P1‐427: TREADMILL EXERCISE PROTECTS HIPPOCAMPUS AND AMYGDALA FROM NEURODEGENERATION IN ALZHEIMER'S DISEASE TRANSGENIC MICE

Methods: We used 2K-1C, DOCA-salt hypertensive models to induce learning and memory defects. Systolic blood pressure (SBP) was measured by tail-cuff method. Elevated plus maze and novel object recognition task (NORT) models were used to evaluate the cognitive improvement. Plasma and brain concentrations of rolipram, roflumilast were studied after the behavioral task. In addition, mRNA expression of PDE4 sub-types A,B,C,D and phosphorylation of CREBwere also assessed in the hippocampus tissue. Results: SBP, kidney weight and heart index were significantly increased in hypertensive rats when compared with their age matched sham operated rats. There was no significant difference in SBP among the PDE4 treatment groups in both the models. The retention latency on the second day in the elevated plus maze model was significantly shortened after repeated administration of rolipram (0.03, 0.1and 0.3mg/kg i.p) or roflumilast (0.1, 0.3 and 1mg/kg p.o). Further, PDE4 inhibitors significantly reversed time induced memory deficit in NORT. Dose linear plasma and brain concentrations of rolipram, roflumilast were observed. The PDE4B and PDE4D gene expression was significantly enhanced in hypertensive rats compared with sham operated however PDE4A and PDE4C remained unaltered. Repeated dose treatment of PDE4 inhibitors caused down regulation of PDE4B and PDE4D leading to dose dependent increase in the pCREB levels. Conclusions: These results suggest that inhibition of PDE4 ameliorates HT-induced impairment of learning and memory functions. These data further support that PDE4 inhibition may be an attractive therapeutic strategy to improve memory performance.