Abstract Body: Diabetes mellitus (DM) is a leading cause of age-related dementia, but the mechanisms involved are not well understood. We previously reported that DM is associated with impaired cerebrovascular dysfunction and cognitive impairment, which can be reversed by lowering blood glucose using an SGLT2 inhibitor, Luseogliflozin. Most recently, we found that a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), has similar vascular and cognitive protective effects in elderly T2DN diabetic rats without normalizing plasma glucose levels. The present study examined mechanisms underlying the cerebrovascular and neuronal protective actions of TPPU in DM. TPPU (1 mg/100g body weight/day in drinking water) was given to 15-month-old T2DN rats for three months. SD rats served as controls. Cognitive function was evaluated using an eight-arm water maze. Cerebral vascular function was assessed via a laser speckle imaging system in vivo. Plasma glucose and HbA1c levels were slightly lowered but remained 273 mg/dL and 10% in TPPU-treated T2DN rats (n=12), respectively. T2DN rats (n=39) spent a longer time to escape in the water maze compared to control rats (n=17) (84 vs 27 secs on day 1 and 74 vs 19 secs on day 2), while TPPU-treated T2DN rats (n=29) shortened escape latency (48 vs 84 secs on day 1 and 36 vs 74 secs on day 2). The increases in CBF in response to whisker stimulation were significantly reduced in T2DN rats (n=6) compared to control rats (n=17) (9% vs 30%), and TPPU (n=13) normalized the CBF response in T2DN rats. This improvement of functional hyperemia was associated with enhanced expression of eNOS and capillary endothelial Kir2.1 proteins in the brain. Capillary density was significantly reduced in the cerebral cortex and hippocampus in T2DN rats, while TPPU partially reversed the degree of capillary rarefaction. The expressions of ZO1 and Occludin were significantly reduced in T2DN rats, but TPPU improved the expression of these BBB markers. Astrocytes and microglia were markedly activated in the brains of T2DN rats and were reduced by TPPU. TPPU increased the expression of pre- and post-synaptic proteins and reduced the loss of hippocampal neurons in T2DN rats. These results demonstrate that long-term TPPU administration may preserve cognitive function by reversing cerebrovascular dysfunction, reducing astrogliosis and microgliosis, and preventing the loss of pre- and postsynaptic junctions and neurons.