神经可塑性
磷酸二酯酶
神经发生
纹状体
神经科学
内科学
大脑皮层
缺血
GSK3B公司
内分泌学
医学
化学
生物
细胞生物学
磷酸化
多巴胺
葛兰素史克-3
生物化学
酶
作者
Mustafa Çağlar Beker,Mahmud E. Pence,Sumeyya Yagmur,Berrak Çağlayan,Aysun Çağlayan,Ülkan Kılıç,Hayriye E. Yelkenci,Mehmet Özgen Altıntaş,Ahmet Burak Çağlayan,Thorsten R. Doeppner,Dirk M. Hermann,Ertuğrul Kılıç
标识
DOI:10.1016/j.expneurol.2022.114221
摘要
The phosphodiesterase (PDE) superfamily comprises enzymes responsible for the cAMP and cGMP degradation to AMP and GMP. PDEs are abundant in the brain, where they are involved in several neuronal functions. High PDE10A abundance was previously observed in the striatum; however its consequences for stroke recovery were unknown. Herein, we evaluated the effects of PDE10A deactivation by TAK-063 (0.3 or 3 mg/kg, initiated 72 h post-stroke) in mice exposed to intraluminal middle cerebral artery occlusion. We found that PDE10A deactivation over up to eight weeks dose-dependently increased long-term neuronal survival, angiogenesis, and neurogenesis in the peri-infarct striatum, which represents the core of the middle cerebral artery territory, and reduced astroglial scar formation, whole brain atrophy and, more specifically, striatal atrophy. Functional motor-coordination recovery and the long-distance plasticity of pyramidal tract axons, which originate from the contralesional motor cortex and descend through the contralesional striatum to innervate the ipsilesional facial nucleus, were enhanced by PDE10A deactivation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed a set of dopamine receptor-related and neuronal plasticity-related PDE10A targets, which were elevated (e.g., protein phosphatase-1 regulatory subunit 1B) or reduced (e.g., serine/threonine protein phosphatase 1α, β-synuclein, proteasome subunit α2) by PDE10A deactivation. Our results identify PDE10A as a therapeutic target that critically controls post-ischemic brain tissue remodeling and plasticity.
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