Empagliflozin alleviates STZ-induced diabetic neuropathy, anxiety and depression-like behavior in C57/BL-6 mice

Background Diabetes mellitus (DM) is frequently associated with neuropathic complications and concurrent neuropsychiatric manifestations, including anxiety and depression-like behaviors. Together these complications add on to disease burden, impair quality of life and need individual drug regime to manage them effectively. Objective To evaluate the pharmacological effects of empagliflozin (EMPA) in managing symptoms of pain and concurrent anxiety- and depression-like behaviors in a streptozotocin (STZ)-induced diabetic neuropathy in mice. Methods Neuropathy and behavioral abnormalities were induced in C57/BL-6 mice by the intraperitoneal single injection of STZ (30 mg/kg). Post STZ injection, mice were treated with oral administration of EMPA (5 and 10 mg/kg), pregabalin (PGB) (30 mg/kg) and clomipramine (CLMP) (10 mg/kg) from day 14–28. Results Neuropathy in diabetes produced significant thermal hypersensitivity (reduced withdrawal latency), allodynia, limb numbness (reduction in fall latency in rotarod) and lessened locomotor activity. Neurobehavioral assessment reported increase in immobility in forced swim test, decrease sucrose preference, reduction in entries and time spent in open arms of elevated plus maze and light-dark box. Biochemical estimation showed alterations in the levels of markers of oxidative stress (elevated LPO with reduced SOD and GSH) and significant increase of inflammatory cytokines (IL-1β, IL-6, TNF-α and TLR4). Treatment with EMPA 5 and 10 mg/kg, p.o.) significantly attenuated these behavioral and biochemical alterations, reduced oxidative stress and inflammatory markers, and improved sciatic nerve and brain histopathological changes, with more pronounced effects observed particularly at the higher dose. Additionally, EMPA contributed to a reduction in blood glucose levels and retained the body weight of diabetic animals. Conclusion Beyond its anti-diabetic activity, EMPA appears to ease STZ-induced neuropathy and accompanying anxiety- and depression-like behaviors, effects that may involve modulation of oxidative stress and inflammation.