Involvement of Nnos, and Α1, Α2, Β1, and Β2 Subunits of Soluble Guanylyl Cyclase Genes Expression in Anticonvulsant Effect of Sumatriptan on Pentylenetetrazole-Induced Seizure in Mice

Document Type: Research article

Authors

1 Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

2 Key Laboratory of Integrated Management of Crop Diseases and Pests, College of Plant Protection, Nanjing Agriculture University, Nanjing, 210095, PR China.

3 Razi Drug Research Center, Iran University of Medical Sciences, Beside Milad Tower, Hemmat Expressway, Tehran, Iran.

4 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

Epileptic seizure is phenomenon of abnormal synchronous neuronal discharge of a set of neurons in brain as a result of neuronal excitation. Evidence shows the nitric oxide (NO) involvement in neuronal excitability. Moreover, the role of NO-mediated cyclic guanosine monophosphate (cGMP) activation in seizure pathogenesis is well-established. Sumatriptan is a selective agonist of 5-Hydroxytryptamine1B/D auto-receptor, has been reassessed for its neuroprotection. This study was aimed to explore the anticonvulsant effect of sumatriptan through possible involvement of NO-cGMP pathway in mice. For this purpose, the protective effect of sumatriptan on PTZ-induced clonic seizure threshold (CST) was measured using NO-cGMP pathway inhibitors including N(G)-nitro-L-arginine (L-NNA, 1, 5, and 10 mg/kg), 7-nitroindazole (7-NI, 30, 45, and 60 mg/kg), aminoguanidine (AG, 30, 50, and 100 mg/kg), methylene blue (MB, 0.1, 0.5, and 1 mg/kg) and sildenafil (5, 10, and 20 mg/kg). The involvement of nitrergic system was further confirmed by measurement of nitrite levels by Griess reaction. The gene expression of neuronal nitric oxide synthase (nNOS) and subunits of soluble guanylyl cyclase (sGC) was studied using qRT-PCR analysis. Acute administration of sumatriptan (1.2 and 0.3 mg/kg) in combination with subeffective doses of NOS, sGC, and phosphodiesterase 5 inhibitors significantly reversed the PTZ-induced CST (P≤0.001). The nitrite level in prefrontal cortex was significantly attenuated by sumatriptan (P≤0.01). Furthermore, sumatriptan downregulated the PTZ-induced mRNA expression of nNOS, and α1, α2, and β1 genes in cerebral cortex of mice (P≤0.0001). In conclusion, the anticonvulsant activity of sumatriptan at least, in part, is mediated through inhibiting NO-cGMP pathway.

Graphical Abstract

Involvement of Nnos, and Α1, Α2, Β1, and Β2 Subunits of Soluble Guanylyl Cyclase Genes Expression in Anticonvulsant Effect of Sumatriptan on Pentylenetetrazole-Induced Seizure in Mice

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