects of behavior, including learning and memory. Alcohol-induced neurocognitive impairment in offsprings is included with activation of oxidative- inflammatory cascade followed with wide apoptotic neurodegeneration in several brain areas, such as the hippocampus. Metformin is the first-line treatment for diabetic patients. It rapidly crosses the blood–brain barrier (BBB) and exerts antioxidant, anti-inflammatory, and neuroprotective effects. In this study, we evaluated the protective effects of metformin on ethanol-related neuroinflammation, as well as neuron apoptosis in the hippocampus of adult male rat in animal model of fetal alcohol spectrum disorders. Treatment with ethanol in milk solution (5.25 and 27.8 g/kg, respectively) was conducted by intragastric intubation at 2–10 days after birth. To examine the antioxidant and anti-inflammatory properties of metformin, an ELISA assay was performed for determining the tumor necrosis factor-α (TNF-α) and antioxidant enzyme concentrations. Immunohistochemical staining was conducted for evaluating the glial fibrillary acidic protein (GFAP) and cleaved caspase-3 expression. Based on the results, metformin caused a significant increase in the superoxide dismutase (SOD) (P < 0.05) and glutathione peroxidase (GSH-Px) (P < 0.01) activities. On the other hand, it reduced the concentrations of TNF-α and malondialdehyde, compared to the ethanol group (P < 0.01). In the metformin group, there was a reduction in cell apoptosis in the hippocampus, as well as GFAP-positive cells (P < 0.01). Overall, apoptotic signaling, regulated by the oxidative inflammatory cascade, can be suppressed by metformin in adult brain rats following animal model of fetal alcohol spectrum disorders.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  • Abd-Elsameea A, Moustaf A, Mohamed A (2014) Modulation of the oxidative stress by metformin in the cerebrum of rats exposed to global cerebral ischemia and ischemia/reperfusion. Eur Rev Med Pharmacol Sci 18:2387–2392

    CAS  PubMed  Google Scholar 

  • Adrian M, Barry SJ (2003) Physical and mental health problems associated with the use of alcohol and drugs. Subst Use Misuse 38:1575–1614

    PubMed  Article  Google Scholar 

  • Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res 5:536–543

    CAS  Article  Google Scholar 

  • Blanco AM, Pascual M, Valles SL, Guerri C (2004) Ethanol-induced iNOS and COX-2 expression in cultured astrocytes via NF-κB. NeuroReport 15:681–685

    CAS  PubMed  Article  Google Scholar 

  • Boschen KE, Ruggiero MJ, Klintsova AY (2016) Neonatal binge alcohol exposure increases microglial activation in the developing rat hippocampus. Neuroscience 324:355–366

    CAS  PubMed  Article  Google Scholar 

  • Brocardo PS, Gil-Mohapel J, Christie BR (2011) The role of oxidative stress in fetal alcohol spectrum disorders. Brain Res Rev 67:209–225

    CAS  PubMed  Article  Google Scholar 

  • Cahova M, Palenickova E, Dankova H, Sticova E, Burian M, Drahota Z, Cervinkova Z, Kucera O, Gladkova C, Stopka P (2015) Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. Am J Physiol Gastrointest Liver Physiol 309:G100–G111

    CAS  PubMed  Article  Google Scholar 

  • Chastain LG, Sarkar DK (2014) Role of microglia in regulation of ethanol neurotoxic action. Elsevier, International review of neurobiology

    Book  Google Scholar 

  • Chong ZZ, Li F, Maiese K (2005) Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 75:207–246

    CAS  PubMed  Article  Google Scholar 

  • Chu J, Tong M, Suzanne M (2007) Chronic ethanol exposure causes mitochondrial dysfunction and oxidative stress in immature central nervous system neurons. Acta Neuropathol 113:659–673

    CAS  PubMed  Article  Google Scholar 

  • Ehrhart F, Roozen S, Verbeek J, Koek G, Kok G, Van Kranen H, Evelo CT, Curfs LM (2019) Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders. Mol Psychiatry 24:10–17

    CAS  PubMed  Article  Google Scholar 

  • El-Ghaiesh SH, Bahr HI, Ibrahiem AT, Ghorab D, Alomar SY, Farag NE, Zaitone SA (2020) Metformin protects from rotenone–induced nigrostriatal neuronal death in adult mice by activating AMPK-FOXO3 signaling and mitigation of angiogenesis. Front Mol Neurosci 13:84

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Elibol B, Beker M, Sahbaz CD, Kilic U, Jakubowska-Doğru E (2019) Prenatal ethanol intoxication and maternal intubation stress alter cell survival and apoptosis in the postnatal development of rat hippocampus. Acta Neurobiol Exp (Wars) 79:133–147

    Google Scholar 

  • Erfani S, Moghimi A, Aboutaleb N, Khaksari M (2019) Protective effects of Nesfatin-1 peptide on cerebral ischemia reperfusion injury via inhibition of neuronal cell death and enhancement of antioxidant defenses. Metab Brain Dis 34:79–85

    CAS  PubMed  Article  Google Scholar 

  • Fang J, Yang J, Wu X, Zhang G, Li T, Wang XE, Zhang H, Wang CC, Liu GH, Wang L (2018) Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell 17:e12765

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Farhadi L, Hojati V, Khaksari M, Vaezi G (2022) Neuroprotective effects of crocin against ethanol neurotoxicity in the animal model of fetal alcohol spectrum disorders. Neurochem Res 1–11

  • Farr SA, Roesler E, Niehoff ML, Roby DA, Mckee A, Morley JE (2019) Metformin improves learning and memory in the SAMP8 mouse model of Alzheimer’s disease. J Alzheimers Dis 68:1699–1710

    CAS  PubMed  Article  Google Scholar 

  • Georgieff MK, Tran PV, Carlson ES (2018) Atypical fetal development: Fetal alcohol syndrome, nutritional deprivation, teratogens, and risk for neurodevelopmental disorders and psychopathology. Dev Psychopathol 30:1063–1086

    PubMed  PubMed Central  Article  Google Scholar 

  • Gerlach M, Ben-Shachar D, Riederer P, Youdim M (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases?. J Neurochem 63:793–807

    CAS  PubMed  Article  Google Scholar 

  • Ghamari F, Vaezi G, Khaksari M, Hojati V (2020) Nesfatin-1 ameliorate learning and memory deficit via inhibiting apoptosis and neuroinflammation following ethanol-induced neurotoxicity in early postnatal rats. Int J Pept Res Ther 1–10

  • Ghanbari F, Khaksari M, Vaezi G, Hojati V, Shiravi A (2019) Hydrogen sulfide protects hippocampal neurons against methamphetamine neurotoxicity via inhibition of apoptosis and neuroinflammation. J Mol Neurosci 67:133–141

    CAS  PubMed  Article  Google Scholar 

  • Goodlett CR, Horn KH (2001) Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res Health 25:175

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guerri C, Pascual M (2010) Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence. Alcohol 44:15–26

    CAS  PubMed  Article  Google Scholar 

  • Henriques JF, Portugal CC, Canedo T, Relvas JB, Summavielle T, Socodato R (2018) Microglia and alcohol meet at the crossroads: microglia as critical modulators of alcohol neurotoxicity. Toxicol Lett 283:21–31

    CAS  PubMed  Article  Google Scholar 

  • Kempuraj D, Thangavel R, Natteru P, Selvakumar G, Saeed D, Zahoor H, Zaheer S, Iyer S, Zaheer A (2016) Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine

  • Komada M, Hara N, Kawachi S, Kawachi K, Kagawa N, Nagao T, Ikeda Y (2017) Mechanisms underlying neuro-inflammation and neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to ethanol. Sci Rep 7:4934

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Li J, Benashski SE, Venna VR, Mccullough LD (2010) Effects of metformin in experimental stroke. Stroke 41:2645–2652

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Luecha T, Peremans L, Dilles T, Van Rompaey B (2019) The prevalence of alcohol consumption during early adolescence: a cross-sectional study in an eastern province, Thailand. Int J Adolesc Youth 24:160–176

    Article  Google Scholar 

  • Marino MD, Cronise K, Lugo JN Jr, Kelly SJ (2002) Ultrasonic vocalizations and maternal–infant interactions in a rat model of fetal alcohol syndrome. Dev Psychobiol 41:341–351

    PubMed  Article  Google Scholar 

  • Markowicz-Piasecka M, Sikora J, Szydłowska A, Skupień A, Mikiciuk-Olasik E, Huttunen KM (2017) Metformin–a future therapy for neurodegenerative diseases. Pharm Res 34:2614–2627

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Mohseni F, Bagheri F, Khaksari M (2020) Hydrogen sulfide attenuates the neurotoxicity in the animal model of fetal alcohol spectrum disorders. Neurotox Res 37:977–986

    CAS  PubMed  Article  Google Scholar 

  • Muralidharan P, Sarmah S, Zhou FC, Marrs JA (2013) Fetal alcohol spectrum disorder (FASD) associated neural defects: complex mechanisms and potential therapeutic targets. Brain Sci 3:964–991

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Oliveira WH, Nunes AK, França MER, Santos LA, Lós DB, Rocha SW, Barbosa KP, Rodrigues GB, Peixoto CA (2016) Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice. Brain Res 1644:149–160

    PubMed  Article  CAS  Google Scholar 

  • Pasbakhsh P, Saeednia S, Abolhassani F, Khansari G, Sobhani A (2008) Melatonin prevents ischemia-reperfusion injury following superior mesenteric artery occlusion in the rat. J Neurol Neurosurg Spine 16:95–101

    CAS  Google Scholar 

  • Pascual M, Blanco AM, Cauli O, Miñarro J, Guerri C (2007) Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci 25:541–550

    PubMed  Article  Google Scholar 

  • Patil S, Jain P, Ghumatkar P, Tambe R, Sathaye S (2014) Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience 277:747–754

    CAS  PubMed  Article  Google Scholar 

  • Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427–434

    PubMed  Article  Google Scholar 

  • Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38

    CAS  PubMed  Article  Google Scholar 

  • Ramanathan M, Jaiswal AK, Bhattacharya S (1999) Superoxide dismutase, catalase and glutathione peroxidase activities in the brain of streptozotocin induced diabetic rats

  • Rasmussen C (2005) Executive functioning and working memory in fetal alcohol spectrum disorder. Alcohol Clin Exp Res 29:1359–1367

    PubMed  Article  Google Scholar 

  • Riley EP, McGee CL (2005) Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior. Exp Biol Med 230:357–365

    CAS  Article  Google Scholar 

  • Saito M, Chakraborty G, Hui M, Masiello K, Saito M (2016) Ethanol-induced neurodegeneration and glial activation in the developing brain. Brain Sci 6:31

    PubMed Central  Article  CAS  Google Scholar 

  • Sanadgol N, Barati M, Houshmand F, Hassani S, Clarner T, Golab F (2020) Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period. Pharmacol Rep 72:641–658

    CAS  PubMed  Article  Google Scholar 

  • Scarpello JH, Howlett HC (2008) Metformin therapy and clinical uses. Diab Vasc Dis Res 5:157–167

    PubMed  Article  Google Scholar 

  • Shah SA, Yoon GH, Kim MO (2015) Protection of the developing brain with anthocyanins against ethanol-induced oxidative stress and neurodegeneration. Mol Neurobiol 51:1278–1291

    CAS  PubMed  Article  Google Scholar 

  • Soleimani E, Goudarzi I, Abrari K, Lashkarbolouki T (2016) The combined effects of developmental lead and ethanol exposure on hippocampus dependent spatial learning and memory in rats: role of oxidative stress. Food Chem Toxicol 96:263–272

    CAS  PubMed  Article  Google Scholar 

  • Song WM, Colonna M (2018) The identity and function of microglia in neurodegeneration. Nat Immunol 19:1048–1058

    CAS  PubMed  Article  Google Scholar 

  • Stephenson J, Nutma E, Van Der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154:204–219

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Swart PC, Currin CB, Russell VA, Dimatelis JJ (2017) Early ethanol exposure and vinpocetine treatment alter learning-and memory-related proteins in the rat hippocampus and prefrontal cortex. J Neurosci Res 95:1204–1215

    CAS  PubMed  Article  Google Scholar 

  • Tao L, Li D, Liu H, Jiang F, Xu Y, Cao Y, Gao R, Chen G (2018) Neuroprotective effects of metformin on traumatic brain injury in rats associated with NF-κB and MAPK signaling pathway. Brain Res Bull 140:154–161

    CAS  PubMed  Article  Google Scholar 

  • Tiwari V, Chopra K (2012) Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol. Psychopharmacology 224:519–535

    CAS  PubMed  Article  Google Scholar 

  • Toosi A, Shajiee H, Khaksari M, Vaezi G, Hojati V (2019) Obestatin improve spatial memory impairment in a rat model of fetal alcohol spectrum disorders via inhibiting apoptosis and neuroinflammation. Neuropeptides

  • Tran TD, Kelly SJ (2003) Critical periods for ethanol-induced cell loss in the hippocampal formation. Neurotoxicol Teratol 25:519–528

    CAS  PubMed  Article  Google Scholar 

  • Vallés SL, Blanco AM, Pascual M, Guerri C (2004) Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 14:365–371

    PubMed  Article  Google Scholar 

  • West JR, Hamre KM, Pierce DR (1984) Delay in brain growth induced by alcohol in artificially reared rat pups. Alcohol 1:213–222

    CAS  PubMed  Article  Google Scholar 

  • Yang D, Elner SG, Bian Z-M, Till GO, Petty HR, Elner VM (2007) Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res 85:462–472

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Zare Mehrjerdi F, Shoshtari A, Mohseni F, Khastar H, Norozi P, Asadi Y, Dadkhah M, Khaksari M (2018) Sulfur dioxide reduces hippocampal cells death and improves learning and memory deficits in rat model of transient global ischemia/reperfusion. Iran J Basic Med Sci 21:998–1003

    PubMed  PubMed Central  Google Scholar 

  • Zhao R-R, Xu X-C, Xu F, Zhang W-L, Zhang W-L, Liu L-M, Wang W-P (2014) Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem Biophys Res Commun 448:414–417

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This paper was extracted as a part of Maryam Sabzali Ph.D. thesis. The authors are very thankful to Pirasteh Norozi, for kind and helpful collaborations.

Author information

Authors and Affiliations

  1. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Maryam Sabzali & Akram Eidi

  2. Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran

    Mehdi Khaksari & Hossein Khastar

Authors
  1. Maryam Sabzali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akram Eidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehdi Khaksari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hossein Khastar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mehdi Khaksari.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sabzali, M., Eidi, A., Khaksari, M. et al. Anti-inflammatory, Antioxidant, and Antiapoptotic Action of Metformin Attenuates Ethanol Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders. Neurotox Res 40, 605–613 (2022). https://doi.org/10.1007/s12640-022-00499-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-022-00499-2

Keywords

  • Metformin
  • Ethanol neurotoxicity
  • Apoptosis
  • Neuroinflammation