TARGETING NK1 AND NLRP3 SIGNALLING PATHWAYS TO ALLEVIATE NEUROPATHIC PAIN IN DIABETIC PERIPHERAL NEUROPATHY

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes characterised by progressive peripheral axonal damage, sensory dysfunction, motor impairment, and chronic pain. Current therapies offer limited symptomatic relief. In this study, we investigated the roles of NK1 and NLRP3, both individually and in combination, in diabetic neuropathy. We propose that NK1-mediated neurogenic inflammation and NLRP3-driven inflammatory signalling may act as complementary mechanisms in DPN. To induce the disease, Wistar rats (IAEC/KMC/91/2024)​ were fed a high-fat diet for six months, and insulin resistance was confirmed through an oral glucose tolerance test. Subsequently, a single dose of Streptozotocin (STZ) was administered (15–16 mg/kg, i.p.). For three weeks following STZ administration, groups of rats received Aprepitant (an NK1 inhibitor, 10 mg/kg i.p.), Parthenolide (an NLRP3 inhibitor, 1.5 mg/kg i.p.), and Pregabalin (30 mg/kg i.p.) as the standard treatment. Peripheral neuropathy symptoms were assessed using thermal nociceptive assays, mechanical allodynia assessments, and motor coordination tests. Additionally, histopathological and biochemical evaluations of the sciatic nerves were initiated. The disease group exhibited a significant increase in body weight and blood glucose levels compared to the control group. However, none of the treatment groups affected glycaemic parameters. All treatment groups showed improved neuropathic behaviours compared to both the disease group. Notably, combination treatment significantly reduced neuropathic-like symptoms compared to other groups. In conclusion, dual targeting of the NK1 and NLRP3 pathways may effectively alleviate neuropathic-like symptoms in experimental DPN. This study supports a multi-mechanistic therapeutic strategy for addressing peripheral nerve disorders.