McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Horm Behav. 2020 Jun;122:104753. doi: 10.1016/j.yhbeh.2020.104753. Epub 2020 Apr 21.
Sildenafil is a phosphodiesterase type 5 inhibitor used to treat male erectile dysfunction and pulmonary hypertension. A potential side effect of sildenafil is a noticeable decrease in seizure threshold. Oxytocin (OXT) secretion and the subsequent cAMP-responsive element-binding (CREB) phosphorylation are involved in proconvulsant effects of sildenafil in experimental models. The aim of the present study was to investigate the potential role of OXT receptors and their downstream calcineurin (CN)/inducible nitric oxide synthase (iNOS) pathways in proconvulsant effects of sildenafil. The pentylenetetrazole (PTZ)-induced seizure was used as a standard convulsion model in this study. Cortical CN activity, hippocampal nitrite levels, and proinflammatory cytokine content were measured. Our results indicated that following PTZ administration, sildenafil significantly increased CN activity at 40 mg/kg, respectively, in the control group. The combination of sildenafil and OXT receptor antagonist, atosiban (10 μg/kg, i.c.v) 30 min before sildenafil administration significantly reduced the CN activity. Also, the subeffective dose of CN inhibitor cyclosporine (5 mg/kg) 30 min before the administration of effective dose of sildenafil (40 mg/kg) reversed proconvulsant actions of sildenafil. This effect was iNOS-dependent because pretreatment of a low dose of aminoguanidine (20 mg/kg) 15 min before the administration of a low dose of cyclosporine (1 mg/kg) reversed the proconvulsant action of sildenafil (40 mg/kg). Finally, sildenafil induced the elevation of tumor necrosis factor alpha (TNF-α) and the nitrite level was blocked by the administration of cyclosporine in PTZ-treated mice. Collectively, our data provide insights into the role of OXT receptor/CN/iNOS pathway in the proconvulsant aspect of sildenafil.
西地那非是一种磷酸二酯酶 5 抑制剂，用于治疗男性勃起功能障碍和肺动脉高压。西地那非的一个潜在副作用是癫痫发作阈值明显降低。在实验模型中，催产素 (OXT) 分泌和随后的 cAMP 反应元件结合 (CREB) 磷酸化参与了西地那非的促惊厥作用。本研究旨在探讨 OXT 受体及其下游钙调神经磷酸酶 (CN)/诱导型一氧化氮合酶 (iNOS) 途径在西地那非促惊厥作用中的潜在作用。本研究中，戊四氮 (PTZ) 诱导的癫痫发作被用作标准惊厥模型。测量皮质 CN 活性、海马亚硝酸盐水平和促炎细胞因子含量。我们的结果表明，在 PTZ 给药后，西地那非分别在对照组中以 40mg/kg 的剂量显著增加 CN 活性。在给予西地那非之前 30 分钟给予 OXT 受体拮抗剂阿托西班（10μg/kg，脑室内）的组合显著降低了 CN 活性。此外，CN 抑制剂环孢素（5mg/kg）的亚效剂量在给予有效剂量的西地那非（40mg/kg）之前 30 分钟给药可逆转西地那非的促惊厥作用。这种作用是 iNOS 依赖性的，因为在给予低剂量环孢素（1mg/kg）之前 15 分钟给予低剂量氨基胍（20mg/kg）预处理可逆转西地那非（40mg/kg）的促惊厥作用。最后，西地那非诱导肿瘤坏死因子-α（TNF-α）升高，环孢素给药可阻断 PTZ 处理小鼠中亚硝酸盐水平的升高。总之，我们的数据提供了关于 OXT 受体/CN/iNOS 途径在西地那非促惊厥方面作用的见解。
