ZINC AND FOCAL CEREBRAL ISCHEMIA

越来越多的证据表明锌可能在缺血性损伤后神经元死亡中起作用。 许多体外研究已经证明锌对多种CNS细胞类型具有毒性，并且有强有力的体内证据表明锌在全脑缺血的选择性神经元死亡中起重要作用。 此外，体外和体内研究表明，锌毒性是可以通过使用锌特异性螯合剂（CaEDTA）预防的。 我推测锌也可能在局灶性缺血后的损伤中发挥作用。 以下三个具体目标将解决这一假设。 首先，将确定在短暂性大脑中动脉闭塞（MCAO）大鼠模型中是否发生锌易位到注定死亡的半影神经元中。 为了实现这一点，我们将利用锌特异性荧光标记物（TSQ）应用于从经历短暂MCAO的大鼠获得的脑切片。 其次，将确定通过CaEDTA的静脉内施用的锌特异性螯合是否会在该相同的短暂MCAO模型中减小梗死面积。 第三，利用两个运动性能评分系统确定这种用于局灶性缺血的CaEDTA治疗是否改善功能结果评分。 上述研究将进一步明确锌在缺血性神经元损伤中的作用，并可能表明新的锌导向治疗方案应应用于局灶性缺血。

There is a growing body of evidence that zinc may play a role in neuronal death following ischemic insults. A number of in vitro studies have demonstrated zinc toxicity on a variety of CNS cell types, and there is strong in vivo evidence that zinc plays an important role in the selective neuronal death of global ischemia. In addition, in vitro and in vivo studies suggest that zinc toxicity is preventable through the use of a zinc specific chelator (CaEDTA). I hypothesize that zinc may play a role in the injury following focal ischemia as well. The following three specific aims will address this hypothesis. First, it will be determined if zinc translocation into penumbral neurons destined to die occurs in a transient middle cerebral artery occlusion (MCAO) rat model. To accomplish this, we will utilize a zinc- specific fluorescent marker (TSQ) applied to brain sections obtained from rats who underwent transient MCAO. Second, it will be determined if zinc-specific chelation through an intravencular administration of CaEDTA will decrease infarct size in this same transient MCAO model. Third, it will be determined if this CaEDTA treatment for focal ischemia improves functional outcome scores utilizing two motor performance scoring systems. The above studies will further define zinc s role in ischemic neuronal injury and potentially show that novel zinc-directed therapeutic regimens should be applied to focal ischemia.