Abstract TP317: The Neuroprotective Effect of Dipyridamole in Ischemia-Reperfusion Injury via Neuronal cGK1/2 Activation

Abstract

Background and rationale: Smooth muscle cell-specific cGK1 knock-out mice (SMKO) due to impaired blood vessel motility is a leading cause of reduced blood flow in ischemic stroke. This study investigated relative cerebral blood flow (rCBF), neuronal cGK1/2, and vessels cGK1/2 activity in smooth muscle cGK1 littermate control (SMLC), and SMKO mice with and without PDE5 inhibitor, dipyridamole. Methods: Middle cerebral artery occlusion (MCAO)-reperfusion was performed in SMLC and SMKO. All mice were measured for the rCBF by laser Doppler flowmetry and investigated the behaviors after ischemic stroke. To confirm the time-kinetics of cGK1/2 changes, brain samples were divided ischemia-reperfusion period in SMLC and SMKO mice with and without dipyridamole (60 mg/kg, p.o.). Results: Infarction volumes were larger in SMKO compared to that of SMLC mice and neurological deficit score was worsening in SMKO compared to that of SMLC mice. The rCBF values during MCAO and at reperfusion were significantly decreased in the SMKO group. During the ischemia and reperfusion period, neuronal cGK1 was sustained without protein degradation. Not only SMLC but also SMKO were the same. However, neuronal cGK2 was decreased time-dependent manner. In contrast, infarction volume was decreased in SMKO by dipyridamole treatment and NDS was improved in SMKO with dipyridamole. The changes of cGK1 and cGK2 were reversed in the reperfusion period in the cerebral cortex and hippocampus with dipyridamole. Conclusion: We conclude that the neuroprotective effect of dipyridamole in ischemic stroke is not only dependent on smooth muscle cell-specific cGK1 function but also related to the neuronal cGK1/2 activation via PDE5 inhibition.