Kordi Jaz Elham, Moghimi Ali, Fereidoni Masoud, Asadi Saeedeh, Shamsizadeh Ali, Roohbakhsh Ali
Department of Biology, Faculty of Sciences, Ferdowsi University of Mashhad, Azadi Sq., Mashhad, Iran.
Physiology-Pharmacology Research Center and Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Pistachio Co Street, Rafsanjan, Iran.
Fundam Clin Pharmacol. 2017 Apr;31(2):201-207. doi: 10.1111/fcp.12249. Epub 2016 Nov 23.
Convulsive seizures are due to abnormal synchronous and repetitive neuronal discharges in the central nervous system (CNS). Finding new therapeutics to overcome the side effects of the current drug therapies and to increase their effectiveness is ongoing. Orexin-A and orexin-B are brain neuropeptides originating from postero-lateral hypothalamic neurons. Studies show that orexins, through activation of OX1 and OX2 receptors, have excitatory effects in the CNS. Accordingly, this study was designed to evaluate the effect of OX1 receptor antagonist (SB-334867) on seizure- and anxiety-related behaviors of pentylenetetrazol (PTZ)-kindled rats. Kindling was induced by repeated intraperitoneal (IP) injections of PTZ (32 mg/kg) with two-day intervals for 24 days in male Wistar rats. Three groups received intracerebroventricular (ICV) injections of SB-334867 (2.5, 5, and 10 μg/rat) before PTZ injections. Two control groups received vehicle (2 μL/rat, ICV) and valproate (26 μg/rat, ICV) before PTZ injections. An extra group of control animals received saline both ICV and IP. Seizure-related behaviors were monitored for 30 min following PTZ administration. The anxiety-like behaviors were also assessed using elevated plus-maze in the first and last days of the study. The results revealed that ICV injection of SB-334867, mainly at the dose of 10 μg/rat, decreased the median of seizure stages, prolonged the latency and reduced the duration of different seizure stages, and reversed the PTZ-induced anxiety-like behaviors. Based on the presented results, it is suggested that pharmacological blockade of the OX1 receptor is a potential target in the treatment of seizure and concomitant anxiety disorders.
惊厥性癫痫发作是由于中枢神经系统（CNS）中神经元异常同步和重复放电所致。寻找新的治疗方法以克服当前药物治疗的副作用并提高其有效性的工作正在进行中。食欲素-A和食欲素-B是源自下丘脑后外侧神经元的脑内神经肽。研究表明，食欲素通过激活OX1和OX2受体，在中枢神经系统中具有兴奋作用。因此，本研究旨在评估OX1受体拮抗剂（SB-334867）对戊四氮（PTZ）点燃大鼠的癫痫发作和焦虑相关行为的影响。在雄性Wistar大鼠中，通过每隔两天腹腔注射（IP）32mg/kg的PTZ，连续注射24天来诱导点燃。三组在PTZ注射前接受脑室内（ICV）注射SB-334867（2.5、5和10μg/只大鼠）。两个对照组在PTZ注射前接受溶剂（2μL/只大鼠，ICV）和丙戊酸盐（26μg/只大鼠，ICV）。另一组对照动物脑室内和腹腔内均接受生理盐水。在给予PTZ后监测30分钟的癫痫发作相关行为。在研究的第一天和最后一天，还使用高架十字迷宫评估焦虑样行为。结果显示，脑室内注射SB-334867，主要是在剂量为10μg/只大鼠时，降低了癫痫发作阶段的中位数，延长了潜伏期并缩短了不同癫痫发作阶段的持续时间，并逆转了PTZ诱导的焦虑样行为。基于所呈现的结果，提示OX1受体的药理学阻断是治疗癫痫发作和伴发焦虑症的潜在靶点。
