Phosphodiesterase 10A Inhibition Leads to Brain Region-Specific Recovery Based on Stroke Type
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ORIGINAL ARTICLE
Phosphodiesterase 10A Inhibition Leads to Brain Region-Specific Recovery Based on Stroke Type Shirin Z. Birjandi 1 & Nora Abduljawad 1 & Shyama Nair 1 & Morteza Dehghani 2 & Kazunori Suzuki 3 & Haruhide Kimura 3 & S. Thomas Carmichael 1 Received: 26 February 2020 / Revised: 19 April 2020 / Accepted: 22 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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 regionspecific enhanced functional recovery after stroke, and indicates that differential molecular signaling between brain regions can be exploited to improve recovery based on stroke subtype. Keywords Repair . Axonal sprouting . Angiogenesis . BDNF . Striatum
Introduction Stroke is one of the leading causes of adult disability in the USA [1]. Neurorehabilitation after stroke leads to modest improvements in motor recovery [2], but there is currently no drug regimen that enhances recovery after stroke. Cellular and molecular mechanisms of recovery after brain injury involve changes in glial cell activation [3], alterations in cellular Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12975-020-00819-8) contains supplementary material, which is available to authorized users. * S. Thomas Carmichael [email protected] 1
Departments of Neurology and of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
2
Departments of Psychology and of Computer Science, University of Southern California, Los Angeles, CA, USA
3
Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
excitability [4, 5], and induction or delivery of a molecular signaling cascade that results in elevated growth factors, such as brain-derived neurotrophic factor (BDNF) [6, 7]. Recentl
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