ZINC AND FOCAL CEREBRAL ISCHEMIA

越来越多的证据表明，锌可能在缺血损伤后神经元死亡中发挥作用。多项体外研究表明锌对多种类型的中枢神经系统细胞具有毒性作用，体内有强有力的证据表明锌在全脑缺血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，锌中毒是可以通过使用锌特异性螯合剂(CaEDTA)来预防的。我推测锌可能在局灶性脑缺血后的损伤中也起到了作用。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阻塞(MCAO)大鼠模型中，锌移位到注定要死亡的半暗带神经元中是否发生。为了做到这一点，我们将利用锌特异的荧光标记(TSQ)应用于从接受一过性大脑中动脉阻塞的大鼠获得的脑切片。其次，在相同的暂时性MCAO模型中，将确定通过脑室内注射CaEDTA进行锌离子特异性螯合是否会减少脑梗塞范围。第三，将利用两种运动功能评分系统来确定这种CaEDTA治疗局灶性脑缺血是否改善了功能结果评分。上述研究将进一步明确S锌在缺血性神经元损伤中的作用，并有可能为新的锌导向治疗方案应用于局灶性脑缺血提供依据。

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.