Department of Applied Neurobiology, Division of Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
J Cereb Blood Flow Metab. 2009 Dec;29(12):1924-32. doi: 10.1038/jcbfm.2009.109. Epub 2009 Jul 29.
Ischemic and traumatic brain injuries often induce non-convulsive seizures (NCSs), which likely contribute to the worsening of neurological outcomes. Here, we evaluated the effect of glycyl-L-methylprolyl-L-glutamic acid (NNZ-2566) to lessen the severity of NCSs caused by permanent middle cerebral artery occlusion (pMCAo). Continuous electroencephalographic recordings were performed in rats during pMCAo. Glycyl-L-methylprolyl-L-glutamic acid (3, 10, or 100 mg/kg bolus followed by an infusion of a fixed dose of 3 mg/kg per hour for 12 h) was delivered at 20 mins after pMCAo (before the first NCS event) or delayed until immediately after the first NCS event occurred. Control rats received pMCAo and saline treatment. The results revealed that 91% of the saline-treated animals had NCSs (23 episodes per rat and 1238 secs per rat) with an onset latency of 35 mins after injury. When NNZ-2566 was administered before the NCS events, it dose-dependently reduced the NCS incidence to 36%-80%, decreased NCS frequency to 5-16 episodes per rat, and shortened the total duration of NCS to 251-706 secs per rat. The two high doses significantly reduced the infarct volume by 28%-30%. Delayed treatment also attenuated NCS duration but had no effect on the infarct volume. Results indicate that NNZ-2566 possesses a unique therapeutic potential as a safe prophylactic agent that synergistically provides neuroprotection and reduces injury-induced seizures.
缺血性和外伤性脑损伤常引起非惊厥性癫痫发作（NCSs），这可能导致神经功能恶化。在这里，我们评估了甘氨酰-L-甲基脯氨酰-L-谷氨酸（NNZ-2566）减轻永久性大脑中动脉闭塞（pMCAo）引起的 NCSs 严重程度的效果。在大鼠 pMCAo 期间进行连续脑电图记录。甘氨酰-L-甲基脯氨酰-L-谷氨酸（3、10 或 100mg/kg 推注，然后以每小时 3mg/kg 的固定剂量输注 12h）在 pMCAo 后 20 分钟（在第一次 NCS 事件之前）或延迟到第一次 NCS 事件发生后立即给予。对照大鼠接受 pMCAo 和生理盐水处理。结果表明，91%的盐水处理动物出现 NCSs（每只大鼠 23 次发作，每只大鼠 1238 秒），损伤后潜伏期为 35 分钟。当 NNZ-2566 在 NCS 事件之前给予时，它剂量依赖性地将 NCS 发生率降低到 36%-80%，将 NCS 频率降低到每只大鼠 5-16 次发作，并将 NCS 总持续时间缩短至每只大鼠 251-706 秒。两个高剂量显著减少 28%-30%的梗死体积。延迟治疗也减轻了 NCS 持续时间，但对梗死体积没有影响。结果表明，NNZ-2566 具有独特的治疗潜力，作为一种安全的预防剂，具有协同的神经保护作用，并减少损伤诱导的癫痫发作。
