Impaired learning and memory: a fallout of metronidazole induced neurotoxicity

Impaired learning and memory

Authors

  • Moses W Bariweni Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Wilberforce Island https://orcid.org/0000-0002-2888-8772
  • Iyele Kamenebali Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Wilberforce Island, Bayelsa State, Nigeria
  • Raymond Iduojemu Ozolua Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Benin, Benin City, Edo State, Nigeria https://orcid.org/0000-0003-1257-6325

DOI:

https://doi.org/10.55940/medphar202493

Keywords:

Metronidazole, Cognitive dysfunction, learning and memory, Antibiotics, Neurotoxicity, Neurotransmission

Abstract

Context: Metronidazole, an old warhorse in treatment of anaerobic, parasitic as well as bacterial infections in human and veterinary medicine has been observed to have neurotoxic adverse effects. An increase in the existing knowledge on the mechanisms of metronidazole-induced neurotoxicity is necessary.

Aim: To evaluate the effects of metronidazole on memory and learning in adult rats.

Methods and material: Eighty adult rats were allotted to 4 groups (n=20).  Group 1 was given 5 mL/kg 0.5% Tween-80®, group 2 was treated with 50 mg/kg metronidazole, group 3 was given 1 mg/kg risperidone, group 4 was treated with metronidazole 50 mg/kg + risperidone 1 mg/kg. All drug administrations were done daily for 28 days using the oral route. On the 28th day the rats were exposed to tests that evaluated cognitive function like the hole-board, Morris water maze and Y-maze test.

Statistical analysis used: One-way ANOVA followed by Dunnet’s post hoc test for multiple comparison. Statistical differences were considered significant at p<0.05.

Results: Metronidazole impaired memory acquisition and learning, and reduced reference memory index (RMI) on the hole board, increased the escape latency in the Moris water maze, and reduced percentage alternation and spatial recognition memory in the Y-maze (p<0.01). Co-administration of metronidazole with risperidone reversed all the memory and learning deficits in the treated rats

Conclusion: In conclusion, it is suggested that metronidazole induces cognitive dysfunction by stimulating 5-HT2A receptors in the CNS.

References

Dai C, Xiao X, Li J, Ciccotosto GD, Cappai R, Tang S, Schneider-Futschik EK, Hoyer D, Velkov T, Shen J. Molecular mechanisms of neurotoxicity induced by polymyxins and chemoprevention. ACS chemical neuroscience. 2018 ;10(1):120-31. DOI: 10.1021/acschemneuro.8b00300

Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environmental health perspectives. 2000 ;108(suppl 3):511-33. DOI:10.1289/ehp.00108s3511

Ikonomidou C, Bittigau P, Koch C, Genz K, Hoerster F, Felderhoff-Mueser U, Tenkova T, Dikranian K, Olney JW. Neurotransmitters and apoptosis in the developing brain. Biochemical pharmacology. 2001; 62(4):401-5.

Bilge S (2022). Neurotoxicity, types, clinical manifestations, diagnosis and treatment. neurotoxicity. New Advances. IntechOpen, Available at: http://dx.doi.org/10.5772/intechopen.101737. Accessed 12th January, 2024.

Sørensen CG, Karlsson WK, Amin FM, Lindelof M. Metronidazole-induced encephalopathy: a systematic review. Journal of neurology. 2020 ;267:1-3. DOI:10.1007/s00415-018-9147-6

Mathew RP, Kunhimohammed SP, Joseph M. A case of topical metronidazole–induced encephalopathy. JAMA neurology. 2020 ;77(10):1318-9. DOI:10.1001/jamaneurol.2020.2596

Gaye A, Sanghavi A. Metronidazole-induced encephalopathy in a pediatric patient. Journal of Allergy and Clinical Immunology. 2007 ;119(1):S38. DOI: 10.1016/j.jaci.2006.11.168

Martins G, Dias Â, Guerreiro C. Metronidazole-induced encephalopathy in a patient with spondylodiscitis. Clinical Toxicology. 2024; 62(9):598-600. DOI: 10.1080/15563650.2024.2385683

Evans J, Levesque D, Knowles K, Longshore R, Plummer S. Diazepam as a treatment for metronidazole toxicosis in dogs: a retrospective study of 21 cases. Journal of veterinary internal medicine. 2003 ;17(3):304-10. DOI: 10.1111/j.1939-1676.2003.tb02452.x

Roy U, Panwar A, Pandit A, Das SK, Joshi B. Clinical and neuroradiological spectrum of metronidazole induced encephalopathy: our experience and the review of literature. Journal of clinical and diagnostic research. 2016 ;10(6):OE01. DOI: 10.7860/JCDR/2016/19032.8054

Institute of Laboratory Animal Resources (US). Committee on Care, Use of Laboratory Animals. Guide for the care and use of laboratory animals. US Department of Health and Human Services, Public Health Service, National Institutes of Health; 1986. Washington DC: National Academies Press.

File SE. Effects of chlorpromazine on exploration and habituation in the rat. British Journal of Pharmacology. 1973 ;49(2):303-10. DOI:10.1111/j.1476-5381.1973.tb08376.x

Shanmugasundaram B, Aher YD, Aradska J, Ilic M, Daba Feyissa D, Kalaba P, Aher NY, Dragacevic V, Saber Marouf B, Langer T, Sitte HH. R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity. PloS one. 2017 Jun 23;12(6):e0179675. DOI: 10.1371/journal.pone.0179675

Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. Journal of neuroscience methods. 1984; 11(1):47-60. DOI: 10.1016/0165-0270(84)90007-4

Prieur EA, Jadavji NM. Assessing spatial working memory using the spontaneous alternation Y-maze test in aged male mice. Bio-protocol. 2019 ;9(3):e3162-.DOI:10.21769/BioProtoc.3162

Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behavior genetics. 1999; 29:177-85.

Sarnyai Z, Sibille EL, Pavlides C, Fenster RJ, McEwen BS, Tóth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A receptors. Proceedings of the National Academy of Sciences. 2000 ;97(26):14731-6.

Basavarajappa BS, Subbanna S. CB1 receptor‐mediated signaling underlies the hippocampal synaptic, learning, and memory deficits following treatment with JWH‐081, a new component of spice/K2 preparations. Hippocampus. 2014; 24(2):178-88. DOI:10.1002/hipo.22213

Markousis-Mavrogenis G, Bacopoulou F, Kolovou G, Pons MR, Giannakopoulou A, Papavasiliou A, Kitas GD, Chrousos GP, Mavrogeni SI. Pathophysiology of cognitive dysfunction and the role of combined brain/heart magnetic resonance imaging. Experimental and Therapeutic Medicine. 2022; 24(3):569. DOI:10.3892/etm.2022.11506

Puri P, Parnami P, Chitkara A, Athwal PSS, Khetrapal S. Antibiomania: A Rare Case of Metronidazole-Induced Mania. Cureus. 2021; 13(1):e12414. DOI: 10.7759/cureus.12414.

Bariweni MW, Kamenebali I, Denyefa JB. Metronidazole-induced neurotoxicity: Possible central serotonergic and noradrenergic system involvement. Medical and Pharmaceutical Journal. 2024; 3(1):22-34. DOI: 10.55940/medphar202474

Ward F, Crowley P, Cotter PE. Acute cerebellar syndrome associated with metronidazole. Practical Neurology. 2015; 15(4):298-9. DOI:10.1136/practneurol-2014-000974

Venneri A, De Marco M. Reduced monoaminergic nuclei MRI signal detectable in pre-symptomatic older adults with future memory decline. Scientific Reports. 2020; 10(1):18707. DOI:10.1038/s41598-020-71368-1.

Morales M, Margolis EB. Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nature Reviews Neuroscience. 2017 ;18(2):73-85. DOI:10.1038/nrn.2016.165

Rochefort C, Arabo A, André M, Poucet B, Save E, Rondi-Reig L. Cerebellum shapes hippocampal spatial code. Science. 2011 ;334(6054):385-9. DOI:10.1126/science.1207403

Krook-Magnuson E, Szabo GG, Armstrong C, Oijala M, Soltesz I. Cerebellar directed optogenetic intervention inhibits spontaneous hippocampal seizures in a mouse model of temporal lobe epilepsy. eneuro. 2014; 1(1). DOI: 10.1523/ENEURO.0005-14.2014.

Onuki Y, Van Someren EJ, De Zeeuw CI, Van der Werf YD. Hippocampal–cerebellar interaction during spatio-temporal prediction. Cerebral cortex. 2015 ;25(2):313-21. DOI:10.1093/cercor/bht221

Bast T, Pezze M, McGarrity S. Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition. British journal of pharmacology. 2017 ;174(19):3211-25. DOI:10.1111/bph.13850

Millan MJ, Agid Y, Brüne M, Bullmore ET, Carter CS, Clayton NS, Connor R, Davis S, Deakin B, DeRubeis RJ, Dubois B. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nature reviews Drug discovery. 2012 ;11(2):141-68. DOI: 10.1038/nrd3628

Bahn Y, Kim E, Park C, Park HC. Metronidazole induced encephalopathy in a patient with brain abscess. Journal of Korean Neurosurgical Society. 2010 ;48(3):301-4. DOI: 10.3340/jkns.2010.48.3.301.

D’Amelio M, Puglisi-Allegra S, Mercuri N. The role of dopaminergic midbrain in Alzheimer’s disease: Translating basic science into clinical practice. Pharmacological research. 2018 ;130:414-9. DOI:10.1016/j.phrs.2018.01.016

Frick LR, Bernardez-Vidal M, Hocht C, Zanutto BS, Rapanelli M. Dual role of serotonin in the acquisition and extinction of reward-driven learning: involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors. Behavioural brain research. 2015 ;277:193-203. DOI:10.1016/j.bbr.2014.06.025

Espadas I, Ortiz O, García-Sanz P, Sanz-Magro A, Alberquilla S, Solis O, Delgado-García JM, Gruart A, Moratalla R. Dopamine D2R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse. Cerebral Cortex. 2021 ;31(4):2187-204. DOI:10.1093/cercor/bhaa354

Marek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology. 2003 ;28(2):402-12. DOI:10.1038/sj.npp.1300057

Downloads

Published

2024-10-15

How to Cite

Bariweni, M. W., Kamenebali, I., & Ozolua, R. I. (2024). Impaired learning and memory: a fallout of metronidazole induced neurotoxicity: Impaired learning and memory. Medical and Pharmaceutical Journal, 3(3), 94–105. https://doi.org/10.55940/medphar202493

Issue

Section

Original Articles

Categories