Mohammadian Maryam, Bahaoddini Aminollah, Namavar Mohammad Reza
Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran.
Histomorphometry and Stereology Research Center and Department of Anatomical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
IBRO Neurosci Rep. 2024 Nov 24;17:463-470. doi: 10.1016/j.ibneur.2024.11.012. eCollection 2024 Dec.
Stroke is the second leading cause of global death and is characterized by excitotoxic neuronal death caused by NMDA (N-Methyl-D-Aspartate) receptor overactivation. The present study was conducted to investigate the therapeutic potential of IC87201, a novel small molecule interfering with the NMDA receptor intracellular signaling pathway, in reducing the extent of ischemic stroke-induced brain damage.
Cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO) method in 24 anesthetized adult male rats for one hour. The animals were randomized into sham, MCAO, MCAO+ DXM (Dextromethorphan hydrobromide monohydrate) as an NMDA antagonist, and MCAO+ IC87201 groups which in the last two groups, DXM (50 mg/kg) and IC87201 (10 mg/kg) were injected intraperitoneally after ischemia. The neurobehavioral scores were appraised for 7 days and after that, brain tissue was appropriately prepared to perform the stereological evaluations.
The administration of IC87201 significantly recovered post-ischemia damages, including neurobehavioral function, reduction of volume of the total hemisphere, cortex, and striatum in rat brain, and the percentage of infarcted areas. Additionally, in the striatum region, IC87201 caused an increase in the total number of neuronal and non-neuronal cells as well as a decrease in the total number of dead cells. Some of these parameters were improved by DXM, but in general, IC87201 outperformed that.
IC87201 was successful in minimizing ischemia-induced damage, especially in the striatal region. In addition, IC87201, as a molecule that acts on the intracellular signaling cascade of the NMDA receptor, performed better than DXM, as an antagonist of this receptor.
中风是全球第二大死因，其特征是由NMDA（N-甲基-D-天冬氨酸）受体过度激活导致的兴奋性毒性神经元死亡。本研究旨在探讨IC87201（一种干扰NMDA受体内细胞信号通路的新型小分子）在减少缺血性中风所致脑损伤程度方面的治疗潜力。
采用大脑中动脉闭塞（MCAO）法，对24只麻醉的成年雄性大鼠诱导脑缺血1小时。将动物随机分为假手术组、MCAO组、MCAO + DXM（氢溴酸右美沙芬一水合物，作为NMDA拮抗剂）组和MCAO + IC87201组，后两组在缺血后腹腔注射DXM（50mg/kg）和IC87201（10mg/kg）。连续7天评估神经行为评分，之后，对脑组织进行适当处理以进行体视学评估。
给予IC87201可显著恢复缺血后损伤，包括神经行为功能、大鼠脑半球、皮质和纹状体总体积的减小以及梗死面积百分比。此外，在纹状体区域，IC87201使神经元和非神经元细胞总数增加，死亡细胞总数减少。DXM改善了其中一些参数，但总体而言，IC87201表现更优。
IC87201成功地将缺血性损伤降至最低，尤其是在纹状体区域。此外，作为一种作用于NMDA受体内细胞信号级联反应的分子，IC87201比作为该受体拮抗剂的DXM表现更好。
