Microglia-dependent neuroprotective effects of 4-octyl itaconate against rotenone-and MPP+-induced neurotoxicity in Parkinson’s disease

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• different PD toxins, the CM from microglia treated with OI showed similarly significant protective capacity

• Itaconate,

• anti-inflammatory responses

• 4-octyl itaconate (OI), a cell-permeable derivative of itaconate

• suppressed lipopolysaccharide-induced proinflammatory cascades

• Nrf2 signaling pathway

• protected against rotenone- and MPP+-induced neurotoxicity

• Although the critical molecular and cellular events underlying DA cell death are unclear

• , inflammation may contribute over time

• midbrain DA neurons exhibit more sensitivity to the death-inducing properties of cytokines such as tumor necrosis factor (TNF) than neurons in the hippocampus or cortex

• targeting the inflammatory processes

• The anti-inflammatory and anti-immune mechanisms of itaconate have been described recently

• in response to (lipopolysaccharide) LPS in macrophages and promotes an anti-inflammatory response by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway

• targeting neuroinflammation could help prevent PD or slow its progression

• by targeting glyceraldehyde 3-phosphate dehydrogenase to decrease aerobic glycolysis in macrophages

• LPS at 100 ng/ml can significantly increase nitrite release without significant cell death

• after 24 h, a highly significant increase in nitrites production was induced by LPS, which was dramatically limited by the cotreatment with OI in a dose-dependent manner

• were significantly suppressed by OI in a dose-dependent manner

• Nrf2 activation

• co-treatment with OI significantly upregulated the Nrf2 protein expression in a dose-dependent manner compared to treatment with LPS or OI alone.