Department of Animal Physiology, Institute of Biology, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland.
Pharmacol Rep. 2010 Mar-Apr;62(2):383-91. doi: 10.1016/s1734-1140(10)70278-4.
Sildenafil is the first marketed phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction and recently, for pulmonary hypertension. While the treatment was found to be highly effective, several adverse effects are associated with this compound. Among numerous central nervous system-related untoward effects, proconvulsant activity was reported. The purpose of this study was to assess the effect of sildenafil on seizure threshold in rodents. Two seizure models/tests were used: the timed intravenous (iv) pentylenetetrazol (PTZ) infusion test in mice and the amygdala-kindling model in rats. Sildenafil was administered intraperitoneally 30 min before induction of seizures. In the iv PTZ paradigm, the first myoclonic twitch, generalized clonus with loss of the righting reflex, and forelimb tonus were recorded. In the amygdala-kindling model in rats, the following parameters were analyzed: threshold for induction of epileptiform discharges in the stimulated amygdala (afterdischarge threshold, ADT), seizure severity, seizure duration, and afterdischarge duration. Sildenafil (dosage range of 5-40 mg/kg) did not significantly affect the threshold for myoclonic twitches in the timed iv PTZ infusion test in mice but significantly decreased the threshold for clonic seizures at a dose of 20 mg/kg. Sildenafil at all doses tested neither significantly influenced the focal seizure threshold in the amygdala-kindling model of epilepsy in rats nor influenced seizure severity. Sildenafil significantly shortened afterdischarge duration and seizure duration recorded at the ADT current, indicative of a weak anticonvulsant activity. Our results show that sildenafil may have both pro- and anticonvulsant activity, which depends on the experimental model of epilepsy, on animal species and the dose of sildenafil. Based on these data and in view of the clinical observations, sildenafil should be used in patients suffering from epilepsy with caution and only based on a careful individual risk/benefit evaluation.
西地那非是第一种用于治疗勃起功能障碍和最近的肺动脉高压的磷酸二酯酶 5 抑制剂。虽然该治疗方法被证明非常有效，但与该化合物相关的有许多不良影响。在众多中枢神经系统相关的不良反应中，有报道称其具有致惊厥作用。本研究旨在评估西地那非对啮齿动物癫痫发作阈值的影响。使用了两种癫痫模型/测试：小鼠的计时静脉（iv）戊四氮（PTZ）输注测试和大鼠的杏仁核点燃模型。西地那非在诱导癫痫发作前 30 分钟腹腔内给药。在 iv PTZ 范式中，记录了第一次肌阵挛性抽搐、全身性阵挛伴翻正反射丧失和前肢张力。在大鼠杏仁核点燃模型中，分析了以下参数：刺激杏仁核中癫痫样放电的诱导阈值（后放电阈值，ADT）、癫痫发作严重程度、发作持续时间和后放电持续时间。西地那非（剂量范围为 5-40mg/kg）对计时 iv PTZ 输注测试中小鼠的肌阵挛性抽搐阈值没有显著影响，但在 20mg/kg 剂量下显著降低了阵挛性抽搐的阈值。在所有测试剂量下，西地那非既没有显著影响大鼠杏仁核点燃模型中局灶性癫痫发作阈值，也没有影响癫痫发作严重程度。西地那非显著缩短了在 ADT 电流记录的后放电持续时间和发作持续时间，表明其具有较弱的抗惊厥活性。我们的结果表明，西地那非可能具有促惊厥和抗惊厥作用，这取决于癫痫的实验模型、动物物种和西地那非的剂量。基于这些数据和临床观察，西地那非应谨慎用于患有癫痫的患者，并且仅基于仔细的个体风险/收益评估。
