Gaire Bhakta Prasad, Sapkota Arjun, Choi Ji Woong
Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea.
Antioxidants (Basel). 2020 Nov 8;9(11):1097. doi: 10.3390/antiox9111097.
Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA) antagonist under clinical trials for lung fibrosis and psoriasis, against both acute and sub-acute injuries after ischemic stroke by employing a mouse model with transient middle cerebral artery occlusion (tMCAO). BMS administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, neurological deficits, and cell apoptosis at day 1 after tMCAO. Neuroprotective effects of BMS were preserved even when administered at 3 h after reperfusion. Neuroprotection by BMS against acute injuries was associated with attenuation of microglial activation and lipid peroxidation in post-ischemic brains. Notably, repeated BMS administration daily for 14 days after tMCAO exerted long-term neuroprotection in tMCAO-challenged mice, as evidenced by significantly attenuated neurological deficits and improved survival rate. It also attenuated brain tissue loss and cell apoptosis in post-ischemic brains. Mechanistically, it significantly enhanced neurogenesis and angiogenesis in injured brains. A single administration of BMS provided similar long-term neuroprotection except survival rate. Collectively, BMS provided neuroprotection against both acute and sub-acute injuries of ischemic stroke, indicating that BMS might be an appealing therapeutic agent to treat ischemic stroke.
中风是主要的死亡原因。中风幸存者常常长期遭受功能残疾之苦。本研究利用短暂性大脑中动脉闭塞（tMCAO）小鼠模型，证明了BMS-986020（BMS）——一种正在进行肺纤维化和银屑病临床试验的选择性溶血磷脂酸受体1（LPA）拮抗剂——对缺血性中风后急性和亚急性损伤均具有神经保护作用。再灌注后立即给予BMS可显著减轻急性脑损伤，包括tMCAO后第1天的脑梗死、神经功能缺损和细胞凋亡。即使在再灌注后3小时给予BMS，其神经保护作用依然存在。BMS对急性损伤的神经保护作用与缺血后脑内小胶质细胞活化和脂质过氧化的减轻有关。值得注意的是，tMCAO后每天重复给予BMS 14天，可在tMCAO小鼠中发挥长期神经保护作用，表现为神经功能缺损显著减轻和存活率提高。它还减轻了缺血后脑组织的损失和细胞凋亡。从机制上讲，它显著增强了受损脑内的神经发生和血管生成。单次给予BMS除存活率外也提供了类似的长期神经保护作用。总体而言，BMS对缺血性中风的急性和亚急性损伤均具有神经保护作用，表明BMS可能是一种有吸引力的治疗缺血性中风的药物。
