Probucol attenuates NF-κB/NLRP3 signalling and augments Nrf-2 mediated antioxidant defence in nerve injury induced neuropathic pain

Abstract

Neuroinflammation is one of the most significant pathological drivers following nerve injury which along with immune cell activation, oxidative stress and other associated molecular mechanisms contribute to development of neuropathic pain characterized by hyperalgesia and allodynia. In the current study we have investigated the pharmacological effect of probucol (prb) using chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain (NP) model in rats. CCI of sciatic nerve resulted in marked decrease in pain threshold along with perturbations in anti-oxidant defence, enhanced inflammatory mediators and abnormal foot posture. Administration of prb at the doses of 8 and 16 mg/kg, p.o. for 14 days significantly attenuated the behavioural, biochemical and functional deficits following CCI of sciatic nerve. To further explore the molecular mechanisms of prb, we assessed the post treatment levels of inflammatory and oxidative stress markers like NLRP3 inflammasome, NF-κB and associated proinflammatory molecules such as IL-1 β, TNF-α & IL-6 along with Nrf-2 and HO-1. Our findings demonstrated that CCI induced changes in levels of these markers were dose dependently reversed by administration of prb. Of note, at molecular level the elevated expression of transcription factors such as NF-κB which is crucial for Nlrp3 activation and diminished levels of Nrf-2 were manifested following CCI induction, these changes were markedly reversed with 14 days treatment of prb at both the doses. Our findings highlighted the dual pharmacological effect of prb, anti-inflammatory and anti-oxidant via modulation of NF-κB/NLRP3 signalling and Nrf-2 pathway in attenuation of CCI of sciatic nerve induced NP.