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

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Abstract

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-3α/β and anti-apoptotic Bcl-xL abundance, decreased phosphorylation of pro-survival mTOR, and HIF-1α, MMP-9 and pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-γ and TNF-α, 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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Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by TUBITAK (The Scientific and Technological Research Council of Turkey/ 218S453; MCB) and Turkish Academy of Sciences (TUBA; EK).

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey

    Mustafa C. Beker, Serdar Altunay, Elif Ozbay, Nilay Ates, Taha Kelestemur & Ertugrul Kilic

  2. Regenerative and Restorative Medical Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey

    Mustafa C. Beker, Ahmet B. Caglayan, Serdar Altunay, Elif Ozbay, Nilay Ates, Taha Kelestemur, Berrak Caglayan & Ertugrul Kilic

  3. Department of Physiology, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey

    Ahmet B. Caglayan

  4. Department of Medical Genetics, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey

    Berrak Caglayan

  5. Department of Medical Biology, International School of Medicine, University of Health Sciences Turkey, Istanbul, Turkey

    Ulkan Kilic

  6. Department of Neurology, University Medicine Göttingen, University of Göttingen, Göttingen, Germany

    Thorsten R. Doeppner

  7. Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    Dirk M. Hermann

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Contributions

This work was carried out in collaboration between all authors. MCB, ABC, and SA carried out experimental work, analyzed data, and helped to write the manuscript. EO and TK performed LC–MS/MS experiments and analyzed data. NA and BC carried out Western blot and immunofluorescence studies. MCB, TRD, UK, DMH, and EK defined the research theme and revised the manuscript critically.

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Correspondence to Mustafa C. Beker.

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Experiments were performed in accordance to National Institutes of Health (NIH) guidelines for the care and use of laboratory animals and approved by local government authorities (Istanbul Medipol University, Animal Research Ethics Committee).

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Beker, M.C., Caglayan, A.B., Altunay, S. et al. Phosphodiesterase 10A Is a Critical Target for Neuroprotection in a Mouse Model of Ischemic Stroke. Mol Neurobiol 59, 574–589 (2022). https://doi.org/10.1007/s12035-021-02621-5

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