Resveratrol ameliorates diabetic encephalopathy through PDE4D/PKA/Drp1 signaling

Diabetic encephalopathy (DE) is a central nervous complication of diabetes mellitus which is characterized by cognitive impairment and neurochemical abnormalities. However, no effective approaches are available to prevent its progression and development. PDE4D serves many functions in the pathogenesis of neurodegenerative diseases involving PKA signaling. This study illustrated the role of PDE4D in DE and investigated whether resveratrol protected against DE via inhibiting PDE4D. db/db male mice and hippocampus cell line (HT22) were used to investigate the role of PDE4D and the protective effect of resveratrol on cognitive function under high glucose (HG). PDE4D overexpression or knockdown lentivirus and PKA specific inhibitor H89 were used to further identify the indispensable role of PDE4D/PKA signaling pathway in resveratrol's amelioration effect of neurotoxicity. Resveratrol attenuated cognitive impairment in db/db mice, reduced PDE4D protein, restored the impaired mitochondrial function in db/db mice. The in vitro study also confirmed the neuroprotective effect of resveratrol on neurotoxicity. PDE4D overexpression resulted in cell injury and downregulation of cAMP, PKA and pDrp1(Ser637) under normal condition. In contrast, PDE4D knockdown improved cell injury and elevated cAMP, PKA and pDrp1(Ser637) levels caused in HG-cultured HT22 cells. PDE4D over-expression blunted the improvement effects of resveratrol on PKA, pDrp1(Ser637) and mitochondrial function. Moreover, PKA inhibitor H89 blunted the inhibitory effects of resveratrol on pDrp1(Ser637) and mitochondrial function in HG-treated HT22. These data indicated that resveratrol may improve cognitive impairment in db/db mice by modulating mitochondrial function through the PDE4D dependent pathway.