OLIGODENDROCYTE DEATH IN CEREBRAL ISCHEMIA

描述(申请人提供)：脑白质(WM)在许多神经疾病中受损，包括局灶性脑缺血、围产期脑损伤、创伤和多发性硬化症。在之前的资助期间，我们和其他人发现少突胶质细胞(OL)非常容易受到AMPA/KA(AMPA/KA)谷氨酸受体过度激活的影响。出乎意料的是，我们发现在缺氧-葡萄糖缺乏期间，AMPA/KA拮抗剂在少突胶质细胞-轴突共培养中和在WM脑片中保护轴突和OL。由于分离的轴突不容易受到谷氨酸受体的激活，因此兴奋性毒性轴突损伤的机制尚不清楚。我们将验证这一假说，即在缺氧-葡萄糖剥夺过程中，少突胶质细胞上AMPA/KA受体的过度激活有助于有髓轴突的损伤，这涉及到活性氧物种(ROS)的释放。我们开发了两个新的模型来研究这些细胞相互作用：(A)细胞培养系统，在该系统中，孤立的轴突和少突胶质细胞比单独的任何一种细胞更容易受到缺氧和兴奋毒性的伤害，以及(B)急性脑片模型，该模型允许测量白质传导并可视化轴突和少突胶质细胞的形态。利用这些模型，我们将确定少突胶质细胞谷氨酸受体激活在轴突损伤中的作用，并评估涉及活性氧的潜在损伤途径。这些研究的结果可能会为疾病的治疗提供建议，这些疾病在中央白质具有共同的病理基础。

DESCRIPTION (provided by applicant): Cerebral white matter (WM) is damaged in many neurologic disorders, including focal ischemia, perinatal brain injury, trauma, and multiple sclerosis. During the previous funding period, we and others established that oligodendrocytes (OLs) are highly vulnerable to over activation of AMPA/kainate (AMPA/KA) glutamate receptors. Unexpectedly, we found that AMPA/KA antagonists during oxygen-glucose deprivation protect axons as well as OLs, in oligodendrocyte-axon co-cultures and in WM brain slices. Since isolated axons are not vulnerable to glutamate receptor activation, the mechanisms of excitotoxic axon injury remain unknown. We will examine the hypothesis that over activation of AMPA/KA receptors on oligodendrocytes during oxygen-glucose deprivation contributes to damage of myelinated axons, and this involves release of reactive oxygen species (ROS). We have developed two new models to study these cellular interactions (a) a cell culture system in which isolated axons and oligodendrocytes are much more vulnerable to hypoxic and excitotoxic insults than either cell type alone, and (b) an acute brain slice model which allows measurement of white matter conduction together with visualization of axon and oligodendrocyte morphology. Using these models we will determine the role of oligodendrocyte glutamate receptor activation in axon injury, and assess potential injury pathways involving reactive oxygen species. Results of these studies may suggest treatment approaches for diseases, which share common pathology in central white matter.