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

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.

• Authors: Mustafa C Beker, Ahmet B Caglayan, Serdar Altunay, Elif Ozbay, Nilay Ates, Taha Kelestemur, Berrak Caglayan, Ulkan Kilic, Thorsten R Doeppner, Dirk M Hermann, Ertugrul Kilic
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 59 Issue 1 Pg. 574-589 (Jan 2022) ISSN: 1559-1182 [Electronic] United States
• PMID: 34735672 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• 1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
• Neuroprotective Agents
• Phosphodiesterase Inhibitors
• Pyrazoles
• Pyridazines
• Proto-Oncogene Proteins c-akt
• Pde10a protein, mouse
• Phosphoric Diester Hydrolases

Topics

• Animals
• Brain Edema (drug therapy, metabolism)
• Cell Survival (drug effects)
• Disease Models, Animal
• Ischemic Stroke (drug therapy, metabolism)
• Mice
• Microcirculation (drug effects)
• Neuroprotection (drug effects)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Phosphodiesterase Inhibitors (pharmacology, therapeutic use)
• Phosphoric Diester Hydrolases (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrazoles (pharmacology, therapeutic use)
• Pyridazines (pharmacology, therapeutic use)
• Signal Transduction (drug effects)