Effects of an SGLT2 inhibitor on cognition in diabetes involving amelioration of deep cortical cerebral blood flow autoregulation and pericyte function

Background Diabetes mellitus (DM) is a leading risk factor for aging‐related dementia. We previously demonstrated that an SGLT2 inhibitor (SGLT2i) reversed the impaired myogenic response (MR) of the middle cerebral artery (MCA) and cerebral blood flow (CBF) autoregulation on the surface cortex, and improved cognition with an eight‐arm water maze in 18‐month old diabetic rats. The present study aims to investigate whether normalizing plasma glucose by inhibition of SGLT2 also ameliorate MR of parenchymal arteriole (PA) and CBF autoregulation in the deep cortex, and the role of pericyte in the regulation of CBF autoregulation and cognitive function in DM. Method Deep cortical CBF autoregulation was studied using laser Doppler flowmetry coupled with an implanted fiber‐optic probe. MR of PA was investigated using a pressure myography. The novel object recognition and open field tests were used to evaluate cognition. Mitochondrial‐derived superoxide production was detected by MitoSOX, and mitochondrial function was evaluated using Seahorse XF e 24. Cell contraction was detected by a collagen gel‐based kit. Result Deep cortical CBF rose by 223.34 ± 28.11, 49.03 ± 12.62, 50.12 ± 0.89%, respectively, in diabetic, SGLT2i treated diabetic and non‐diabetic rats when blood pressure was increased from 100 to 180 mmHg. PA constricted in response to elevated transmural pressure in SGLT2i treated diabetic and non‐diabetic rats, whereas dilated in diabetic rats. The percentage of time spent in the novel object was 43.32 ± 8.04%, 71.94 ± 8.48%, 75.68 ± 3.33% respectively in diabetic, SGLT2i treated diabetic, and non‐diabetic rats. No significant differences in total travel distance and resting time were found between these rats. High glucose‐treated pericytes displayed elevated mitochondrial ROS, and decreased ATP production, and lower their contractile capabilities. Conclusion These results indicate that the SGLT2 Inhibitor reversed the impaired MR of the PA, CBF autoregulation in the deep cortex, and cognitive impairments in old DM, which may involve amelioration of hyperglycemia‐induced mitochondrial ROS production and ATP depletion in pericytes.