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Pharmacological Phosphodiesterase Inhibition as a Therapeutic for Cortical and Striatal Stroke


Stroke is the leading cause of adult disability, but there is no drug regimen available that promotes recovery after stroke. Recovery of function after stroke involves molecular signaling events mediated by cAMP and cGMP signaling, such as CREB activation and axonal sprouting. Cyclic nucleotide signaling is regulated by a variety of phosphodiesterase (PDE) isoforms, which degrade cAMP and cGMP and exhibit region-specific distribution in the brain. PDE10A is highly enriched in the basal ganglia/striatum. A novel PDE10A inhibitor, TAK-063, was tested for its effect on functional recovery and neuroplasticity after both striatal and cortical stroke. Inhibition of PDE10A improves recovery of function after striatal but not cortical stroke, consistent with its brain distribution, in young adult mice. Recovery of motor function correlated with increases in striatal BDNF, downstream of the cAMP signaling cascade, as well as axonal sprouting and angiogenesis. However, PDE10A inhibition did not improve functional recovery in aged mice after striatal stroke. PDE2A is the most prevalent phosphodiesterase expressed in cortex. A second novel PDE inhibitor specific to PDE2A, PDE2A-T1, was tested for its effect on tissue repair and functional gains after cortical stroke. PDE2A-T1 treatment improved behavioral outcomes in both young adult and aged mice after stroke and increased the density of cortical axonal connections in aged animals after stroke. This 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, with an important effect of age on therapeutic efficacy.

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