【摘 要】
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Subcortical ischemic vascular dementia(SIVD)caused by chronic cerebral hypoperfusion exhibits progressive white matter and cognitive impairments.However,its pathogenetic mechanisms are poorly understo
【机 构】
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Zhejiang University
【出 处】
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第九届海内外华人神经科学家研讨会(The 9th Symposium for Chinese Neuroscientis
论文部分内容阅读
Subcortical ischemic vascular dementia(SIVD)caused by chronic cerebral hypoperfusion exhibits progressive white matter and cognitive impairments.However,its pathogenetic mechanisms are poorly understood.We investigated the role of interleukin-1β(IL-1β)and its receptor IL-1R1 in an experimental SIVD model generated via right unilateral common carotid arteries occlusion(rUCCAO)in mice.We found that IL-1β expression was elevated in the corpus callosum at the early stages after rUCCAO.IL-1 receptor antagonist(IL-1Ra),when delivered at an early stage,as well as IL-1R1 knockout,rescued the downregulation of myelin basic protein(MBP)and improved remyelination at the later stage after rUCCAO.Our data suggest that the recruitment of OPCs,but not the proliferation or differentiation of OPCs,is the only compromised step of remyelination following chronic cerebral ischemia.IL-1Ra treatment and IL-1R1 knockout had no effect on the oligodendrocyte progenitor cell(OPC)proliferation,but did promote the recruitment of newly generated OPCs to the corpus callosum,which can be reversed by compensatory expression of IL-1R1 in IL-1R1 knockout mice.Further,we found that recruited OPCs contribute to oligodendrocyte regeneration and functional recovery.In transwell assays,IL-1β inhibited OPC migration through IL-1R1.Moreover,Kdpt(a modified analog of IL-1β),which can enter the brain to block IL-1R1,also showed comparable protection when intraperitoneally delivered.Our results suggest that IL-1β during the early stages following chronic cerebral hypoperfusion impedes OPC recruitment via IL-1R1,which inhibits white matter repair and functional recovery.IL-1R1 inhibitors may have potential uses in the treatment of SIVD.
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