Metronidazole-induced neurotoxicity: Possible central serotonergic and noradrenergic system involvement


  • Moses W Bariweni Niger Delta University, Wilberforce Island
  • Iyele Kamenebali Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University
  • Denyefa, Johnson Bedford Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University



Neurotoxicity, Neurotransmission, Metronidazole, Antibiomania, Antidepressants, Depression


Background: Metronidazole is a synthetic 5-nitroimidazole antibiotic. It remains a first-line therapy for anaerobic, parasitic, and bacterial infections in human and veterinary medicine. However, Metronidazole-induced neurotoxicity is a rising challenge. The mechanism of neurotoxicity induction is still unknown.
Objective: To investigate a possible interference of metronidazole with central monoaminergic mechanisms using the Forced Swim Test.
Methods: sixty adult rats were divided into 10 groups (n=10 for metronidazole and saline, n=5 for other groups). Group 1 = 5 ml/kg normal saline; Group 2 = 50 mg/kg metronidazole; group 3= 15 mg/kg imipramine; Group 4 =15 mg/kg imipramine + 50 mg/kg metronidazole. Group 5 = 5 mg/kg fluoxetine; Group 6 received 5 mg/kg fluoxetine + 50 mg/kg metronidazole; Group 7 = labetalol 10 mg/kg; Groups 8, 9 and 10 received labetalol 10 mg/kg + 50 mg/kg metronidazole, PCPA (p-chlorophenylalanine) 100 mg/kg and PCPA 100 mg/kg + 50 mg/kg metronidazole daily X 28 days. On day 28, FST was done 1h after the respective treatments. On day 29, blood samples were collected under halothane anesthesia for hematological assessment.
Results: Immobility time increased (P<0.01) in the groups treated with metronidazole, labetalol, PCPA, labetalol + metronidazole, and PCPA+ metronidazole. Swimming was reduced by metronidazole, PCPA, metronidazole + PCPA and metronidazole + labetalol. Metronidazole + labetalol reduced climbing. These effects were not reduced by co-treatment with imipramine or fluoxetine. White blood cell count increased (p<0.01) in all treatment groups. Lymphocyte percent increased in the metronidazole-treated groups.
Conclusion: Interference with postsynaptic central monoaminergic neurotransmission and immunomodulation may contribute to metronidazole-induced neurotoxicity.


Kim E, Na DM, Kim EY, Kim JH, Son KR, Chang KH.MR imaging of metronidazole-induced encephalopathy: lesion distribution and diffusion-weighted imaging findings. Am. J. Neuroradiol. 2007, 28, 1652-1658. DOI: 10.3174/ajnr.A0655

Plumb, DC. Veterinary Drug Handbook. (4th ed). Iowa : Iowa State University Press, 2002.

Löfmark S, Edlund C, Nord CE. (2010). Metronidazole is still the drug of choice for treatment of anaerobic infections. CLIN infect Dis. 2010; 50 Suppl 1: S16–S23. DOI: 10.1086/647939

Bahn Y, Kim E, Park C, Park HC. Metronidazole induced encephalopathy in a patient with brain abscess. J. Korean Neurosurg. Soc. 2010; 48: 301-304. DOI: 10.3340/jkns.2010.48.3.301

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

Ward F, Crowley P, Cotter P. Acute cerebellar syndrome associated with metronidazole. J Pract Neurol. 2015; 298-299. DOI:10.1136/practneurol-2014-000974

Kuriyama A, Jackson JL, Doi A, Kamiya T. Metronidazole-induced central nervous system toxicity: a systematic review. Clin Neuropharmacol. 2011; 34: 241-247. DOI: 10.1097/WNF.0b013e3182334b35

Ujawal R, Ajay P, Alak P, Susanta K, Bhushan J. Clinical and Neuroradiological Spectrum of Metronidazole Induced Encephalopathy: Our Experience and the Review of Literature. J Clin Diagn Res. 2016; 10(6): 1-9. DOI: 10.7860/JCDR/2016/19032.8054

Schreiber W, Spernal J. Metronidazole-induced psychotic disorder. Am J Psychiatr. 1997; 154:1170-1171. DOI: 10.1176/ajp.154.8.1170b.

Krishnarao A, Feller E, Shah S. Metronidazole-induced mania: recurrence with re-challenge. Am J Gastroenterol. 2011; 106: 346. DOI: 10.14309/00000434-201110002-00924

National Research Council. Institute for Laboratory Animal Research: Guide for the care and use of laboratory animals. Washington DC: National Academies Press. 2011

Porsolt RD, Le Pichon M, Jalfre ML. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977 Apr 21;266(5604):730-2. DOI: 10.1038/266730a0

Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacol. 1995; 121: 66–72. DOI: 10.1007/BF02245592

Thomas C, Gwenin CD. The role of nitroreductases in resistance to nitroimidazoles. Biology. 2021;10(5):388. DOI: 10.3390/biology10050388

Ramakrishna DNR, Ronald PM. Generation of nitro radical anions of some 5-nitrofurans, 2- and 5-nitroimidazoles by norepinephrine, dopamine, and serotonin. A possible mechanism for neurotoxicity caused by nitroheterocyclic drugs. J Biol Chem. 1987; 226(24): 11731-11736.

Talapatra SN, Dasgupta S, Guha G, Auddy M, Mukhopadhyay A. Therapeutic efficacies of Coriandrum sativum aqueous extract against metronidazole induced genotoxicity in Channa punctatus peripheral erythrocytes. Food Chem Toxicol. 2010; 48:3458-3461. DOI: 10.1016/j.fct.2010.09.021

Ceruelos HA, Romero-Quezada LC, Ledezma JCR, Contreras LL. Therapeutic uses of metronidazole and its uses: an update. Eur Rev Med Pharmacol Sci. 2019; 23: 397-401. DOI: 10.26355/eurrev_201901_16788

Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacol. 1985; 85: 367-70.

DOI: 10.1007/BF00428203

Alarcon BG, Walterfang M, Thevathasan W. Anxiety and depression in tyrosine hydroxylase deficiency: a case report. European Journal of Medical Case Reports. 2021;5(9):270-3. DOI: 10.24911/ejmcr/2/18

Detke MJ, Rickels M, Lucki I. Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp Clin Psychopharmacol. 1997; 5: 107-112. DOI: 10.1037//1064-1297.5.2.107

Cryan JF, Page ME, Lucki I. Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacol. 2005; 182: 335–44. DOI: 10.1007/s00213-005-0093-5

Murray NM, Buchanan GF, Richerson GB. (2015). Insomnia caused by Serotonin depletion is due to hypothermia. Sleep. 2015; 38: 1985–1993. DOI: 10.5665/sleep.5256.

Pham TH, Mendez-David I, Defaix C, Guiard BP, Tritschler L, David DJ, et al. Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in Balb/cJ mice. Neuropharmacol. 2017; 112: 198–209. DOI: 10.1016/j.neuropharm.2016.05.010.

Riga MS, Sanchez C, Celada P, Artigas F. Sub-chronic vortioxetine (but not escitalopram) normalizes brain rhythm alterations and memory deficits induced by serotonin depletion in rats. Neuropharmacol. 2020; 178:108238. doi:10.1016/j.neuropharm.2020.108238.

Ghaheri S, Niapour A, Sakhaie N, Sadegzadeh F, Saadati H. Postnatal depletion of serotonin affects the morphology of neurons and the function of the hippocampus in male rats. Int J Dev Neurosci. 2022; 82: 222–230. DOI: 10.1002/jdn.10174.

Liu Y, Li Z, Sun T, He Z, Xiang H, Xiong J. Gut microbiota-generated short-chain fatty acids are involved in para-chlorophenylalanine-induced cognitive disorders. Front. Microbiol. 2022; 13: 1028913. doi: 10.3389/fmicb.2022.1028913.

Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacol. 1988; 94: 147-60. DOI: 10.1007/BF00176837

O'Donnell JM, Shelton RC. Drug Therapy of Depression and Anxiety Disorders. In Brunto L, Chabner B, Knollman B, editors, Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). McGraw-Hill Companies, Inc. 2011; p. 398

El-Borm HT, Gobara MS, Badawy GM. Ginger extract attenuates labetalol induced apoptosis, DNA damage, histological and ultrastructural changes in the heart of rat fetuses. Saudi Journal of Biological Sciences. 2021 Jan 1;28(1):440-7. DOI:10.1016/j.sjbs.2020.10.027

Westfall TC, Westfall DP. Adrenergic Agonists and Antagonists. In Brunto L, Chabner B, Knollman B, editors, Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). McGraw-Hill Companies, Inc. 2011; p. 304

Huffman JC, Stern TA. Neuropsychiatric consequences of cardiovascular medications. Dialogues Clin Neurosci. 2007; 9: 29–45. DOI: 10.31887/DCNS.2007.9.1/jchuffman.

DeBattista C. Antidepressant Agents. In Katzung BG, Trevor AJ, editors. Basic and Clinical Pharmacology (13th ed.) Lange, McGraw-Hill Education. 2012; p. 520

Boku S, Nakagawa S, Toda H, Hishimoto A. Neural basis of major depressive disorder: Beyond monoamine hypothesis. Psych Clin Neurosci. 2018; 72: 3–12. DOI: 10.1111/pcn.12604

Bondy B. Pathophysiology of depression and mechanisms of treatment. Dialog Clin Neurosci. 2002; 4(1): 7-20. DOI: 10.31887/DCNS.2002.4.1/bbondy.

Wang J, Hodes G, Zhang H, Zhang S, Zhao W, Golden S, et al. Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun. 2018; 9: 477.

Bariweni WM, Yibala YI, Ozolua R. Toxicological studies on the aqueous leaf extract of Pavetta crassipes (K. Schum) in rodents. J Pharm Pharmacogn Res. 2018; 6(1): 1-16.

Kwan P, Darah I, Chen Y, Sreeramanan S, Sasidharan S. Acute and subchronic toxicicty study of Euphorbia hirta L. methanol extract in rats. J Biomed Res. 2013; 10: 1–14. DOI: 10.1155/2013/182064

Blum K, Pabst R. Lymphocyte numbers and subsets in the human blood. Do they mirror the situation in all organs? Immunol Lett. 2007; 108: 45-51.

Peterson HM, Manley CI, Trepanier LA, Pritchard JC. Genotoxicity from metronidazole detected in vitro, but not in vivo, in healthy dogs in a randomized clinical trial. American Journal of Veterinary Research. 2023;84(1). DOI: 10.2460/ajvr.22.07.0112

Elizondo G, Ostrosky-Wegman P. Effects of metronidazole and its metabolites on histamine immunosuppression activity. Life Sci. 1996; 59: 285–297. DOI: 10.1016/0024-3205(96)00297-4

Fararjeh M, Mohammad M, Bustanji Y, Alkhatib H, Abdalla S. Evaluation of immunosuppression induced by metronidazole in Balb/c mice and human peripheral blood lymphocytes. Int Immunopharmacol. 2007; 8:341-350.

DOI: 10.1016/j.intimp.2007.10.018

Shakir L, Javeed A, Ashraf M, Riaz A. Metronidazole and the immune system. Pharmazie. 2011; 66: 393–398. DOI: 10.1691/ph.2011.0790.

Tian H, Hu Z, Xu J, Wang C. The molecular pathophysiology of depression and the new therapeutics. Med Comm. 2022; 3:e156. DOI: 10.1002/mco2.156.

Haroon E, Daguanno A, Woolwine B, Goldsmith D, Baer W, Wommack E et al. Antidepressant treatment resistance is associated with increased inflammatory markers in patients with major depressive disorder. Psychoneuroendocrinol. 2018; 95: 43–49.

Mao R, Zhang C, Chen J, Zhao G, Zhou R, Wang F et al. Different levels of pro- and anti-inflammatory cytokines in patients with unipolar and bipolar depression. J Affect Disord. 2018; 237: 65–72. DOI:10.1016/j.jad.2018.04.115.

Chousterman B, Swirski F, Weber G. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017; 39(5): 517–528. DOI: 10.1007/s00281-017-0639-8.

Syed S, Beurel E, Loewenstein D, Lowell J, Craighead W, Dunlop B et al. Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response. Neuron. 2018; 99(5): 914–924.e3. DOI :10.1016/j.neuron.2018.08.001.

Köhler C, Freitas T, Stubbs B, Maes M, Solmi M, Veronese N et al. Peripheral Alterations in Cytokine and Chemokine Levels After Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis. Molec Neurobiol. 2018; 55(5): 4195–4206. DOI: 10.1007/s12035-017-0632-1.




How to Cite

Bariweni, M. W., Kamenebali, I., & Bedford, D. J. (2024). Metronidazole-induced neurotoxicity: Possible central serotonergic and noradrenergic system involvement. Medical and Pharmaceutical Journal, 3(1), 22–34.



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