A novel analgesic development strategy : targeting NRF2 as an upstream regulator for NaV1.7 inhibition

Abstract

Nerve lesion-induced peripheral neuropathic pain (PNP) is a global long-term disease caused by nervous system injury or systemic illness, with a high incident rate, high cost, and poor therapeutic effect. It is challenging to manage as the most available analgesics have limited efficacy but undesirable side effects. Thus, there is a vast unmet need for developing novel analgesics that present ideal efficiency and less off-target effects in pain therapy. The abnormal activity of voltage-gated sodium channel subtype 1.7 (NaV1.7) in dorsal root ganglion (DRG) is a promising target for PNP therapy. However, disappointing pharmacokinetics and poor efficacy of direct NaV1.7 inhibitors have resulted in unsatisfactory clinical trials. Here, we identified an alternative approach to regulate NaV1.7 that presented analgesic effects in preclinical models. We found that pharmacologically and genetically upregulating the nuclear factor erythroid 2–related factor 2 (NRF2) in rodent DRG neurons is sufficient for PNP relief. NRF2 exerts antinociceptive properties by selectively inhibiting NaV1.7 current. As a transcription factor, NRF2 binds to the promoter of E3 ubiquitin ligase neural precursor cell expressed developmentally down-regulated protein 4 type 2 (NEDD4-2), and upregulates NEDD4-2-mediated NaV1.7 endocytosis. Through network pharmacology screening strategy and in silico molecular docking analysis, we identified echinacoside (ECH) and artesunate (ART) as two prospective novel analgesics exerting their antinociceptive effects via NRF2 activation and NaV1.7 inhibition in DRG neurons. These findings provide valuable insights into the role of NRF2 in NaV1.7 inhibition in sensory neurons and discover new avenues for novel analgesic development.