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

Shirin Z Birjandi,Shyama Nair,Nora Abduljawad,Haruhide Kimura,Morteza Dehghani,Kazunori Suzuki,S Thomas Carmichael

doi:10.1007/s12975-020-00819-8

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.

Highlights

Stroke is one of the leading causes of adult disability in the USA [1]
We show that mice given a novel PDE10A inhibitor, TAK-063 [16, 17], have improved motor recovery after striatal stroke in a dosedependent manner, but not cortical stroke
Mice were given a stroke in the striatum [24] or in the motor cortex [4, 5, 19, 25] in separate cohorts (Supplemental Fig. 1a–c)

Summary

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. Phosphodiesterases (PDEs) degrade the intracellular second messengers cAMP and/or cGMP and terminate intracellular signaling that leads to CREB activation [9]. Eleven isoforms of PDEs have been identified [14]. Among these PDE families, PDE10A is unique in its abundance in the basal ganglia/ striatum. Elevated levels of cAMP and/or cGMP in this brain lead to increases in BDNF [13]. The use of a PDE10A inhibitor has not been examined in recovery after stroke. (2021) 12:303–315 enhance recovery in subcortical or striatal stroke, a common stroke subtype [15], but not have an effect in other stroke subtypes, such as in cortex or other brain areas in which PDE10A levels are low Stroke Res. (2021) 12:303–315 enhance recovery in subcortical or striatal stroke, a common stroke subtype [15], but not have an effect in other stroke subtypes, such as in cortex or other brain areas in which PDE10A levels are low

Methods

Results

Conclusion