Pathology activated prodrugs targeting Nrf2 to treat neuropathic pain

Abstract

The antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) is a desirable therapeutic target for a broad range of pathologies, including chronic pain. However, current Nrf2 activators are limited by unwanted effects due to non-specificity, and systemic distribution and action. We aimed to overcome these long-standing issues by creating a compound that would mask the unwanted electrophilic nature of the Nrf2 activator monomethyl fumarate (MMF) until selective generation of MMF at sites of oxidative pathology associated with pain. Neuropathic pain was established with the spared nerve injury (SNI) model, cisplatin chemotherapy-induced peripheral neuropathy (CIPN), and osteoarthritis in male and female C57BL/6J mice. Nrf2 activators/MMF/vehicle was orally administrated daily, beginning 7 days after SNI/sham surgery. The von Frey test, paintbrush test, and a conflict-avoidance task were used to quantify nociceptive hypersensitivity. Western blot and qPCR were used to assay Nrf2 translocation and levels of antioxidants in ipsilateral L4/5 dorsal root ganglia (DRG). Oral treatment with Nrf2 activator 1c reversed chronic neuropathic and osteoarthritis pain in mice, selectively activated Nrf2 at sites of oxidative stress, and selectively increased expression of Nrf2 target antioxidant genes in the ipsilateral DRG. These results highlight the potential for our Nrf2 activator 1c to treat neuropathic pain at sites of oxidative stress.