اثر درمانی متفورمین بر مرگ سلولی نکروتیک سلول های هیپوکمپ و بهبود اختلال حافظه فضایی در موش صحرایی نر مدل سندرم جنین الکلی

نوع مقاله : مقاله پژوهشی

نویسندگان

1 گروه زیست شناسی ، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران

2 مرکز تحقیقات اعتیاد، دانشگاه علوم پزشکی شاهرود، شاهرود، ایران

چکیده

مواجهه با الکل در دوران جنینی سبب طیف گسترده­ای از آثار فیزیولوژیکی و رفتاری طولانی مدت می­شود که در مجموع اختلال سندرم جنین الکلی (FASD) نامیده می­شود.اختلالات عصبی ناشی از سوء مصرف الکل در کودکان با آپوپتوز در چندین منطقه از مغز مانند هیپوکامپ که به دنبال فعال شدن آبشار اکسیداتیو- التهابی و سطح بالای دژنراسیون عصبی رخ می­دهد مرتبط است. مطالعات نشان دادند که متفورمین (1،1- دی­متیل هیدروکلراید) که به عنوان داروی خط اول برای درمان دیابت نوع 2 استفاده می­شود می­تواند به سرعت از سد خونی مغزی عبور کرده و آثار نوروپروتکتیو آن در چندین بیماری سیستم عصبی مورد تأیید قرار گرفته است. این پژوهش با هدف ارزیابی فعالیت­های محافظتی متفورمین بر روی اختلالات حافظه و نکروز سلول­های عصبی در هیپوکامپ موش صحرایی با قرار گرفتن در معرض الکل پس از تولد انجام شد.نوزادان نر موش صحرایی 5.27 گرم در کیلوگرم اتانول محلول در 8.27 میلی­لیتر بر کیلوگرم شیر خشک را از طریق گاواژ در روزهای 10-2 بعد از تولد دریافت کردند .نوزادان همچنین 20 و 40 میلی­گرم بر کیلوگرم متفورمین را در روزهای 10-2 بعد از تولد دریافت کردند. برای بررسی حافظه فضایی ، آزمایش ماز آبی موریس 36 روز پس از تولد انجام شد. پس از آزمون رفتاری ، رنگ­آمیزی نیسل برای ارزیابی سلولهای دچار نکروز انجام شد. نتایج بیانگر این است که درمان با متفورمین می­تواند به طور قابل توجهی اختلال در حافظه مکانی را بهبود بخشد (01/0 p <) و همچنین کاهش معنی­دار نورون­های دچار نکروز در گروه درمان با متفورمین در مقایسه با گروه اتانول شد (01/0 p <). بر اساس یافته­ها، متفورمین سبب بهبود اختلال در حافظه فضایی در نوزادان موش قرار گرفته در معرض اتانول می­شود و از مرگ نکروتیک نورون­های هیپوکمپ به طور قابل توجهی جلوگیری می­نماید.

کلیدواژه‌ها

عنوان مقاله [English]

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

نویسندگان [English]

  • Maryam Sabzali 1
  • Akram Eidi 1
  • Mahdi Khaksari 2
  • Hossin Khastar 2
1 Department of Biology, Islamic Azad University, Science & Research Institute, Tehran, Iran
2 Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
چکیده [English]

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.

کلیدواژه‌ها [English]

  • Metformin
  • ethanol
  • spatial memory
  • Necrosis
  • Hippocampus

مراجع

  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.

 

فصلنامه زیست شناسی جانوری
دوره 14، شماره 3
فروردین 1401
صفحه 207-220

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