OLIGODENDROCYTE DEATH IN CEREBRAL ISCHEMIA

描述（由申请人提供）：大脑白色物质（WM）在许多神经系统疾病中受损，包括局灶性缺血、围产期脑损伤、创伤和多发性硬化。在之前的资助期间，我们和其他人确定少突胶质细胞（OL）非常容易过度激活AMPA/红藻氨酸（AMPA/KA）谷氨酸受体。出乎意料的是，我们发现，AMPA/KA拮抗剂在氧-葡萄糖剥夺保护轴突以及OL，在少突胶质细胞-轴突共培养物和WM脑切片。 由于孤立的轴突不容易受到谷氨酸受体激活，兴奋性毒性轴突损伤的机制仍然未知。我们将研究的假设，AMPA/KA受体的过度激活少突胶质细胞在氧-葡萄糖剥夺导致有髓轴突的损伤，这涉及释放活性氧（ROS）。我们已经开发了两种新的模型来研究这些细胞的相互作用（a）细胞培养系统中，孤立的轴突和少突胶质细胞更容易受到缺氧和兴奋性毒性的侮辱比单独的细胞类型，和（B）急性脑切片模型，它允许测量白色物质的传导与轴突和少突胶质细胞形态的可视化。使用这些模型，我们将确定少突胶质细胞谷氨酸受体激活轴突损伤的作用，并评估潜在的损伤途径，涉及活性氧。 这些研究的结果可能为疾病的治疗方法提供建议，这些疾病在中央白色物质中具有共同的病理学。

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.