The present study evaluates the effect of modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) by inhibiting them in the acute phase and activating them in the sub-acute phase on post-stroke recovery in middle cerebral artery occlusion (MCAo) model of stroke in rats. After 90 min of MCAo, perampanel (an AMPAR antagonist, 1.5 mg/kg i.p) and aniracetam (an AMPA agonist, 50 mg/kg i.p.) were administered for different durations after MCAo. Later, after obtaining the best time point for the antagonist and the agonist treatment protocols, sequential treatment with perampanel and aniracetam were given, and the effect on neurological damage and post stroke recovery were assessed. Perampanel and aniracetam significantly protected MCAo-induced neurological damage and diminished the infarct percentage. Furthermore, treatment with these study drugs improved the motor coordination and grip strength. Sequential treatment with perampanel and aniracetam reduced the infarct percentage as assessed by MRI. Moreover, these compounds diminished the inflammation via reducing the levels of pro-inflammatory cytokines (TNF-α, IL-1β) and increasing the levels of anti-inflammatory cytokine (IL-10) along with reductions in GFAP expression. Moreover, the neuroprotective markers (BDNF and TrkB) were found to be significantly increased. Levels of apoptotic markers (Bax, cleaved-caspase-3; Bcl2 and TUNEL positive cells) and neuronal damage (MAP-2) were normalized with the AMPA antagonist and agonist treatment. Expressions of GluR1 and GluR2 subunits of AMPAR were significantly enhanced with sequential treatment. The present study thus showed that modulation of AMPAR improves neurobehavioral deficits and reduces the infarct percentage through anti-inflammatory, neuroprotective and anti-apoptotic effects.

本研究通过在急性期抑制α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯受体（AMPAR）并在亚急性期激活它们来评估调节α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯受体（AMPAR）对中风后恢复的影响大鼠大脑中动脉闭塞（MCAo）模型。 MCAo 90 分钟后，在 MCAo 后给予不同持续时间的吡仑帕奈（一种 AMPAR 拮抗剂，1.5 mg/kg ip）和阿尼拉西坦（一种 AMPA 激动剂，50 mg/kg ip）。随后，在获得拮抗剂和激动剂治疗方案的最佳时间点后，给予吡仑帕奈和阿尼西坦序贯治疗，评估对神经损伤和卒中后恢复的影响。吡仑帕奈和阿尼拉西坦显着保护 MCAo 引起的神经损伤并降低梗塞百分比。此外，这些研究药物的治疗改善了运动协调性和握力。根据 MRI 评估，吡仑帕奈和阿尼西坦序贯治疗降低了梗塞百分比。此外，这些化合物通过降低促炎细胞因子（TNF-α、IL-1β）水平、增加抗炎细胞因子（IL-10）水平以及减少 GFAP 表达来减轻炎症。此外，发现神经保护标记物（BDNF 和 TrkB）显着增加。通过 AMPA 拮抗剂和激动剂治疗，细胞凋亡标记物（Bax、cleaved-caspase-3；Bcl2 和 TUNEL 阳性细胞）和神经元损伤 (MAP-2) 水平恢复正常。 AMPAR 的 GluR1 和 GluR2 亚基的表达随着序贯治疗显着增强。 因此，本研究表明，调节 AMPAR 可通过抗炎、神经保护和抗凋亡作用改善神经行为缺陷并降低梗塞百分比。