Anticonvulsant Effect of Minocycline on Pentylenetetrazole-Induced Seizure in Mice: Involvement of 5-HT₃ Receptor

Abstract

Minocycline, widely used as an antibiotic, has recently been found to have an anti-inflammatory, neuroprotective and anticonvulsant effects. This study was aimed to investigate the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole (PTZ)-induced seizures considering the possible involvement of 5-HT₃ receptor in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Also, 1-(m-chlorophenyl)-biguanide (mCPBG, a 5-HT₃ receptor agonist) and Tropisetron (a 5-HT₃ receptor antagonist) were used 45 minutes before minocycline treatment. Our results demonstrate that acute minocycline treatment (80 and 120 mg/kg) increased the seizure threshold. In addition, the 5-HT₃ antagonist, tropisetron, at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of minocycline (40 mg/kg), while mCPBG (0.2 mg/kg) blunted the anticonvulsant effect of minocycline (80 mg/kg). In conclusion, our findings revealed that the anticonvulsant effect of minocycline is mediated, at least in part, by inhibition of 5-HT₃ receptor.

Key words

Minocycline - 5-HT₃ receptor; Seizure Threshold - Pentylenetetrazole - Mice

• References

• 1 Hirose S, Okada M, Kaneko S. et al. Are some idiopathic epilepsies disorders of ion channels? – A working hypothesis. Epilepsy Res 2000;
• 2 Beheshti Nasr SM, Moghimi A, Mohammad-Zadeh M. et al. The effect of minocycline on seizures induced by amygdala kindling in rats. Seizure 2013;
• 3 Młodzikowska-Albrecht J, Steinborn B, Zarowski M. Cytokines, epilepsy, and antiepileptic drugs – Is there a mutual influence?. Pharmacol Reports. 2007
• 4 Vezzani A, Granata T. Brain inflammation in epilepsy: Experimental and clinical evidence. Epilepsia 2005;
• 5 Wang DD, Englot DJ, Garcia PA. et al. Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo. Epilepsy Behav 2012;
• 6 Amini-Khoei H, Kordjazy N, Haj-Mirzaian A. et al. Anticonvulsant effect of minocycline on pentylenetetrazole-induced seizure in mice: involvement of nitric oxide and N-methyl-D-aspartate receptor. Can J Physiol Pharmacol 2018;
• 7 Colovic M, Caccia S. Liquid chromatographic determination of minocycline in brain-to-plasma distribution studies in the rat. J Chromatogr B Anal Technol Biomed Life Sci 2003;
• 8 Nogueira CRA, Damasceno FM, De Aquino-Neto MR. et al. Doxycycline protects against pilocarpine-induced convulsions in rats, through its antioxidant effect and modulation of brain amino acids. Pharmacol Biochem Behav 2011;
• 9 Liu Z, Fan Y, Won SJ. et al. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 2007;
• 10 Morimoto N, Shimazawa M, Yamashima T. et al. Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res 2005;
• 11 Kim SS, Kong PJ, Kim BS. et al. Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells. Arch Pharm Res 2004;
• 12 Munzar P, Li H, Nicholson KL. et al. Enhancement of the discriminative stimulus effects of phencyclidine by the tetracycline antibiotics doxycycline and minocycline in rats. Psychopharmacology (Berl) 2002;
• 13 Vezzani A, Bartfai T, Bianchi M. et al. Therapeutic potential of new antiinflammatory drugs In:. Epilepsia 2011; 67-69
• 14 Li B, Wang L, Sun Z. et al. The anticonvulsant effects of SR 57227 on pentylenetetrazole-induced seizure in mice. PLoS One 2014;
• 15 Fakhfouri G, Mousavizadeh K, Mehr SE. et al. From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists. Mol Neurobiol 2015;
• 16 BONNYCASTLE DD, GIARMAN NJ, PAASONEN MK. Anticonvulsant compounds and 5-hydroxytryptamine in rat brain. Br J Pharmacol Chemother 1957;
• 17 Puthuran GJ, Patil PA, Majagi SI. Effect of ondansetron on convulsions and its interactions with phenytoin. Pharmacologyonline. 2009
• 18 Jain S, Agarwal NB, Mediratta PK. et al. Evaluation of anticonvulsant and nootropic effect of ondansetron in mice. Hum Exp Toxicol 2012;
• 19 Payandemehr B, Bahremand A, Rahimian R. et al. 5-HT3 receptor mediates the dose-dependent effects of citalopram on pentylenetetrazole-induced clonic seizure in mice: Involvement of nitric oxide. Epilepsy Res 2012;
• 20 Roshanpour M, Ghasemi M, Riazi K. et al. Tolerance to the anticonvulsant effect of morphine in mice: Blockage by ultra-low dose naltrexone. Epilepsy Res 2009;
• 21 Amiri S, Haj-Mirzaian A, Amini-Khoei H. et al. Protective effects of gabapentin against the seizure susceptibility and comorbid behavioral abnormalities in the early socially isolated mice. Eur J Pharmacol 2017;
• 22 Nieoczym D, Socała K, Wlaź P. Assessment of the Anticonvulsant Potency of Ursolic Acid in Seizure Threshold Tests in Mice. Neurochem Res 2018;
• 23 Bahremand A, Payandemehr B, Rahimian R. et al. The role of 5-HT3 receptors in the additive anticonvulsant effects of citalopram and morphine on pentylenetetrazole-induced clonic seizures in mice. Epilepsy Behav 2011;
• 24 Grieco JC, Ciarlone SL, Gieron-Korthals M. et al. An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome. BMC Neurol 2014;
• 25 Bektas T, Erdur B, Yilmaz A. et al. Protective effects of minocycline, doxycycline and tetracycline on seizure and lethality in a mice cocaine toxicity model. Am J Emerg Med 2019;
• 26 Nowak M, Strzelczyk A, Reif PS. et al. Minocycline as potent anticonvulsant in a patient with astrocytoma and drug resistant epilepsy. Seizure 2012;
• 27 Mhatre MC, Garrett KM, Holloway FA. 5-HT3 receptor antagonist ICS 205-930 alters the discriminative effects of ethanol. Pharmacol Biochem Behav 2001;
• 28 Szyndler J, Wierzba-Bobrowicz T, Maciejak P. et al. Pentylenetetrazol-kindling of seizures selectively decreases [3H]-citalopram binding in the CA-3 area of rat hippocampus. Neurosci Lett 2002;
• 29 Fakhfouri G, Rahimian R, Dyhrfjeld-Johnsen J. et al. 5-HT3 receptor antagonists in neurologic and neuropsychiatric disorders: The iceberg still lies beneath the surface. Pharmacol Rev 2019;
• 30 Puzerey PA, Decker MJ, Galán RF. Elevated serotonergic signaling amplifies synaptic noise and facilitates the emergence of epileptiform network oscillations. J Neurophysiol 2014;
• 31 Wilde MI, Markham A. Ondansetron: A review of its pharmacology and preliminary clinical findings in novel applications. Drugs 1996;
• 32 Ye JH, Ponnudurai R, Schaefer R. Ondansetron: A selective 5-HT3 receptor antagonist and its applications in CNS-related disorders. CNS Drug Rev 2001;
• 33 Balakrishnan S, Bhargava VK, Pandhi P. Anticonvulsant Profile of Ondansetron in Rats. Epilepsy Behav 2000;
• 34 Wada Y, Shiraishi J, Nakamura M. et al. Effects of the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide in the rat kindling model of epilepsy. Brain Res 1997;
• 35 Watanabe KI, Ashby CR, Katsumori H. et al. The effect of the acute administration of various selective 5-HT receptor antagonists on focal hippocampal seizures in freely-moving rats. Eur J Pharmacol 2000;
• 36 Mishra A, Goel RK. Chronic 5-HT3 receptor antagonism ameliorates seizures and associated memory deficit in pentylenetetrazole-kindled mice. Neuroscience 2016;
• 37 Swain TR, Mohanty M. Antiepileptic action of ondansetron [2]. Indian J Pharmacol. 1999
• 38 Gholipour T, Ghasemi M, Riazi K. et al. Seizure susceptibility alteration through 5-HT3 receptor: Modulation by nitric oxide. Seizure 2010;