Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke

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2022Author
Beker, Mustafa ÇağlarÇağlayan, Ahmet Burak
Altunay, Serdar
Özbay, Elif
Ateş, Nilay
Keleştemur, Taha
Çağlayan, Berrak
Kılıç, Ülkan
Doeppner, Thorsten Roland
Hermann, Dirk Matthias
Kılıç, Ertuğrul
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Beker, M. Ç., Çağlayan, A. B., Altunay, S., Özbay, E., Ateş, N., Keleştemur, T. ... Kılıç, E. (2022). Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke. Molecular Neurobiology, 59(1), 574-589. https://dx.doi.org/10.1007/s12035-021-02621-5Abstract
Phosphodiesterase 10A (PDE10A) hydrolyzes adenosine 3 ',5 '-cyclic monophosphate (cAMP) and guanosine 3 ',5 '-cyclic monophosphate (cGMP). It is highly expressed in the striatum. Recent evidence implied that PDE10A may be involved in the inflammatory processes following injury, such as ischemic stroke. Its role in ischemic injury was unknown. Herein, we exposed mice to 90 or 30-min middle cerebral artery occlusion, followed by the delivery of the highly selective PDE10A inhibitor TAK-063 (0.3 mg/kg or 3 mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72 h, respectively. Both TAK-063 doses enhanced neurological function, reduced infarct volume, increased neuronal survival, reduced brain edema, and increased blood-brain barrier integrity, alongside cerebral microcirculation improvements. Post-ischemic neuroprotection was associated with increased phosphorylation (i.e., activation) of pro-survival Akt, Erk-1/2, GSK-3 alpha/beta and anti-apoptotic Bcl-xL abundance, decreased phosphorylation of pro-survival mTOR, and HIF-1 alpha, MMP-9 and pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-gamma and TNF-alpha, analyzed by planar surface immunoassay. In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy.
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