Chronic neuroinflammation is one of the critical processes involved in Parkinson’s disease (PD) pathogenesis. Recently, anti-inflammatory agents have been implicated in a promising therapeutic strategy against PD. Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) is a promising target against neuroinflammation in PD. Itaconate is an endogenous metabolite from the tricarboxylic acid cycle and can function as a regulatory mediator of the inflammatory response. Itaconate has been recently characterized as an activator of the Nrf2 antioxidant pathway. Here, we aim to investigate the neuroprotective role of itaconate using its cell-permeable derivate, 4-octyl itaconate (OI), in a cellular PD model.
100 ng/ml LPS wasused to activate BV2 microglial cells in our in vitro experiments. Conditioned medium (CM) from LPS with or without OI-treated BV2 cells was collected to treat N2a neuronal cells.
OI suppressed the LPS-induced upregulation of proinflammatory cascades of inducible nitric oxide synthase, cyclooxygenase-2 and cytokines release in BV2 microglial cells. OI upregulated the p62/Nrf2/HO-1/NF-κB axis pathway in the presence of LPS treatment. CM derived from OI-treated BV2 cells showed significant protective effects against Rotenone/MPP+ induced neurotoxicity.
OI exerts a dramatic anti-inflammatory effect on microglia, resulting in neuron survival against toxin-induced cell death in vitro.