SGLT2 Inhibition Attenuates Hippocampal Injury and Cognitive Impairment in Adult-Onset Hypothyroidism

Thyroid hormones play a critical role in the maturation of developing brain regions. The aim of this study is to determine the effects of the SGLT2 inhibitor empagliflozin on learning and memory, locomotor activity, neuroinflammation, and oxidative stress levels in adult rats with hypothyroidism induced by propylthiouracil administration. 60 adult male Sprague-Dawley rats (250-350 g) were used in the study. The rats were randomly divided into 5 groups of 12 each: Con, PTU, Vehicle, EMP, and PTU+EMP. The Con and EMP groups were allowed free access to drinking water. For the PTU, Vehicle, and PTU+EMP groups, propylthiouracil was added to the rats' drinking water at a concentration of 0.05% w/v for 21 days. Starting from day 15, the EMP and PTU+EMP groups received i.p. empagliflozin injections at a dose of 10 mg/kg/day for 7 days, while the Vehicle group received empagliflozin solvent (DMSO, 5% w/w). Morris water maze test and open field test were performed. SOD and CAT enzyme activities, GSH, and MDA levels were determined from serum samples. CREB and nNOS levels and p-CREB immunoreactivity were examined in the hippocampus tissue using immunohistochemical methods. In the PTU group, locomotor activity decreased, and anxiety-like behaviors were observed. Escape latency (EL) was prolonged, and time spent in the target quadrant (TSTQ) decreased. Antioxidant enzyme activities decreased while MDA levels increased. Significant reductions in CREB, p-CREB, and nNOS levels, which are critical for learning and memory processes, and hippocampal degeneration were recorded. Empagliflozin treatment improved cognitive and morphological impairments caused by hypothyroidism to control group levels by reducing anxiety-like behavior, suppressing oxidative stress, and restoring CREB/nNOS signaling pathways. The data obtained show that thyroid hormone deficiency developing in adulthood leads to serious cognitive losses by disrupting the ERK/CREB/BDNF and nNOS/NO pathways. Empagliflozin emerges as a potential new therapeutic option for treating cognitive impairments caused by hypothyroidism by modulating these molecular cascades.