Therapeutic Effect of Metformin on Necrotic Cell Death of Hippocampal Cells and Improvement of Spatial Memory in the Fetal Rat of Model Alcohol Spectrum Disorders

Subject Areas : Journal of Animal Biology

Maryam Sabzali ¹ (Department of Biology, Islamic Azad University, Science & Research Institute, Tehran, Iran)
Akram Eidi ² (Department of Biology, Islamic Azad University, Science & Research Institute, Tehran, Iran)
Mahdi Khaksari ³ (Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran)
Hossin Khastar ⁴ (Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran)

Received: 2021-06-16 Accepted : 2021-08-03 Published : 2022-05-22

Keywords: ethanol, Hippocampus, Metformin, spatial memory, Necrosis,

Abstract :

Exposure to alcohol during pregnancy causes a wide range of long-term physiological and behavioral effects, collectively referred to as fetal alcohol syndrome (FASD). Nervous disorders due to alcohol abuse in children with apoptosis in several areas of the brain such as the hippocampus is associated with activation of the oxidative-inflammatory cascade and high levels of nerve degeneration. Studies have shown that metformin (1,1-dimethyl hydrochloride), used as a first-line drug for the treatment of type 2 diabetes, can rapidly cross the blood-brain barrier (BBB) ​​and have neuroprotective effects in several diseases of the nervous system. The aim of this study was to assess the protective activities of metformin on memory impairment and neuronal necrosis in the rat hippocampus by postnatal alcohol exposure received by gavage on days 2-10 after birth. Moreover, infants received 20 and 40 mg/kg of metformin on days 2-10 after birth. To assess spatial memory, the Morris water maze test was performed 36 days after birth. After the behavioral test, nickel staining was performed to assess necrotic cells. The results revealed that metformin treatment could significantly improve spatial memory impairment (P <0.01) and significantly reduced necrotic neurons in the metformin treatment group compared to the ethanol group (P <0.01). Metformin has been shown to improve spatial memory impairment in neonatal rats exposed to ethanol and significantly prevent necrotic death of hippocampal neurons.

References:

1. Ashabi G., Khalaj L., Khodagholi F., Goudarzvand M., Sarkaki A. 2015. Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metabolic Brain Disease, 30(3): 747-754.


2. Association A. 2020. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes. Diabetes Care, 43: S98-S110.


3. Bellinger F.P., Bedi K.S., Wilson P., Wilce P.A. 1999. Ethanol exposure during the third trimester equivalent results in long‐lasting decreased synaptic efficacy but not plasticity in the CA1 region of the rat hippocampus. Synapse, 31(1):51-8.


4. Chen F., Dong R.R., Zhong K.L., Ghosh A., Tang S.S., Long Y. 2016. Antidiabetic drugs restore abnormal transport of amyloid-β across the blood–brain barrier and memory impairment in db/db mice. Neuropharmacology, 101: 123-136.


5. D’Arcy M.S. 2019. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell biology international, 43(6): 582-592.


6. De Gruyter S. 2013. Teratogenität des Alkohols. Walter de Gruyter GmbH: Berlin, Germany.


7. Elmore S. 2007. Apoptosis: a review of programmed cell death. Toxicologic pathology,35(4):495-516.


8. Giglia R, Binns C. 2006. Alcohol and lactation: a systematic review. Nutrition & Dietetics,63(2):103-16.


9. Guo Y., Wang F., Li H., Liang H., Li Y., Gao Z. 2018. Metformin protects against spinal cord injury by regulating autophagy via the mTOR signaling pathway. Neurochemical Research, 43(5): 1111-1117.


10. Hamilton D.A., Kodituwakku P., Sutherland R.J., Savage D.D. 2003. Children with Fetal Alcohol Syndrome are impaired at place learning but not cued-navigation in a virtual Morris water task. Behavioural Brain Research, 143(1): 85-94.


11. Hamilton G., Hernandez I., Krebs C., Bucko P., Rhodes J. 2017. Neonatal alcohol exposure reduces number of parvalbumin-positive interneurons in the medial prefrontal cortex and impairs passive avoidance acquisition in mice deficits not rescued from exercise. Neuroscience, 352: 52-63.


12. Jacobson S.W., Hoyme H.E., Carter R.C., Dodge N.C., Molteno C.D., Meintjes E.M. 2020. Evolution of the Physical Phenotype of Fetal Alcohol Spectrum Disorders from Childhood through Adolescence. Alcoholism: Clinical and Experimental Research, 45(2): 395-408.


13. Kaminen‐Ahola N. 2021. Fetal alcohol spectrum disorders: Genetic and epigenetic mechanisms. Prenatal Diagnosis, 40(9): 1185-1192.


14. Kane C.J., Drew P.D. 2021. Neuroinflammatory contribution of microglia and astrocytes in fetal alcohol spectrum disorders. Journal of Neuroscience Research, 99(8): 1973-1985.


15. Kelly SJ, Goodlett CR, Hannigan JH. 2009. Animal models of fetal alcohol spectrum disorders: impact of the social environment. Developmental Disabilities Research Reviews, 15(3): 200-208.


16. Kosnicki K.L., Penprase J.C., Cintora P., Torres P.J., Harris G.L., Brasser S.M. 2019. Effects of moderate, voluntary ethanol consumption on the rat and human gut microbiome. Addiction Biology, 24(4): 617-30.


17. Livy D., Miller E.K., Maier S.E., West J.R. 2003. Fetal alcohol exposure and temporal vulnerability: effects of binge-like alcohol exposure on the developing rat hippocampus. Neurotoxicology and Teratology, 25(4): 447-458.


18. Malisza K.L., Allman A.A., Shiloff D., Jakobson L., Longstaffe S., Chudley A.E. 2005. Evaluation of spatial working memory function in children and adults with fetal alcohol spectrum disorders: a functional magnetic resonance imaging study. Pediatric Research, 58(6): 1150-1157.


19. May P.A., Chambers C.D., Kalberg W.O., Zellner J., Feldman H., Buckley D. 2018. Prevalence of fetal alcohol spectrum disorders in 4 US communities. Jama, 319(5): 474-482.


20. Mohseni F., Bagheri F., Khaksari M. 2020. Hydrogen sulfide attenuates the neurotoxicity in the animal model of fetal alcohol spectrum disorders. Neurotoxicity Research, 37(4): 977-986.


21. Mohseni F., Bagheri F., Rafaiee R., Norozi P., Khaksari M. 2020. Hydrogen sulfide improves spatial memory impairment via increases of BDNF expression and hippocampal neurogenesis following early postnatal alcohol exposure. Physiology and Behavior, 215:112784.


22. Novick Brown N., Connor P.D., Adler R.S. 2012. Conduct-disordered adolescents with fetal alcohol spectrum disorder: Intervention in secure treatment settings. Criminal Justice and Behavior, 39(6):770-793.


23. Ortiz J.B., Conrad C.D. 2018. The impact from the aftermath of chronic stress on hippocampal structure and function: Is there a recovery? Frontiers in Neuroendocrinology, 49: 114-123.


24. Raju M., Kulkarni Y.A., Wairkar S. 2019. Therapeutic potential and recent delivery systems of berberine: A wonder molecule. Journal of Functional Foods, 61: 103517.


25. Rehman S.U., Ikram M., Ullah N., Alam S.I., Park H.Y., Badshah H. 2019. Neurological enhancement effects of melatonin against brain injury-induced oxidative stress, neuroinflammation, and neurodegeneration via AMPK/CREB signaling. Cells, 8(7): 760.


26. Rodriguez C.I.., Vergara V.M., Davies S., Calhoun V.D., Savage D.D., Hamilton D.A. 2021. Detection of prenatal alcohol exposure using machine learning classification of resting-state functional network connectivity data. Alcohol, 93: 25-34.


27. Shankar K., Ronis M.J., Badger T.M. 2007. Effects of pregnancy and nutritional status on alcohol metabolism. Alcohol Research and Health, 30(1): 55.


28. Shi Q., Liu S., Fonseca V.A., Thethi T.K., Shi L. 2019. Effect of metformin on neurodegenerative disease among elderly adult US veterans with type 2 diabetes mellitus. BMJ Open, 9(7): e024954.


29. Takata F., Dohgu S., Matsumoto J., Machida T., Kaneshima S., Matsuo M. 2013. Metformin induces up-regulation of blood–brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells. Biochemical and Biophysical Research Communications, 433(4): 586-590.


30. 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,74: 88-94.


31. Uecker A., Nadel L. 1996. Spatial locations gone awry: object and spatial memory deficits in children with fetal alcohol syndrome. Neuropsychologia, 34(3): 209-223.


32. Wang Y., Wei J., Li L., Fan C., Sun Y. 2015. Combined use of metformin and everolimus is synergistic in the treatment of breast cancer cells. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, 22(4): 193-201.


33. Wechsler D., Kodama H. 1949. Wechsler intelligence scale for children: Psychological corporation New York.


34. Zhao M., Cheng X., Lin X., Han Y., Zhou Y., Zhao T. 2019. Metformin administration prevents memory impairment induced by hypobaric hypoxia in rats. Behavioral Brain Research, 363:30-7.


35. Zhong S., Ding W., Sun L., Lu Y., Dong H., Fan X. 2020. Decoding the development of the human hippocampus. Nature, 577(7791): 531-536.


36. Zhu J., Liu K., Huang K., Gu Y., Hu Y., Pan S. 2018. Metformin improves neurologic outcome via amp‐activated protein kinase–mediated autophagy activation in a rat model of cardiac arrest and resuscitation. Journal of the American Heart Association, 7(12): e008389.