Mishra Awanish, Goel Rajesh Kumar
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Rae Bareli, Uttar Pradesh, India.
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
Neuroscience. 2016 Dec 17;339:319-328. doi: 10.1016/j.neuroscience.2016.10.010. Epub 2016 Oct 13.
Our previous studies have suggested a strong involvement of serotonergic innervations in epileptogenesis and associated memory impairment. Several studies have suggested that the modulation of 5-HT receptors could serve as a promising tool for the management of epilepsy and memory deficit. The present study was envisaged to confirm this hypothesis. In this study, kindling was induced in male Swiss Albino mice using a subconvulsive dose of pentylenetetrazole (PTZ) (35mg/kg at 48±2h). Once the animals were kindled, they were treated with a vehicle, ondansetron (0.1, 0.5, 1mg/kg/day; i.p.), m-chlorophenylbiguanide (m-CPBG) (1mg/kg/day; i.p.), and ondansetron+m-CPBG for 20days. On days 5, 10, 15, and 20, they were administered a PTZ challenging dose (35mg/kg) to assess the seizure severity score; thereafter, memory was evaluated. After behavioral assessment on day 20, the animals were sacrificed and their brains were isolated to estimate cortical and hippocampal neurotransmitter levels (glutamate and gamma aminobutyric acid (GABA) by the high-performance liquid chromatography with the fluorescence detection method, and the nitrite level and acetylcholinesterase (AChE) activity by the microplate reader method). Ondansetron treatment significantly reduced the seizure severity and improved the acquisition performance in a dose-dependent manner. Neurochemical analysis suggested that ondansetron treatment significantly reduced the nitrite level and AChE activity in the cortex as well as in the hippocampus. The outcome of this study suggests the reduction in AChE activity and the nitrite level could be considered as protective mechanisms of ondansetron for amelioration of PTZ kindling and associated memory deficit.
我们之前的研究表明，血清素能神经支配在癫痫发生及相关记忆损伤中起重要作用。多项研究表明，调节5-羟色胺受体可能是治疗癫痫和记忆缺陷的一种有前景的方法。本研究旨在证实这一假设。在本研究中，使用亚惊厥剂量的戊四氮（PTZ）（48±2小时时35mg/kg）在雄性瑞士白化小鼠中诱导点燃。动物一旦被点燃，就用溶剂、昂丹司琼（0.1、0.5、1mg/kg/天；腹腔注射）、间氯苯双胍（m-CPBG）（1mg/kg/天；腹腔注射）以及昂丹司琼+m-CPBG治疗20天。在第5、10、15和20天，给它们注射PTZ激发剂量（35mg/kg）以评估癫痫发作严重程度评分；此后，评估记忆。在第20天进行行为评估后，处死动物并分离其大脑以估计皮质和海马神经递质水平（通过高效液相色谱荧光检测法测定谷氨酸和γ-氨基丁酸（GABA），通过酶标仪法测定亚硝酸盐水平和乙酰胆碱酯酶（AChE）活性）。昂丹司琼治疗以剂量依赖方式显著降低了癫痫发作严重程度并改善了习得表现。神经化学分析表明，昂丹司琼治疗显著降低了皮质和海马中的亚硝酸盐水平及AChE活性。本研究结果表明，AChE活性和亚硝酸盐水平的降低可被视为昂丹司琼改善PTZ点燃及相关记忆缺陷的保护机制。
