Alhaj Momen W, Zaitone Sawsan A, Moustafa Yasser M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
Behav Pharmacol. 2015 Jun;26(4):369-82. doi: 10.1097/FBP.0000000000000127.
Epilepsy has been documented to lead to many changes in the nervous system including cell loss and mossy fiber sprouting. Neuronal loss and aberrant neuroplastic changes in the dentate gyrus of the hippocampus have been identified in the pentylenetetrazole (PTZ) kindling model. Antiseizure activity of selective serotonin reuptake inhibitors has been reported in several studies. In the current study, the protective effect of fluvoxamine against PTZ-kindling was investigated in terms of seizure scores, neuronal loss, and regulation of hippocampal neuroplasticity. Further, the role of 5-HT3 receptors was determined. Kindling was induced by repeated injections of PTZ (35 mg/kg) thrice weekly, for a total of 13 injections. One hundred male albino mice were allocated into 10 groups: (1) saline, (2) PTZ, (3) diazepam (1 mg/kg)+PTZ, (4-6) fluvoxamine (5, 10 or 20 mg/kg)+PTZ, (7) ondansetron+fluvoxamine (20 mg/kg)+PTZ, (8) ondansetron+PTZ group, (9) ondansetron (2 mg/kg, i.p.)+saline, and (10) fluvoxamine (20 mg/kg)+saline. PTZ-kindled mice showed high seizure activity, hippocampal neuronal loss, and expression of growth-associated phosphoprotein (GAP-43) compared with saline-treated mice. Repeated administration of fluvoxamine (20 mg/kg) in PTZ-kindled mice suppressed seizure scores, protected against hippocampal neuronal loss, and downregulated GAP-43 expression, without producing any signs of the 5-HT syndrome in healthy rats. Importantly, pretreatment with a selective 5-HT3 receptor blocker (ondansetron) attenuated the aforementioned effects of fluvoxamine. In conclusion, the ameliorating effect of fluvoxamine on hippocampal neurons and neuroplasticity in PTZ-kindled mice was, at least in part, dependent on enhancement of hippocampal serotoninergic transmission at 5-HT3 receptors.
已有文献记载，癫痫会导致神经系统发生许多变化，包括细胞丢失和苔藓纤维发芽。在戊四氮（PTZ）点燃模型中，已发现海马齿状回中的神经元丢失和异常神经可塑性变化。多项研究报道了选择性5-羟色胺再摄取抑制剂的抗癫痫活性。在本研究中，从癫痫发作评分、神经元丢失和海马神经可塑性调节方面研究了氟伏沙明对PTZ点燃的保护作用。此外，还确定了5-HT3受体的作用。通过每周三次重复注射PTZ（35mg/kg）诱导点燃，共注射13次。将100只雄性白化小鼠分为10组：（1）生理盐水组，（2）PTZ组，（3）地西泮（1mg/kg）+PTZ组，（4-6）氟伏沙明（5、10或20mg/kg）+PTZ组，（7）昂丹司琼+氟伏沙明（20mg/kg）+PTZ组，（8）昂丹司琼+PTZ组，（9）昂丹司琼（2mg/kg，腹腔注射）+生理盐水组，（10）氟伏沙明（20mg/kg）+生理盐水组。与生理盐水处理的小鼠相比，PTZ点燃的小鼠表现出高癫痫发作活性、海马神经元丢失和生长相关磷蛋白（GAP-43）表达。在PTZ点燃的小鼠中重复给予氟伏沙明（20mg/kg）可抑制癫痫发作评分，防止海马神经元丢失，并下调GAP-43表达，且在健康大鼠中未产生任何5-HT综合征迹象。重要的是，用选择性5-HT3受体阻滞剂（昂丹司琼）预处理可减弱氟伏沙明的上述作用。总之，氟伏沙明对PTZ点燃小鼠海马神经元和神经可塑性的改善作用至少部分依赖于5-HT3受体处海马5-羟色胺能传递的增强。
