A new look at glutamate and ischemia: NMDA agonist improves long-term functional outcome in a rat model of stroke.
A new look at glutamate and ischemia: NMDA agonist improves long-term functional outcome in a rat model of stroke.
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DOI：
10.2217/fnl.11.55
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发表时间：
2011-11-01
期刊：
影响因子：
1.3
通讯作者：
Biegon A
中科院分区：
文献类型：
--
作者：
Dhawan J;Benveniste H;Luo Z;Nawrocky M;Smith SD;Biegon A
缺血性中风会引发大量但短暂的谷氨酸流出和 NMDA 受体 (NMDAR) 的过度激活，可能导致神经元死亡。然而，多项 NMDA 拮抗剂临床试验未能改善甚至恶化中风结果。最近发现中风后 NMDAR 密度持续下降，这在可塑性和记忆形成中起着关键作用，这表明 NMDAR 刺激而不是抑制可能在中风后的亚急性期有益。本研究旨在探讨 NMDAR 部分激动剂 d-环丝氨酸 (DCS) 对短暂大脑中动脉闭塞大鼠（缺血性中风动物模型）的长期结构、功能和行为结果的影响。大脑中动脉闭塞 90 分钟的大鼠 (n = 36) 在闭塞后 24 小时单次注射 DCS (10 mg/kg) 或载体（磷酸盐缓冲盐水），并随访 30 天。 MRI（结构性和功能性）用于测量前爪电刺激引起的梗塞、萎缩和皮质激活。使用新物体识别测试在咬合后第 7、21 和 30 天评估记忆功能。总共纳入 20 个非缺血对照进行比较。相对于赋形剂治疗，DCS 治疗可显着改善体感和认知功能。到第 30 天，DCS 治疗动物的认知表现与非缺血对照组没有区别，而媒介物治疗动物表现出稳定的记忆缺陷。 DCS对梗塞或萎缩没有显着影响。这些结果支持 NMDAR 刺激在中风后恢复期间发挥有益作用，很可能是由于神经可塑性增强而不是神经保护。
Ischemic stroke triggers a massive, although transient, glutamate efflux and excessive activation of NMDA receptors (NMDARs), possibly leading to neuronal death. However, multiple clinical trials with NMDA antagonists failed to improve, or even worsened, stroke outcome. Recent findings of a persistent post-stroke decline in NMDAR density, which plays a pivotal role in plasticity and memory formation, suggest that NMDAR stimulation, rather than inhibition, may prove beneficial in the subacute period after stroke. This study aims to examine the effect of the NMDAR partial agonist d-cycloserine (DCS) on long-term structural, functional and behavioral outcomes in rats subjected to transient middle cerebral artery occlusion, an animal model of ischemic stroke. Rats (n = 36) that were subjected to 90 min of middle cerebral artery occlusion were given a single injection of DCS (10 mg/kg) or vehicle (phosphate-buffered saline) 24 h after occlusion and followed up for 30 days. MRI (structural and functional) was used to measure infarction, atrophy and cortical activation due to electrical forepaw stimulation. Memory function was assessed on days 7, 21 and 30 postocclusion using the novel object recognition test. A total of 20 nonischemic controls were included for comparison. DCS treatment resulted in significant improvement of somatosensory and cognitive function relative to vehicle treatment. By day 30, cognitive performance of the DCS-treated animals was indistinguishable from nonischemic controls, while vehicle-treated animals demonstrated a stable memory deficit. DCS had no significant effect on infarction or atrophy. These results support a beneficial role for NMDAR stimulation during the recovery period after stroke, most likely due to enhanced neuroplasticity rather than neuroprotection.