Does Nitric Oxide Control Synaptic Zinc Release?

描述（由申请人提供）：突触释放的锌在癫痫发作、缺血和创伤中具有毒性作用，在这三种情况下都会导致神经元损伤。相反，用锌螯合剂阻断兴奋毒性突触锌通量可使神经元变性标志物减少多达80%。我们最近发现的证据表明，一氧化氮（NO）可能控制锌的突触释放。如果NO被证明是控制因素，这将为中风、缺血、创伤和癫痫等锌引起的脑损伤的治疗开辟全新的途径。此外，通过NO调节预防Zn2+毒性可作为心脏搭桥和颈动脉内膜切除术的治疗前处理。我们的实验数据表明，注入大脑的NO同时消耗突触前钮扣的锌，同时将锌释放到透析液中，我们从脑切片制备中获得的补充数据表明，NO导致Zn2+释放到浴液中。也许更令人信服的是，额外的数据表明，锌诱导的脑外伤后神经元损伤在阻断NO*合成后减少了50%。本提案的目的是确定是否，事实上，在兴奋性毒性过程中，NO控制Zn2+释放。

DESCRIPTION (provided by applicant): Synaptically-released zinc has toxic impact in seizure, ischemia, and trauma, contributing to neuronal injury in all three conditions. Conversely, blockade of the excitotoxic synaptic zinc flux with zinc chelators can reduce neuronal degeneration markers by as much as 80%. We have recently discovered evidence indicating that Nitric Oxide (NO) may control the synaptic release of zinc. Should NO prove to be the controlling factor, this would open completely new avenues for management of zinc-induced brain damage in stroke, ischemia, trauma, and seizure. Moreover, prophylactic control of the Zn2+ toxicity via NO modulation could be used as therapeutic pretreatment in cardiac bypass and carotid endarterectomy procedures. Our pilot data indicate that NO infused into the brain simultaneously depletes presynaptic boutons of their zinc while releasing zinc into dialysates, and we have complementary data from brain slice preparations indicating that NO causes the release of Zn2+ into the bath. Perhaps more compelling, additional data suggest that zinc-induced neuronal injury after head trauma is decreased by up to 50% after blockade of NO* synthesis. The objective of the present proposal is to establish with certainty whether, in fact, NO controls Zn2+ release during excitotoxicity.