Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Iranian Center of Neurological Research, Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran; Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Eur J Pharmacol. 2018 Apr 5;824:140-147. doi: 10.1016/j.ejphar.2018.01.025. Epub 2018 Feb 2.
Sumatriptan has been among the top choices in the management of migraine headaches. The association between migraine and epilepsy highlights the possible effect of sumatriptan on seizures. In this regard, we investigated sumatriptan effects on PTZ-induced seizures thresholds and delineated the modulatory role of 5-HT1B/D receptors and NOS/NO pathway. Our data revealed the anti-convulsant effects of lower doses of sumatriptan, and pro-convulsant effects of higher doses of sumatriptan. GR 127935, a selective 5-HT1B/D antagonist, could abolish the sumatriptan anti-convulsant effects, but it was ineffective against the sumatriptan pro-convulsant effects. Serotonin depletion by consecutive administration of p-CPA, a selective irreversible inhibitor of tryptophan hydroxylase, could not affect the anti-convulsant effects of sumatriptan. The anti-convulsant effects of sumatriptan was potentiated by L-NAME, a non-selective NOS inhibitor, 7-NI, a selective nNOS inhibitor, but not AG, an iNOS inhibitor. It was also neutralized by L-ARG, a NO precursor. The pro-convulsant effects of sumatriptan were blocked by L-NAME and AG, but not 7-NI. It was also potentiated by L-ARG. Our data revealed that anti-convulsive effects of sumatriptan is mediated by interaction between non-serotonergic 5-HT1B/D receptors and nNOS/NO pathway. Besides, the pro-convulsive effect of sumatriptan is mediated by iNOS/NO pathway independent of 5-HT1B/D receptors. For the first time, this study reported the biphasic effect of sumatriptan on an animal model of GCS and its modulatory pathways.
舒马曲坦是治疗偏头痛的首选药物之一。偏头痛和癫痫之间的关联突出了舒马曲坦对癫痫发作的可能影响。在这方面，我们研究了舒马曲坦对 PTZ 诱导的癫痫发作阈值的影响，并描绘了 5-HT1B/D 受体和 NOS/NO 途径的调节作用。我们的数据显示，较低剂量的舒马曲坦具有抗惊厥作用，而较高剂量的舒马曲坦则具有促惊厥作用。5-HT1B/D 受体的选择性拮抗剂 GR 127935 可以消除舒马曲坦的抗惊厥作用，但对舒马曲坦的促惊厥作用无效。连续给予色氨酸羟化酶的选择性不可逆抑制剂 p-CPA 可使血清素耗竭，但不能影响舒马曲坦的抗惊厥作用。非选择性 NOS 抑制剂 L-NAME、选择性 nNOS 抑制剂 7-NI 可增强舒马曲坦的抗惊厥作用，但 iNOS 抑制剂 AG 则不能。NO 前体 L-ARG 也能中和其作用。舒马曲坦的促惊厥作用被 L-NAME 和 AG 阻断，但 7-NI 则不能。L-ARG 还能增强其作用。我们的数据表明，舒马曲坦的抗惊厥作用是由非血清素能 5-HT1B/D 受体和 nNOS/NO 途径之间的相互作用介导的。此外，舒马曲坦的促惊厥作用是由 iNOS/NO 途径介导的，与 5-HT1B/D 受体无关。本研究首次报道了舒马曲坦对 GCS 动物模型的双相作用及其调节途径。
