Neuroprotective effect of sumatriptan in pentylenetetrazole‐induced seizure is mediated through N‐methyl‐D‐aspartate/nitric oxide and cAMP response element‐binding protein signaling pathway.

Mumtaz, Faiza; Rashki, Asma; Imran Khan, Muhammad; Shadboorestan, Amir; Abdollahi, Alireza; Ghazi‐Khansari, Mahmoud; Alotaibi, Ghallab; Dehpour, Ahmad Reza

Seizure occurs as a result of uncontrolled electrical disturbances within the brain. Various biomolecules such as N‐methyl‐D‐aspartate (NMDA), nitric oxide (NO), and cAMP response element‐binding protein (CREB) have been implicated in the pathophysiology of seizure. Sumatriptan is a specific 5‐Hydroxytryptamine 1B/1D receptor agonist and has neuroprotective effects in various neuropsychiatric disorders. In the current study, we tried to investigate the possible interaction of sumatriptan with NMDA/NO and CREB signaling pathway in PTZ induced seizure. For this purpose, various agonist and antagonist of NMDA such as MK‐801 and Ketamine, NO precursor L‐ARG, and NOS inhibitors L‐NAME and 7‐NI were co‐administered with sumatriptan in PTZ induced seizure model. The level of nitrite in mice hippocampus was determined by Griess reaction. The gene expression of NR1, NR2A, NR2B, and CREB were quantified by quantitative real time‐polymerase chain reaction (qRT‐PCR). Furthermore, the involved neuronal nitric oxide synthase (nNOS) protein expression was examined via western blot analysis. Effective dose of sumatriptan (1.2 mg/kg) alone and subeffective dose of sumatriptan (0.3 mg/kg) in combination with NMDA and/or NO antagonist showed significant (P < 0.001) anticonvulsant activity in mice. Furthermore, sumatriptan significantly inhibited the PTZ‐induced mRNA expression of NR2A (P < 0.0001), NR2B (P < 0.05), and CREB (P < 0.01). Also, the expression of nNOS protein in PTZ treated group was reversed by sumatriptan (P < 0.01). Hence, current findings suggest that the anticonvulsant effect of sumatriptan was due to down regulation of NMDA/NO and CREB signaling pathway.

CELLULAR signal transduction; SUMATRIPTAN; NITRIC-oxide synthases; SEROTONIN receptors; WESTERN immunoblotting; SEIZURES (Medicine)

Fundamental & Clinical Pharmacology, 2022, Vol 36, Issue 2, p250

0767-3981

Academic Journal

10.1111/fcp.12728