Phosphodiesterase 10A deactivation induces long-term neurological recovery, peri-infarct remodeling and pyramidal tract plasticity after transient focal cerebral ischemia in mice
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Erişim
info:eu-repo/semantics/embargoedAccessTarih
2022Yazar
Beker, Mustafa ÇağlarPençe, Mahmud Esad
Yağmur, Sümeyya
Çağlayan, Berrak
Çağlayan, Aysun
Kılıç, Ülkan
Yelkenci, Hayriye Ecem
Altıntaş, Mehmet Özgen
Çağlayan, Ahmet Burak
Doeppner, Thorsten Roland
Hermann, Dirk M.
Kılıç, Ertuğrul
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Beker, M. Ç., Pençe, M. E., Yağmur, S., Çağlayan, B., Çağlayan, A., Kılıç, Ü. ... Kılıç, E. (2022). Phosphodiesterase 10A deactivation induces long-term neurological recovery, peri-infarct remodeling and pyramidal tract plasticity after transient focal cerebral ischemia in mice. Experimental Neurology, 358. https://dx.doi.org/10.1016/j.expneurol.2022.114221Özet
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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Experimental NeurologyCilt
358Bağlantı
https://dx.doi.org/10.1016/j.expneurol.2022.114221https://hdl.handle.net/20.500.12511/9755
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