Empagliflozin Improves Learning and Memory Deficits in Streptozotocin-Induced Hyperglycemic Male Wistar Rats

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic agents that lower blood glucose independently of insulin by inhibiting renal SGLT2 in the proximal tubule, thereby increasing urinary glucose and sodium excretion. Empagliflozin (Empa), an FDA-approved SGLT2 inhibitor, exhibits antioxidant, anti-inflammatory, and additional metabolic effects beyond glycemic control. Given the high expression of SGLT2 in the central nervous system and the established link between cognitive impairment, chronic hyperglycemia, oxidative stress, and inflammation, this study investigated Empa's neuroprotective potential on learning and memory deficits in streptozotocin-induced hyperglycemic male Wistar rats.

Hyperglycemia was induced using streptozotocin (40 mg/kg/IP), followed by Empa treatment (10 mg/kg/day/PO). Cognitive performance was evaluated using the radial arm water maze, assessing learning and both short-term and long-term memory. Concurrently, hippocampal oxidative stress markers and key molecular mediators, including brain-derived neurotrophic factor (BDNF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), were measured to elucidate possible underlying neuroprotective mechanisms.

Hyperglycemic rats exhibited significant impairments in learning, short-term memory, and long-term memory compared to normoglycemic controls. Empa treatment significantly improved short-term memory, restoring performance to near-control levels. However, its impact on long-term memory was minimal. Unexpectedly, Empa induced only modest, non-statistically significant changes in hippocampal oxidative stress markers and BDNF and NF-κB levels.

The findings underscore the complexity of oxidative stress and inflammatory pathways involved in hyperglycemia-associated cognitive impairment. The beneficial effects of Empa on short-term memory may involve alternative mechanisms unrelated to oxidative stress modulation. Further studies involving extended durations, higher dosages, or larger sample sizes are warranted to better elucidate the neuroprotective mechanisms of Empa.