El-Megiri Nada, Mostafa Yasser M, Ahmed Amal, Mehanna Eman T, El-Azab Mona F, Alshehri Fatma, Alahdal Hadil, El-Sayed Norhan M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University, Badr 11829, Egypt.
Pharmaceuticals (Basel). 2022 Sep 6;15(9):1113. doi: 10.3390/ph15091113.
Disturbance of glucose metabolism, nerve growth factor (NGF) and m-TOR signaling have been associated with the pathophysiology of epilepsy. Pioglitazone (PGZ) is an anti-diabetic drug that shows a protective effect in neurodegenerative diseases including epilepsy; however, its exact mechanism is not fully elucidated. The present study aimed to investigate the potential neuroprotective effect of PGZ in pentylenetetrazole (PTZ) kindled seizure in mice. Swiss male albino mice were randomly distributed into four groups, each having six mice. Group 1 was considered the control. Epilepsy was induced by PTZ (35 mg/kg i.p.) thrice a week for a total of 15 injections in all other groups. Group 2 was considered the untreated PTZ group while Group 3 and Group 4 were treated by PGZ prior to PTZ injection at two dose levels (5 and 10 mg/kg p.o., respectively). Seizure activity was evaluated after each PTZ injection according to the Fischer and Kittner scoring system. At the end of the experiment, animals were sacrificed under deep anesthesia and the hippocampus was isolated for analysis of glucose transporters by RT-PCR, nerve growth factor (NGF) by ELISA and mTOR by western blotting, in addition to histopathological investigation. The PTZ-treated group showed a significant rise in seizure score, NGF and m-TOR hyperactivation, along with histological abnormalities compared to the control group. Treatment with PGZ demonstrated a significant decrease in NGF, seizure score, m-TOR, GLUT-1 and GLUT-3 in comparison to the PTZ group. In addition, improvement of histological features was observed in both PGZ treated groups. These findings suggest that PGZ provides its neuroprotective effect through modulating m-TOR signaling, glucose metabolism and NGF levels.
葡萄糖代谢紊乱、神经生长因子（NGF）和m-TOR信号传导与癫痫的病理生理学相关。吡格列酮（PGZ）是一种抗糖尿病药物，在包括癫痫在内的神经退行性疾病中显示出保护作用；然而，其确切机制尚未完全阐明。本研究旨在探讨PGZ对小鼠戊四氮（PTZ）点燃性癫痫发作的潜在神经保护作用。将瑞士雄性白化小鼠随机分为四组，每组六只。第1组为对照组。在所有其他组中，每周三次腹腔注射PTZ（35mg/kg），共注射15次以诱导癫痫。第2组为未治疗的PTZ组，而第3组和第4组在PTZ注射前分别以两个剂量水平（5和10mg/kg口服）用PGZ治疗。根据Fischer和Kittner评分系统在每次PTZ注射后评估癫痫发作活动。实验结束时，在深度麻醉下处死动物，分离海马用于通过RT-PCR分析葡萄糖转运蛋白、通过ELISA分析神经生长因子（NGF）以及通过蛋白质印迹分析mTOR，此外还进行组织病理学研究。与对照组相比，PTZ治疗组的癫痫发作评分、NGF和m-TOR过度激活显著升高，同时伴有组织学异常。与PTZ组相比，PGZ治疗显示NGF、癫痫发作评分、m-TOR、GLUT-1和GLUT-3显著降低。此外，在两个PGZ治疗组中均观察到组织学特征的改善。这些发现表明，PGZ通过调节m-TOR信号传导、葡萄糖代谢和NGF水平发挥其神经保护作用。
