Neuroprotective effects of ranolazine versus pioglitazone in experimental diabetic neuropathy: Targeting Nav1.7 channels and PPAR-γ

Diabetic neuropathy (DN) is a common complication of diabetes mellitus (DM). Pathophysiology of DN includes inflammation and changes in expression and function of voltage-gated sodium channels (Nav) in peripheral nerves; and central reduction of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ) expression. This study explored the effect of ranolazine (RN) versus pioglitazone (PIO) in DN induced in rats. The role of sciatic interleukin (IL)-1β, tumor necrosis factor-alpha (TNF)-α, Nav1.7, and spinal PPAR-γ expressions were determined. For induction of Type-2 DM, 40 high fat diet-fed rats were challenged by a single dose of intraperitoneal streptozotocin (30 mg/kg). One week later, oral PIO (10 mg/kg; once daily) or RN (20, 50 and 100 mg/kg; twice daily) were administered for six weeks. Weekly body weight and fasting blood sugar (FBS) were measured. Rats were tested for thermal hyperalgesia and mechanical allodynia. At the end of the experiment, sciatic nerves homogenates were examined for TNF-α and IL-1B levels, and Nav1.7 channel expression. Segments of spinal cords were investigated for the PPAR-γ gene expression. Evaluation of histopathology of sciatic nerves and spinal cords were done. In diabetic rats, PIO and RN individually improved evoked-pain behaviors, reduced sciatic TNF-α and 1L-1B levels; downregulated expressional levels of Nav1.7 channels; and increased the spinal PPAR-γ gene expression. RN in the dose of 100 mg/kg/day showed the most advantageous effects. RN has neuroprotective effects in Type-2 diabetes-induced DN. Further studies of combined RN-PIO treatment are recommended, especially in diabetic patients with cardiovascular co-morbidity.