Itaconate as a Promising Therapy for Neuropathic Pain and Inflammatory Pain

Abstract Background: Chronic pain is a complex experience that often leads to multiple complications. Neuroinflammation in the immune system as well as in the peripheral and central nervous system contributes to the development and persistence of chronic pain. The metabolite itaconate, recently emerged as a regulator of immune cell functions, has features of anti-inflammation and immunomodulation via the activation of Nrf2. However, its effect on chronic pain is unclear. Methods: Chronic C57BL/6 neuropathic pain and inflammatory pain were induced followed by dimethyl itaconate (DI) treatment, an itaconate derivative. We evaluated the effect of DI on the changes of pain behaviors induced by chronic pain model. The effect of DI on inflammatory cytokine release, glial cells activation, ERK1/2 phosphorylation, inflammatory cell infiltration and Nrf2 expression in the DRGs, spinal cord and hind paw tissues was determined using the histochemistry, RT-PCR and western blot. Microglia was cultured to study the effect of DI on microglial inflammatory response and Nrf2 level.Results: DI reduced the secretion of inflammatory cytokines in DRGs, spinal cord and hind paw tissues, suppressed the activation of glial cells (like microglia and astrocytes) in spina dorsal horn and infiltration of inflammatory cells in the hind paw tissues, and decreased the phosphorylation of ERK1/2, but boosted Nrf2 levels in the DRGs and spinal dorsal horn. Similarly, administration of DI potently reversed the LPS-induced inflammatory effect in the microglia. Reduction of endogenous itaconate pretreated with irg1 siRNA prevented the expression of Nrf2, which did not exert the analgesic and anti-inflammatory effects in vitro experiment. Conclusions: Our findings verify for the first time that DI alleviates painful behaviors and suppresses neuroinflammation in neuropathic pain and inflammatory pain models through molecular mechanisms, suggesting that DI elicits sustained chronic pain relief, which will be regarded as a novel therapeutic agent for chronic pain treatment.