The Effect of Chlordiazepoxide Consumption on the Hippocampus of Neonatal Rats During Pregnancy

Authors

  • Mehrdad Hashemi Department of Genetics, Faculty of advanced sciences and technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
  • Amin Dinarvand Department of Genetics, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
  • Rasoul Dinarvand Department of Pharmacy, Faculty of Pharmacy, Tehran Medical Sciences University, Tehran, Iran
  • Shabnam Movassaghi Department of Anatomy, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
  • Mojtaba Jafarinia Department of Genetics, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran

DOI:

https://doi.org/10.31661/gmj.v11i.2283

Keywords:

Apoptosis, Pregnancy, Chlordiazepoxide, Anti-Apoptotic, Pro-Apoptotic

Abstract

Background: Chlordiazepoxide is an anti-anxiety drug commonly used by young people and pregnant women to reduce anxiety. The adverse effects of this drug on cholinergic nervous system function have been demonstrated. Therefore, in this study, the effect of chlordiazepoxide consumption during pregnancy was evaluated on the rats infant hippocampus. Materials and Methods: Nine pregnant Wistar rats were randomly divided (n=3 per group) into control, experimental (daily intraperitoneal injection of chlordiazepoxide at a dose of 10 mg/kg for 21 days), and vehicle (same amount of normal saline) groups. Two weeks after birth, the neonate brains were removed from the skull and prepared for Nissl and TUNEL stainings. The expressions of pro- and anti-apoptotic genes were evaluated. Results: The number of healthy neurons in different areas of the neonatal hippocampus in the experimental group was significantly reduced compared to control and vehicle groups, and the number of apoptotic bodies was increased (P<0.05). However, there was no significant difference between the numbers of these cells in the control and vehicle groups. The expression of pro-apoptotic genes in the experimental group increased significantly compared to the control group instead of the expression of anti-apoptotic genes decreased significantly. Conclusion: Chlordiazepoxide during pregnancy can cause neuronal damage in the hippocampus of neonatal Wistar rats.

References

Alvarez JA, Emory E. Executive function and the frontal lobes: a meta-analytic review. Neuropsychology Review. 2006;16(1):17-42. https://doi.org/10.1007/s11065-006-9002-xPMid:16794878 Glykys J, Staley KJ. Diazepam effect during early neonatal development correlates with neuronal Cl(.). Ann Clin Transl Neurol. 2015;2(12):1055-70. https://doi.org/10.1002/acn3.259PMid:26734658 PMCid:PMC4693588 Kellogg CK. Benzodiazepines: influence on the developing brain. Prog Brain Res. 1988;73:207-28. https://doi.org/10.1016/S0079-6123(08)60506-3PMid:2843947 Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005;30(9):1649-61. https://doi.org/10.1038/sj.npp.1300710PMid:15756305 Kanto JH. Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations. Drugs. 1982;23(5):354-80. https://doi.org/10.2165/00003495-198223050-00002PMid:6124415 Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26(30):7870-4. https://doi.org/10.1523/JNEUROSCI.1184-06.2006PMid:16870732 PMCid:PMC6674229 Cecil KM, Brubaker CJ, Adler CM, Dietrich KN, Altaye M, Egelhoff JC, et al. Decreased brain volume in adults with childhood lead exposure. PLoS Med. 2008;5(5):e112. https://doi.org/10.1371/journal.pmed.0050112PMid:18507499 PMCid:PMC2689675 Iqbal MM, Aneja A, Fremont WP. Effects of chlordiazepoxide (Librium) during pregnancy and lactation. Conn Med. 2003;67(5):259-62. Gazitt Y, Rothenberg ML, Hilsenbeck SG, Fey V, Thomas C, Montegomrey W. Bcl-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells. Int J Oncol. 1998;13(4):839-48. https://doi.org/10.3892/ijo.13.4.839PMid:9735415 Gazitt Y, Fey V, Thomas C, Alvarez R. Bcl-2 overexpression is associated with resistance to dexamethasone, but not melphalan, in multiple myeloma cells. Int J Oncol. 1998;13(2):397-405. https://doi.org/10.3892/ijo.13.2.397PMid:9664139 Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;281(5381):1322-6. https://doi.org/10.1126/science.281.5381.1322PMid:9735050 Yadollah-Damavandi S, Sharifi ZN, Arani HZ, Jangholi E, Karimi A, Parsa Y, Movassaghi S. Atorvastatin Prevents the Neuron Loss in the Hippocampal Dentate Gyrus Region through its Anti-Oxidant and Anti-Apoptotic Activities. CNS Neurol Disord Drug Targets. 2021;20(1):76-86. https://doi.org/10.2174/1871527319666200922160627PMid:32962624 Armstrong C. ACOG guidelines on psychiatric medication use during pregnancy and lactation. American Family Physician. 2008;78(6):772. Buttar HS. Effects of chlordiazepoxide on the pre- and postnatal development of rats. Toxicology. 1980;17(3):311-21. https://doi.org/10.1016/0300-483X(80)90012-8PMid:7210016 Hodges JR. The hypothalamus and pituitary ACTH release. Prog Brain Res. 1970;32:12-20. https://doi.org/10.1016/S0079-6123(08)61514-9PMid:4321514 Cirulli F, Santucci D, Laviola G, Alleva E, Levine S. Behavioral and hormonal responses to stress in the newborn mouse: effects of maternal deprivation and chlordiazepoxide. Dev Psychobiol. 1994;27(5):301-16. https://doi.org/10.1002/dev.420270505PMid:7926282 Bellantuono C, Tofani S, Di Sciascio G, Santone G. Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. Gen Hosp Psychiatry. 2013;35(1):3-8. https://doi.org/10.1016/j.genhosppsych.2012.09.003PMid:23044244 Mountz JD, Wu J, Cheng J, Zhou T. Autoimmune disease. A problem of defective apoptosis. Arthritis Rheum. 1994;37(10):1415-20. https://doi.org/10.1002/art.1780371002PMid:7524507 Thatte U, Dahanukar S. Apoptosis: clinical relevance and pharmacological manipulation. Drugs. 1997;54(4):511-32. https://doi.org/10.2165/00003495-199754040-00002PMid:9339959 Hongmei Z. Extrinsic and intrinsic apoptosis signal pathway review. In Apoptosis and medicine. TechOpen; 2012. https://doi.org/10.5772/50129PMCid:PMC3705112 Choi DW, Farb DH, Fischbach GD. Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature. 1977;269(5626):342-4. https://doi.org/10.1038/269342a0PMid:561893 Katzung BG, Masters SB, Trevor AJ, editors. Basic & clinical pharmacology. New York: McGraw-Hill Lange; 2015. Zhang F, Li C, Wang R, Han D, Zhang QG, Zhou C, et al. Activation of GABA receptors attenuates neuronal apoptosis through inhibiting the tyrosine phosphorylation of NR2A by Src after cerebral ischemia and reperfusion. Neuroscience. 2007;150(4):938-49. https://doi.org/10.1016/j.neuroscience.2007.09.070PMid:18022328 Hartz SC, Heinonen OP, Shapiro S, Siskind V, Slone D. Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality. N Engl J Med. 1975;292(14):726-8. https://doi.org/10.1056/NEJM197504032921405PMid:1113782 Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9(1):47-59. https://doi.org/10.1038/nrm2308PMid:18097445

Downloads

Published

2022-12-13

Issue

Vol. 11 (2022): 2022

Section

Original Article

License

https://creativecommons.org/licenses/by/4.0/