Abstract Body: Diabetes increases the risk of Vascular Contributions to Cognitive Impairment & Dementia (VCID) and stroke further amplifies this effect. Diabetes also dysregulates the Endothelin (ET) system. Elevated brain ET-1 levels correlate with tissue perfusion status and disease severity in patients with ADRD. There is emerging evidence that ETB receptor agonism improves outcomes in patients with cerebral ischemic stroke, but long-term effects, especially in diabetes, are unknown. Therefore, we hypothesized that intranasal treatment with ETA antagonist or ETB agonist will improve sensorimotor/cognitive outcomes in diabetic animals after ischemic stroke. Methods: We used a post-stroke cognitive impairment (PSCI) model of VCID. Male rats underwent 60-min middle cerebral artery occlusion surgery (MCAO) 8 weeks after diabetes onset. Rats that met the preset inclusion criteria (adhesive removal time > 35 sec. and either a modified Bederson score <= 6 on Day 1 or weight loss > 10% on Day 3) were randomized to ETA antagonist BQ-123 (3 µg/100 µl PBS), ETB agonist Sovateltide (5 µg/kg), or vehicle intranasal treatment for 3 days per week until 8 weeks post-stroke (n=6-8). Sensorimotor and cognitive outcomes were monitored for 8 weeks. Results (Table 1): Behavior indices from the novel object recognition (NOR) test and Y-Maze test showed that diabetic rats developed cognitive deficits even in the sham group. Sovateltide improved both recognition memory and working spatial memory after stroke. BQ-123 partially prevented the decline in recognition memory. Animals treated with BQ-123 showed an improvement in depressive symptoms after stroke. Conclusions: These results suggest that intranasal stimulation of brain ETB receptors or ETA receptor inhibition can prevent the development of progressive cognitive decline after stroke. While further studies are required to better understand how the brain ET system impacts stroke recovery in diabetes, our findings provide novel insights into potential neuroprotective therapies for VCID.