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 (0.3mg/kg or 3mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72h, 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/βand 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.
Highlights
IntroductionPhosphodiesterase 10A (PDE10A) is a dual-substrate specific enzyme and an essential regulator of cell signaling by hydrolyzing the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [1, 2], which play crucial roles in neuronal activity, synaptic plasticity, neurogenesis and apoptosis in the central nervous system (CNS) [3, 4]
Phosphodiesterase 10A (PDE10A) is a dual-substrate specific enzyme and an essential regulator of cell signaling by hydrolyzing the second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate [1, 2], which play crucial roles in neuronal activity, synaptic plasticity, neurogenesis and apoptosis in the central nervous system (CNS) [3, 4].In the CNS, PDE10A is highly expressed in medium spiny neurons (MSNs), which make up approximately 95% of all striatal neurons
The dual substrate enzyme PDE10A, which is highly abundant in the mammalian striatum, acts as an essential regulator of the signaling pathway by hydrolyzing the second messengers, cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) [1, 2]
Summary
Phosphodiesterase 10A (PDE10A) is a dual-substrate specific enzyme and an essential regulator of cell signaling by hydrolyzing the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [1, 2], which play crucial roles in neuronal activity, synaptic plasticity, neurogenesis and apoptosis in the central nervous system (CNS) [3, 4]. In the CNS, PDE10A is highly expressed in medium spiny neurons (MSNs), which make up approximately 95% of all striatal neurons. Through degradation of cAMP and cGMP, PDE10A regulates MSN excitability [5]. Inhibition of PDE10A increases cyclic nucleotide levels and activates its downstream signal transduction pathways including cAMP/ protein kinase A (PKA) signaling [4, 6, 7].
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