Unraveling the Interplay of 5-hydroxytryptamine-3 and N-methyl-d-aspartate Receptors in Seizure Susceptibility

Abstract

Background Epilepsy, a prevalent neurological disorder characterized by recurrent seizures, presents significant challenges in treatment and management. This study aimed to evaluate the effect of tropisetron, a selective 5-HT3 receptor antagonist on pentylenetetrazole (PTZ) – induced seizure in mice by exploring the potential role of the NMDA receptor and inflammatory responses.

Methods For this purpose, seizures were induced by intravenous PTZ infusion. Tropisetron at 1-, 2-, 3-, 5-, 10- mg/kg were administered intraperitoneally 30 minutes before PTZ. To evaluate probable role of NMDA signaling, selective NMDAR antagonists, ketamine and MK-801, were injected 15 minutes before tropisetron. Also, TNF-α level of hippocampus were measured following administration of mentioned drugs in mice.

Results Our results demonstrate that tropisetron displayed a dose-dependent impact on seizure threshold, with certain doses (5 and 10 mg/kg) exhibiting anticonvulsant properties. In addition, the noncompetitive NMDAR antagonists, ketamine (1 mg/kg) and MK-801 (0.5 mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of tropisetron (3 mg/kg). Also, tropisetron led to a reduction in hippocampal TNF-α levels, indicating its anti-inflammatory potential independent of 5-HT receptor activity.

Conclusion In conclusion, we demonstrated that the anticonvulsant effect of tropisetron is mediated by the inhibition of NMDA receptors and a decline in hippocampal TNF-α level. These findings highlight a potential connection between 5-HT3 and NMDA receptors in the pharmacological treatment of inflammatory diseases, such as seizure, warranting further investigation into their combined therapeutic effects.

Keywords

5-HT3 antagonist - NMDA receptor - seizure - mice - TNF-α

Publication History

Received: 25 May 2024

Accepted: 20 August 2024

Article published online:
19 September 2024

• References

• 1 Wirrell E. Evaluation of first seizure and newly diagnosed epilepsy. CONTINUUM Lifelong Learning in Neurology 2022; 28: 230-260
• 2 Nasiri-Boroujeni S, Rahimi-Madiseh M, Lorigooini Z. et al. NMDA Receptor Mediates the Anticonvulsant Effect of Hydroalcoholic Extract of Artemisia persica in PTZ-Induced Seizure in Mice. Evidence-based Complementary and Alternative Medicine 2021;
• 3 Jain S, Agarwal NB, Mediratta PK. et al. Evaluation of anticonvulsant and nootropic effect of ondansetron in mice. Human and Experimental Toxicology 2012; 31(9): 905–12
• 4 Li B, Wang L, Sun Z. et al. The anticonvulsant effects of SR 57227 on pentylenetetrazole-induced seizure in mice. PLoS ONE 2014; 1;9(4): e93158
• 5 Fakhfouri G, Rahimian R, Daneshmand A. et al. Granisetron ameliorates acetic acid-induced colitis in rats. Human and Experimental Toxicology 2010; 29: 321-328
• 6 Rahimian R, Daneshmand A, Mehr SE. et al. Tropisetron ameliorates ischemic brain injury in an embolic model of stroke. Brain Research 2011; 1392: 101-109
• 7 Beheshti Nasr SM, Moghimi A, Mohammad-Zadeh M. et al. The effect of minocycline on seizures induced by amygdala kindling in rats. Seizure 2013; 22(8): 670–4
• 8 Vezzani A, Granata T. Brain inflammation in epilepsy: Experimental and clinical evidence. In 2005;
• 9 Xia L, Liu L, Hong X. et al. One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia. Neuropsychopharmacology 2020; 45(8): 1362–1368
• 10 Liu Z, Zeng Z, Wu C. et al. Tropisetron inhibits sepsis by repressing hyper-inflammation and regulating the cardiac action potential in rat models. Biomedicine and Pharmacotherapy 2019; 110: 380–388
• 11 Zhang Yf, Yu D, Gong Xr. et al. Tropisetron attenuates neuroinflammation and chronic neuropathic pain via α7nAChR activation in the spinal cord in rats. Journal of Spinal Cord Medicine 2022; 47(2): 277–285
• 12 Fakhfouri G, Mousavizadeh K, Mehr SE. et al. From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists. In 2015;
• 13 Mousavizadeh K, Rahimian R, Fakhfouri G. et al. Anti-inflammatory effects of 5-HT 3 receptor antagonist, tropisetron on experimental colitis in rats. European Journal of Clinical Investigation 2009; 39(5): 375–83
• 14 Zhao H, Lin Y, Chen S. et al. 5-HT3 Receptors: A Potential Therapeutic Target for Epilepsy. Current Neuropharmacology 2017; 16: 29-36
• 15 Gholipour T, Ghasemi M, Riazi K. et al. Seizure susceptibility alteration through 5-HT(3) receptor: modulation by nitric oxide. Seizure 2010; 19: 17-22
• 16 Swartz MM, Linn DM, Linn CL. Tropisetron as a neuroprotective agent against glutamate-induced excitotoxicity and mechanisms of action. Neuropharmacology 2013; 73: 111-121
• 17 Hanada T. Ionotropic glutamate receptors in epilepsy: A review focusing on ampa and nmda receptors. Biomolecules 2020; 10
• 18 Groc L, Choquet D. AMPA and NMDA glutamate receptor trafficking: multiple roads for reaching and leaving the synapse. Cell and tissue research 2006; 326: 423-438
• 19 Bowie D. Ionotropic Glutamate Receptors & CNS Disorders. CNS & Neurological Disorders – Drug Targets 2008; 7: 129-143
• 20 Sivakumar S, Ghasemi M, Schachter SC. Targeting NMDA Receptor Complex in Management of Epilepsy. Pharmaceuticals 2022; 15: 1-20
• 21 Mealing GA, Lanthorn TH, Murray CL. et al. Differences in degree of trapping of low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists with similar kinetics of block. The Journal of pharmacology and experimental therapeutics 1999; 288: 204-210
• 22 Song X, Jensen MO, Jogini V. et al. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature 2018; 55 6: 515-519
• 23 Gaspard N, Foreman B, Judd LM. et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. 2014; 54: 1498-1503
• 24 Kordjazy N, Haj-Mirzaian A, Amiri S. et al. Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test. Pharmacology Biochemistry and Behavior 2016; 141: 1-9
• 25 Nieoczym D, Socała K, Wlaź P. Assessment of the Anticonvulsant Potency of Ursolic Acid in Seizure Threshold Tests in Mice. Neurochemical Research 2018; 43(5): 995–1002
• 26 Amiri Gheshlaghi S, Mohammad Jafari R, Algazo M. et al. Genistein modulation of seizure: involvement of estrogen and serotonin receptors. Journal of Natural Medicines 2017; 71: 537-544
• 27 Bahremand A, Payandemehr B, Rahimian R. et al. The role of 5-HT(3) receptors in the additive anticonvulsant effects of citalopram and morphine on pentylenetetrazole-induced clonic seizures in mice. Epilepsy Behav 2011; 21: 122-127
• 28 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. Canadian Journal of Physiology and Pharmacology 2018; 96(8): 742–750
• 29 Mhatre MC, Garrett KM, Holloway FA. 5-HT3 receptor antagonist ICS 205-930 alters the discriminative effects of ethanol. Pharmacology Biochemistry and Behavior 2001; 68(1): 163–70
• 30 Puthuran GJ, Patil PA, Majagi SI. Effect of ondansetron on convulsions and its interactions with phenytoin. Pharmacologyonline. 2009 24(2). 130–3
• 31 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 Research 2012; 101(3): 217–27
• 32 Balakrishnan S, Bhargava VK, Pandhi P. Anticonvulsant Profile of Ondansetron in Rats. Epilepsy and Behavior 2000; 1(1): 22–6
• 33 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 Research 1997; 13;759(2): 313–6
• 34 Yakel JL, Jackson MB. 5-HT3 receptors mediate rapid responses in cultured hippocampus and a clonal cell line. Neuron 1988; 1: 615-621
• 35 Sugita S, Shen KZ, North RA. 5-hydroxytryptamine is a fast excitatory transmitter at 5-HT3 receptors in rat amygdala. Neuron 1992; 8: 199-203
• 36 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. European Journal of Pharmacology 2000; 16;398(2): 239–46
• 37 Mishra A, Goel RK. Chronic 5-HT3 receptor antagonism ameliorates seizures and associated memory deficit in pentylenetetrazole-kindled mice. Neuroscience 2016; 17:339: 319–328
• 38 Rahimi-Madiseh M, Lorigooini Z, Boroujeni SN. et al. The Role of the NMDA Receptor in the Anticonvulsant Effect of Ellagic Acid in Pentylenetetrazole-Induced Seizures in Male Mice. Behavioural Neurology 2022; 2022
• 39 Manocha A, Sharma KK, Mediratta PK. Possible mechanism of anticonvulsant effect of ketamine in mice. Indian Journal of Experimental Biology 2001; 39: 1002-1008
• 40 Gözüaçık N, Türkmen AZ, Nurten A. et al. Ketamine and its combinations with valproate and carbamazepine are ineffective against convulsions induced by atropine treatment and food intake in fasted mice. Iranian Journal of Basic Medical Sciences 2019; 22: 310-314
• 41 Kos T, Popik P, Pietraszek M. et al. Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 2006; 16: 297-310
• 42 Suzuki T, Aoki T, Kato H. et al. Effects of the 5-HT3 receptor antagonist ondansetron on the ketamine- and dizocilpine-induced place preferences in mice. European Journal of Pharmacology 1999; 385: 99-102
• 43 Błaszczyk B, Czuczwar SJ. Epilepsy coexisting with depression. Pharmacological Reports 2016; 68(5): 1084-1092
• 44 Brookes G, Crawford P. The associations between epilepsy and depressive illness in secondary care. Seizure 2002; 11: 352-355
• 45 Bagdy G, Kecskemeti V, Riba P. et al. Serotonin and epilepsy. Journal of Neurochemistry 2007; 857-873
• 46 Browning RA, Wade DR, Marcinczyk M. et al. Regional brain abnormalities in norepinephrine uptake and dopamine beta-hydroxylase activity in the genetically epilepsy-prone rat. Journal of Pharmacology and Experimental Therapeutics 1989; 249: 229-235
• 47 Azzaro AJ, Wenger GR, Craig CR. et al. Reserpine-induced alterations in brain amines and their relationship to changes in the incidence of minimal electroshock seizures in mice. Journal of Pharmacology and Experimental Therapeutics 1972; 180: 558-568
• 48 Chen TS, Huang TH, Lai MC. et al. The Role of Glutamate Receptors in Epilepsy. Biomedicines 2023; 4;11(3): 783
• 49 Ghasemi M, Schachter SC. The NMDA receptor complex as a therapeutic target in epilepsy: A review. In 2011; 617-640
• 50 Amiri S, Haj-Mirzaian A, Amini-khoei H. et al. NMDA receptor antagonists attenuate the proconvulsant effect of juvenile social isolation in male mice. Brain Research Bulletin 2016; 121: 158-168
• 51 Esplugues JV. NO as a signalling molecule in the nervous system. In 2002;
• 52 Krass M, Wegener G, Vasar E. et al. The antidepressant action of imipramine and venlafaxine involves suppression of nitric oxide synthesis. Behavioural Brain Research 2011; 218: 57-63
• 53 Zomkowski ADE, Engel D, Gabilan NH. et al. Involvement of NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effects of escitalopram in the forced swimming test. European Neuropsychopharmacology 2010; 20: 793-801
• 54 Joca SRL, Guimarães FS. Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects. Psychopharmacology 2006; 185(3): 298–305
• 55 Balosso S, Ravizza T, Aronica E. et al. The dual role of TNF-α and its receptors in seizures. Experimental Neurology 2013; 267-271
• 56 Han K, Wang QY, Wang CX. et al. Ghrelin improves pilocarpine-induced cerebral cortex inflammation in epileptic rats by inhibiting NF-κB and TNF-α. Molecular Medicine Reports 2018; 18: 3563-3568
• 57 Balosso S, Ravizza T, Perego C. et al. Tumor necrosis factor-α inhibits seizures in mice via p75 receptors. Annals of Neurology 2005; 57: 804-812
• 58 Fiebich BL, Akundi RS, Lieb K. et al. Antiinflammatory effects of 5-HT3 receptor antagonists in lipopolysaccharide-stimulated primary human monocytes. In: 119 edn 28-32
• 59 De La Vega L, Muñoz E, Calzado MA. et al. The 5-HT3 receptor antagonist tropisetron inhibits T cell activation by targeting the calcineurin pathway. Biochemical Pharmacology 2005; 70: 369-380
• 60 Maleki-Dizaji N, Eteraf-Oskouei T, Fakhrjou A. et al. The effects of 5HT3 receptor antagonist granisetron on inflammatory parameters and angiogenesis in the air-pouch model of inflammation. International Immunopharmacology 2010; 10(9): 1010–6