Phosphodiesterase 10A Inhibition Leads to Brain Region-Specific Recovery Based on Stroke Type.
Phosphodiesterase 10A Inhibition Leads to Brain Region-Specific Recovery Based on Stroke Type.
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DOI：
10.1007/s12975-020-00819-8
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发表时间：
2021-04
影响因子：
6.9
通讯作者：
Carmichael ST
中科院分区：
文献类型：
--
作者：
Birjandi SZ;Abduljawad N;Nair S;Dehghani M;Suzuki K;Kimura H;Carmichael ST
中风是成人残疾的主要原因。中风后的功能恢复涉及由cAMP和cGMP途径介导的信号传导事件，如轴突发芽、神经发生和突触可塑性。cAMP和cGMP被磷酸二酯酶（PDE）降解，其在脑区域中差异表达。PDE 10A在基底神经节/纹状体中高度表达。我们检测了一种新型PDE 10A抑制剂（TAK-063）对功能恢复的影响。中风是在小鼠的皮层或纹状体中产生的。行为恢复测量到9周。组织结果测量包括生长因子水平、血管生成、神经发生、胶质生成和炎症的分析。TAK-063以剂量相关的方式改善纹状体卒中后的运动恢复，但在皮质卒中中则不然。运动功能的恢复与纹状体脑源性神经营养因子的增加相关。TAK-063治疗还增加了运动系统轴突连接。中风影响不同的大脑区域，每个区域都包含不同的细胞和分子元素。抑制PDE 10A可改善纹状体卒中后的功能恢复，但不能改善皮质卒中后的功能恢复，这与PDE 10A的脑定位一致。该实验是脑区域特异性增强中风后功能恢复的第一个证明，并表明脑区域之间的差异分子信号传导可用于改善基于中风亚型的恢复。本文的在线版本（10.1007/s12975-020-00819-8）包含补充材料，可供授权用户使用。
Stroke is the leading cause of adult disability. Recovery of function after stroke involves signaling events that are mediated by cAMP and cGMP pathways, such as axonal sprouting, neurogenesis, and synaptic plasticity. cAMP and cGMP are degraded by phosphodiesterases (PDEs), which are differentially expressed in brain regions. PDE10A is highly expressed in the basal ganglia/striatum. We tested a novel PDE10A inhibitor (TAK-063) for its effects on functional recovery. Stroke was produced in mice in the cortex or the striatum. Behavioral recovery was measured to 9 weeks. Tissue outcome measures included analysis of growth factor levels, angiogenesis, neurogenesis, gliogenesis, and inflammation. TAK-063 improved motor recovery after striatal stroke in a dose-related manner, but not in cortical stroke. Recovery of motor function correlated with increases in striatal brain-derived neurotrophic factor. TAK-063 treatment also increased motor system axonal connections. Stroke affects distinct brain regions, with each comprising different cellular and molecular elements. Inhibition of PDE10A improved recovery of function after striatal but not cortical stroke, consistent with its brain localization. This experiment is the first demonstration of brain region-specific enhanced functional recovery after stroke, and indicates that differential molecular signaling between brain regions can be exploited to improve recovery based on stroke subtype. The online version of this article (10.1007/s12975-020-00819-8) contains supplementary material, which is available to authorized users.
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通讯作者：
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作者：
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