| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 102 === Cerebral white matter injury has been thought to contribute to cognitive deficits in human cerebral ischemia. However, the relatively low white matter volume in rodents led to difficulties in studying cerebral white matter injury (WMI) in this brain area, and to date very few experimental models can specifically produce post-stroke white matter damage. Recent clinical studies indicated that patients with unilateral cerebrovascular stenosis showed impaired WM structure and cognitive deficit, but molecular signature and underlying mechanism remain unknown. Besides, some studies indicated that combine of hypoxia and ischemia insults are more likely in patient with brain stroke injury. Therefore, we have established a model of unilateral permanent common carotid artery occlusion (pCCAO) sensitized with a transient hypoxia (tH) in 10 week-old adult Sprague-Dawley rats to simulate this clinical condition. Sham-operated animals served as control. Our data show this model impairs both locomotor activity and preference for social novelty 7 days after injury in the open field test and three-chambered social interaction, respectively. Besides, animal subjected to tH-pCCAO shows reduction of non-spatial working memory in novel object recognition test. Furthermore, this injury causes marked reduction in both myelin basic protein (MBP) and brain-derived neurotrophic factor (BDNF), an important myelin-axon coupling factor, of the ipsilateral side in corpus callosum. However, this model does not show either significant infarction in the cerebral gray matter or neuroinflammatory responses as indicated by lacking of inducible nitric oxide synthase and cyclooxygenase-2 induction on the ipsilateral side. To further understand whether the WM integrity was disrupted, we used immunofluorescent double labeling of voltage-gated sodium channel 1.6 (Nav1.6) for the Node of Ranvier and myelin-interacting axonal protein caspr, for the paranodal region to represent a functional organization of myelinated axons. Data revealed that tH-pCCAO insult increases the length of Nav1.6 domain and colocalization of both Nav1.6 and caspr but without increase Nav1.6 protein expression. Thus, provide a possibility that damage the barrier of septate-like junctions in paranodal junctions. In conclusion, our results demonstrate that tH-pCCAO animal model exhibited the damages are specific in central nervous system (CNS) white matter, but not gray matter, without inducing neuroinflammation, and leads to disrupted of proteins critical to the stability of axon–myelin coupling. This model may serve as a useful tool to understand the pathophysiology of white matter injury after stroke and for the development of therapeutics for treating WMI.
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