Phosphodiesterase 10A Inhibition Leads to Brain Region-Specific Recovery Based on Stroke Type

Overview

Journal Transl Stroke Res

Publisher Springer

Date 2020 May 8

PMID 32378029

Citations 6

Authors

Shirin Z Birjandi

Nora Abduljawad

Shyama Nair

Morteza Dehghani

Kazunori Suzuki

Haruhide Kimura

S Thomas Carmichael

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Temporal and Spatial Gene Expression Profile of Stroke Recovery Genes in Mice.

Gotz J, Wieters F, Fritz V, Kasgen O, Kalantari A, Fink G Genes (Basel). 2023; 14(2).

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A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects.

Matloka M, Janowska S, Pankiewicz P, Kokhanovska S, Kos T, Holuj M Front Pharmacol. 2022; 13:999685.

PMID: 36438799 PMC: 9681820. DOI: 10.3389/fphar.2022.999685.

PDE2A Inhibition Enhances Axonal Sprouting, Functional Connectivity, and Recovery after Stroke.

Bechay K, Abduljawad N, Latifi S, Suzuki K, Iwashita H, Carmichael S J Neurosci. 2022; 42(44):8225-8236.

PMID: 36163142 PMC: 9653274. DOI: 10.1523/JNEUROSCI.0730-22.2022.

Phosphodiesterase 10A Is a Critical Target for Neuroprotection in a Mouse Model of Ischemic Stroke.

Beker M, Caglayan A, Altunay S, Ozbay E, Ates N, Kelestemur T Mol Neurobiol. 2021; 59(1):574-589.

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Delayed atomoxetine or fluoxetine treatment coupled with limited voluntary running promotes motor recovery in mice after ischemic stroke.

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