Beker Mustafa C, Caglayan Ahmet B, Altunay Serdar, Ozbay Elif, Ates Nilay, Kelestemur Taha, Caglayan Berrak, Kilic Ulkan, Doeppner Thorsten R, Hermann Dirk M, Kilic Ertugrul
Department of Physiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
Regenerative and Restorative Medical Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey.
Mol Neurobiol. 2022 Jan;59(1):574-589. doi: 10.1007/s12035-021-02621-5. Epub 2021 Nov 4.
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.
磷酸二酯酶10A（PDE10A）可水解3',5'-环磷酸腺苷（cAMP）和3',5'-环磷酸鸟苷（cGMP）。它在纹状体中高度表达。最近的证据表明，PDE10A可能参与损伤后的炎症过程，如缺血性中风。其在缺血性损伤中的作用尚不清楚。在此，我们将小鼠暴露于90或30分钟的大脑中动脉闭塞，再灌注后立即给予高选择性PDE10A抑制剂TAK-063（0.3 mg/kg或3 mg/kg）。分别在24或72小时后处死动物。TAK-063的两个剂量均增强了神经功能，减少了梗死体积，增加了神经元存活，减轻了脑水肿，并增加了血脑屏障完整性，同时改善了脑微循环。缺血后神经保护作用与促存活的Akt、Erk-1/2、GSK-3α/β的磷酸化（即激活）增加以及抗凋亡的Bcl-xL丰度增加、促存活的mTOR的磷酸化减少以及HIF-1α、MMP-9和促凋亡的Bax丰度降低有关。有趣的是，通过平面表面免疫分析，PDE10A抑制降低了炎症细胞因子/趋化因子，包括IFN-γ和TNF-α。此外，液相色谱-串联质谱分析显示，TAK-063显著改变了40种蛋白质。我们的研究确定PDE10A为缺血性中风治疗的一个靶点。
