Departments of Neurology and of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Departments of Psychology and of Computer Science, University of Southern California, Los Angeles, CA, USA.
Transl Stroke Res. 2021 Apr;12(2):303-315. doi: 10.1007/s12975-020-00819-8. Epub 2020 May 6.
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.
中风是导致成年人残疾的主要原因。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 (PDEs) 降解，PDEs 在脑区中差异表达。PDE10A 在基底节/纹状体中高度表达。我们测试了一种新型的 PDE10A 抑制剂 (TAK-063) 对功能恢复的影响。在皮层或纹状体中诱导小鼠中风。在 9 周内测量行为恢复情况。组织结果测量包括生长因子水平、血管生成、神经发生、神经胶质发生和炎症的分析。TAK-063 以剂量相关的方式改善纹状体中风后的运动恢复，但对皮层中风没有影响。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的连接。中风影响不同的脑区，每个脑区包含不同的细胞和分子成分。PDE10A 的抑制作用改善了纹状体中风后的功能恢复，但不改善皮层中风后的功能恢复，这与其在大脑中的定位一致。该实验首次证明了中风后大脑区域特异性功能恢复增强，表明基于中风亚型，可以利用脑区之间的差异分子信号来改善恢复。
