siRNA targeting PARP-1 alleviates diabetic peripheral neuropathy in a streptozotocin-induced rat model

Abstract

Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus, affecting nearly 50% of diabetic patients and leading to chronic pain, numbness and progressive sensory and motor function loss. This study investigates the potential of siRNA-mediated silencing of poly(ADP-ribose) polymerase 1 (PARP1) to alleviate DPN in a rat model. PARP1 overactivation, driven by hyperglycaemia-induced oxidative stress, exacerbates neuronal damage in DPN. Using chitosan nanoparticles (ChNPs) to deliver PARP1-targeting siRNA intrathecally in diabetic rats induced with streptozotocin (STZ) 55 mg/kg intraperitoneally, we conducted behavioural and physiological assessments, including Sciatic Functional Index (SFI), motor nerve conduction velocity (MNCV), grip strength and pain sensitivity tests, alongside qRT-PCR analyses, to evaluate therapeutic outcomes. Our findings indicate statistically significant improvements, with siRNA ChNPs-mediated PARP1 silencing alleviating neuropathic symptoms in DPN rats (p < .001 for SFI and MNCV improvements). Biochemical analyses revealed reductions in oxidative stress markers, such as MDA, and increased antioxidant levels, including GSH, CAT and SOD (p < .001). Pro-inflammatory cytokines and apoptotic markers, including NF-κB, IL6, IL1β, TNFa, TGF-β, CAS3, CAS9, BAK and BAX, also showed significant reductions (p < .01), confirming the neuroprotective effects of PARP1 inhibition. These results highlight the potential of siRNA-based therapies targeting PARP1 as a promising therapeutic approach for DPN, paving the way for future research with clinical applications.

Keywords: PARP1; diabetic; gene silencing; peripheral neuropathy; siRNA.