申请人:Tymianski Michael
公开号:US20050059597A1
公开(公告)日:2005-03-17
A method of inhibiting the binding between N-methyl-D-aspartate receptors and neuronal proteins in a neuron is disclosed. The method comprises administering to the neuron an effective inhibiting amount of a peptide replacement agent for the NMDA receptor or neuronal protein interaction domain that effect said inhibition of the NMDA receptor—neuronal protein interaction. The method is of value in reducing the damaging effect of injury to mammalian cells. Postsynaptic density-95 protein (PSD-95) couples neuronal N-methyl-D-aspartate receptors (NMDARs) to pathways mediating excitotoxicity, ischemic and traumatic brain damage. This coupling was disrupted by transducing neurons with peptides that bind to modular domains on either side of the PSD-95/NMDAR interaction complex. This treatment attenuated downstream NMDAR signaling without blocking NMDAR activity, protected cultured cortical neurons from excitotoxic insults, dramatically reduced cerebral infarction volume in rats subjected to transient focal cerebral ischemia, and traumatic brain injury (TBI) in rats.
本发明公开了一种抑制神经元中N-甲基-D-天冬氨酸受体和神经元蛋白之间结合的方法。该方法包括向神经元施用有效抑制量的 NMDA 受体或神经元蛋白相互作用结构域的多肽替代物,从而达到抑制 NMDA 受体与神经元蛋白相互作用的效果。该方法对减少哺乳动物细胞损伤的破坏作用具有重要价值。突触后密度-95 蛋白(PSD-95)将神经元 N-甲基-D-天冬氨酸受体(NMDAR)与介导兴奋毒性、缺血和创伤性脑损伤的途径耦合在一起。用与 PSD-95/NMDAR 相互作用复合物两侧模块化结构域结合的多肽转导神经元,可以破坏这种耦合。这种处理方法在不阻断 NMDAR 活性的情况下减弱了下游 NMDAR 信号传导,保护了培养的大脑皮层神经元免受兴奋性毒性损伤,显著减少了遭受短暂局灶性脑缺血和创伤性脑损伤(TBI)的大鼠的脑梗塞体积。