Prenatal treatment with metronidazole induces cerebellar folia alteration in guinea pig fetuses

Authors

  • Ivan Đ. Čapo 1. Department of Histology and Embryology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad; 2. Center for Medical and Pharmaceutical Investigations and Quality Control, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad http://orcid.org/0000-0001-7531-5099
  • Ivan J. Milenković Department of Neurology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna https://orcid.org/0000-0001-7531-5099
  • Nataša P. Čapo 1. Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad; 2. Oncology Institute of Vojvodina, Put doktora Goldmana, 21204 Sremska Kamenica https://orcid.org/0000-0001-7547-222X
  • Nebojša P. Stilinović Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad https://orcid.org/0000-0003-0118-9418
  • Saša N. Vukmirović Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad https://orcid.org/0000-0002-3271-4492
  • Branislava D. Teofilović Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad https://orcid.org/0000-0002-0917-3974
  • Branka B. Petković Department of Neurophysiology, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade https://orcid.org/0000-0001-7817-4092
  • Slobodan R. Sekulić Department of Neurology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad https://orcid.org/0000-0001-7889-310X

DOI:

https://doi.org/10.2298/ABS200619041C

Keywords:

metronidazole, neurotoxicity, neuronal migration, cerebellum, foliation

Abstract

Paper description:

  • The neurotoxic side effect of metronidazole in therapy of adults is established but there is insufficient data about the prenatal consequences of metronidazole treatment.
  • Pathohistological techniques were used to study the effect of metronidazole on guinea pig fetuses.
  • Metronidazole caused cell depletion in proliferative zones of the cerebellum and decrease of the areal fraction value in all cortical layers, as well as intensive folia alteration.
  • The presented results question the use of metronidazole during pregnancy.

Abstract: The most sensitive period in brain development is during prenatal life. The use of antibiotics in pregnancy is still controversial. Recent studies revealed the high neurotoxic potential of the antibiotic and antiprotozoal medication, metronidazole. However, there are insufficient data from animal studies about prenatal treatment effects. We investigated the effect of prenatal treatment with metronidazole on cerebellar development in guinea pigs. Treatment with metronidazole was performed from the 42nd to the 49th day of gestation. On the 50th day of pregnancy, all dams were killed, and the cerebella of the fetuses were analyzed. Gross cerebellar changes characterized by malposition of the folia with partial atrophy were found in 12 of 19 fetuses in the experimental group, but in none of 20 control fetuses that received saline. The most affected were folia VII with depletion of the areal fraction of the external granular layer, molecular layer and the internal granular layer. Purkinje cells displayed cell distortion with loss of normal dendritic polarity. The investigation revealed cell depletion, with a disturbance of the cytoarchitectonic of the cerebellar cortex and folia alteration.

Downloads

Download data is not yet available.

References

Rakic P. Neuron-glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electronmicroscopic study in Macacus Rhesus. J Comp Neurol. 1971;141(3):283-312.

Hillman DE, Chen S, Ackman J. Perinatal methylazoxymethanol acetate uncouples coincidence of orientation of cerebellar folia and parallel fibers. Neuroscience. 1988;24(1):99-110.

Chen S, Hillman DE. Developmental factors related to abnormal cerebellar foliation induced by methylazoxymethanol acetate (MAM). Brain Res. 1988;468(2):201-12.

Ohmori H, Ogura H, Yasuda M, Nakamura S, Hatta T, Kawano K, Michikawa T, Yamashita K, Mikoshiba K. Developmental neurotoxicity of phenytoin on granule cells and Purkinje cells in mouse cerebellum. J Neurochem. 1999;72(4):1497-506.

Mathisen GH, Yazdani M, Rakkestad KE, Aden PK, Bodin J, Samuelsen M, Nygaard UC, Goverud IL, Gaarder M, Løberg EM, Bølling AK, Becher R, Paulsen RE. Prenatal exposure to bisphenol A interferes with the development of cerebellar granule neurons in mice and chicken. Int J Dev Neurosci. 2013;31(8):762-9.

Altman J, Anderson WJ. Irradiation of the cerebellum in infant rats with low-level x-ray: histological and cytological effects during infancy and adulthood. Exp Neurol. 1971;30(3):492-509.

Čapo I, Hinić N, Lalošević D, Vučković N, Stilinović N, Marković J, Sekulić S. Vitamin C depletion in prenatal guinea pigs as a model of lissencephaly type II. Vet Pathol. 2015;52(6):1263-71.

Tolcos M, McDougall A, Shields A, Chung Y, O'Dowd R, Turnley A, Wallace M, Rees S. Intrauterine growth restriction affects cerebellar granule cells in the developing guinea pig brain. Dev Neurosci. 2018;40(2):162-74.

Gerald GB, Roger KF, Sumner JY. Drugs in pregnancy and lactation. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. 573p

Freeman CD, Klutman NE, Lamp KC. Metronidazole: a therapeutic review and update. Drugs. 1997;54(6):679-708.

Kuriyama A, Jackson JL, Doi A, Kamiya T. Metronidazole-induced central nervous system toxicity: a systematic review. Clin Neuropharmacol. 2011;34(6):241-7.

Bhattacharyya S, Darby RR, Raibagkar P, Gonzalez Castro LN, Berkowitz AL. Antibiotic-associated encephalopathy. Neurology. 2016;86(22):2116-26.

Giknis ML, Damjanov I. The transplacental effects of ethanol and metronidazole in Swiss Webster mice. Toxicol Lett. 1983;19(1-2):37-42.

Tiboni GM, Marotta F, Castigliego AP. Teratogenic effects in mouse fetuses subjected to the concurrent in utero exposure to miconazole and metronidazole. Reprod Toxicol. 2008;26(3-4):254-61.

Lossi L, Coli A, Giannessi E, Stornelli MR, Marroni P. Cell proliferation and apoptosis during histogenesis of the guinea pig and rabbit cerebellar cortex. Ital J Anat Embryol. 2002;107(2):117-25.

Dobbing J, Sands J. Growth and development of the brain and spinal cord of the guinea pig. Brain Res. 1970;17(1):115-23.

de Oliveira e Silva FM, Alcantara D, Carvalho RC, Oliveira Favaron P, Dos Santos AC, Viana DC, Miglino MA. Development of the central nervous system in guinea pig (Cavia porcellus, Rodentia, Caviidae). Pesq Vet Bras. 2016;36(8):753-60.

Altman J. Autoradiographic and histological studies of postnatal neurogenesis, 3: dating the time of production and onset of differentiation of cerebellar microneurons in rats. J Comp Neurol. 1969;136(3):269-93.

Morrison JL, Botting KJ, Darby JRT, David AL, Dyson RM, Gatford KL, Gray C, Herrera EA, Hirst JJ, Kim B, Kind LK, Krause JB, Matthews GS, Palliser KH, Regnault RHT, Richardson SB, Sasaki A, Thompson PL, Berry JM. Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic. J Physiol. 2018;596(23):5535-69.

Rood JP, Weir BJ. Reproduction in female wild guinea-pigs. J Reprod Fertil. 1970;23(3):393-409.

Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers [internet]. Rockville: Department of Health and Human Services, Food and Drug Administration; 2005 July [cited 2005 06 07]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078932.pdf.

Tomás M, Palmeira de Oliveira A, Simões S, Martinez-de-Oliveira J, Palmeira de Oliveira R. Bacterial vaginosis: standard treatments and alternative strategies. Int J Pharm. 2020;587:119659.

Tavakoli N, Varshosaz J, Dorkoosh F, Zargarzadeh MR. Development and validation of a simple HPLC method for simultaneous in vitro determination of amoxicillin and metronidazole at single wavelength. J Pharm Biomed Anal. 2007;43(1):325‐29.

Larsell O. The morphogenesis and adult pattern of the lobules and fissures of the cerebellum of the white rat. J Comp Neurol. 1952;97(2):281-356.

Sidman RL, Rakic P. Neuronal migration, with special reference to developing human brain: a review. Brain Res. 1973;62:1-35.

Rakic P. Principles of neuronal cell migration. Experientia. 1990;46:882-91.

Hatten ME. Central nervous system neuronal migration. Annu.Rev.Neurosci. 1999;22:511-39.

Miller MW. Effects of alcohol on generation and migration of cerebral cortex neurons. Science. 1986;233:1308-11.

Mehl A, Schanke TM, Torvik A, Fonnum F. The effect of trichlorfon and methylazoxymethanol on the development of guinea pig cerebellum. Toxicol Appl Pharmacol. 2007;219(2-3):128-35.

Uher BF, Golden JA. Neuronal migration defects of the cerebral cortex: a destination debacle. Clin Genet. 2000;58:16-24.

Flint AC, Kriegstein AR. Mechanisms underlying neuronal migration disorders and epilepsy. Curr Opin Neurol. 1997;10:92-7.

McIntosh GH, Baghurst KI, Potter BJ, Hetzel BS. Foetal brain development in the sheep. Neuropathol Appl Neurobiol. 1979;5:103-14.

Cosar C, Julou L. The activity of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (R. P. 8823) against experimental Trichomonas vaginalis infections. Ann Inst Pasteur (Paris). 1959;96(2):238-41.

Holden JM, Itil TM, Keskiner A. The effects of metronidazole on schizophrenic psychopathology. J Clin Pharmacol J New Drugs. 1968;8(5):333-41.

Itil TM, Holden JM, Keskiner A, Shapiro D. Central effects of metronidazole. Psychiatr Res Rep Am Psychiatr Assoc. 1968;24:148-65.

von Rogulja P, Kovac W, Schmid H. Metronidazole encephalopathy in rats. Acta Neuropathol (Berl). 1973;25:36-45.

Scharer K. Selective injury to Purkinje cells in the dog after oral administration of high doses of nitroimidazole derivates. Verh Dtsch Ges Pathol. 1972;56:407-10.

Giknis ML, Damjanov I. The transplacental effects of ethanol and metronidazole in Swiss Webster mice. Toxicol Lett. 1983;19(1-2):37-42.

Tiboni GM, Marotta F, Castigliego AP. Teratogenic effects in mouse fetuses subjected to the concurrent in utero exposure to miconazole and metronidazole. Reprod Toxicol. 2008;26(3-4):254-61.

Altman J, Bayer SA. Development of the cerebellar system in relation to its evolution, structure, and functions. 1st ed. New York: CRC Press; 1997. p. 39-43.

Schwartz PM, Borghesani PR, Levy RL, Pomeroy SL, Segal RA. Abnormal cerebellar development and foliation in BDNF-/- mice reveals a role for neurotrophins in CNS patterning. Neuron. 1997;19(2):269-81.

Rokni D, Llinas R, Yarom Y. The morpho/functional discrepancy in the cerebellar cortex: Looks alone are deceptive. Front Neurosci. 2008;2(2):192-8.

Volpe JJ. Cerebellum of the premature infant: Rapidly developing, vulnerable, clinically important. J Child Neurol. 2009;24:1085-104.

Lejeune E, Dortdivanlioglu B, Kuhl E, Linder C. Understanding the mechanical link between oriented cell division and cerebellar morphogenesis. Soft Matter. 2019;15(10):2204-15.

Altman J. Experimental reorganization of the cerebellar cortex. IV. Parallel fiber reorientation following regeneration of the external germinal layer. J Comp Neurol. 1973;149(2):181-92.

Wright KH, Tyler JW. Recognizing metronidazole toxicosis in dogs. Vet Med. 2003;98:410-8.

Bradley WG, Karlsson IJ, Rassol CG. Metronidazole neuropathy. BMJ. 1977;2:610-1.

Xiao Y, Xiong T, Meng X, Yu D, Xiao Z, Song L. Different influences on mitochondrial function, oxidative stress and cytotoxicity of antibiotics on primary human neuron and cell lines. J Biochem Mol Toxicol. 2019;33(4):e22277.

Altman J. Autoradiographic and histological studies of postnatal neurogenesis, 3: dating the time of production and onset of differentiation of cerebellar microneurons in rats. J Comp Neurol. 1969;136(3):269-93.

Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol. 1995;172(2 Pt 1):525-9.

Czeizel AE, Rockenbauer M. A population based case-control teratologic study of oral metronidazole treatment during pregnancy. Br J Obstet Gynaecol. 1998;105(3):322-7.

Sheehy O, Santos F, Ferreira E, Berard A. The use of metronidazole during pregnancy: a review of evidence. Curr Drug Saf. 2015;10(2):170-9.

Koss CA, Baras DC, Lane SD, Aubry R, Marcus M, Markowitz LE, Koumans eh. Investigation of metronidazole use during pregnancy and adverse birth outcomes. Antimicrob Agents Chemother. 2012;56(9):4800-5.

Caro-Patón T, Carvajal A, Martin de Diego I, Martin-Arias LH, Alvarez Requejo A, Rodríguez Pinilla E. Is metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol. 1997;44(2):179-82.

Kazy Z, Puhó E, Czeizel AE. Teratogenic potential of vaginal metronidazole treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2005;123(2):174-8

Muanda FT, Sheehy O, Bérard A. Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ. 2017;189(17):E625-33.

Kazy Z, Puhó E, Czeizel AE. The possible association between the combination of vaginal metronidazole and miconazole treatment and poly-syndactyly Population-based case-control teratologic study. Reprod Toxicol. 2005;20(1):89-94.

Dobiás L, Cerná M, Rössner P, Srám R. Genotoxicity and carcinogenicity of metronidazole. Mutat Res. 1994;317(3):177-94.

Thom M. Epilepsy part I: cortical dysplasia. In: Golden JA, Harding BH, editors. Pathology & Genetics: Developmental Neuropathology. Basel, Switzerland: ISN Neuropath Press; 2004. p. 61-6.

Wegiel J, Kuchna I, Nowicki K, Imaki H, Wegiel J, Marchi E, Ma SY, Chauhan A, Chauhan V, Bobrowicz TW, de Leon M, Saint Louis LA, Cohen IL, London E, Brown TW, Wisniewski T. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. 2010;119(6):755-70.

Downloads

Published

2020-12-25

How to Cite

1.
Čapo I Đ., Milenković IJ, Čapo NP, Stilinović NP, Vukmirović SN, Teofilović BD, Petković BB, Sekulić SR. Prenatal treatment with metronidazole induces cerebellar folia alteration in guinea pig fetuses. Arch Biol Sci [Internet]. 2020Dec.25 [cited 2022Aug.7];72(4):473-82. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/6035

Issue

Section

Articles

Most read articles by the same author(s)