Clinically, high amounts of acrolein (a very reactive |á, |?-unsaturated aldehyde) and acrolein adducts are detected within the brain of patients with CNS neurodegenerative illnesses, including Alzheimer’s and spinal-cord injuries. Our previous study supports this notion by showing acrolein like a neurotoxin inside a Parkinsonian animal model. In our study, the result of AZD6244 (an ATP non-competitive MEK1/2 inhibitor) on acrolein-caused neuroinflammation was investigated using BV-2 cells and first cultured microglia. Our immunostaining study demonstrated that lipopolysaccharide (LPS, an inflammatory reaction inducer like a positive control) elevated co-localized immunoreactivities of phosphorylated ERK and Erectile dysfunction-1 (a biomarker of activated microglia) within the treated BV-2 cells. Similar elevation in co-localized immunoreactivities of phosphorylated ERK and Erectile dysfunction-1 was detected within the acrolein-treated BV-2 cells. In addition, Western blot assay demonstrated increases in phosphorylated ERK in BV-2 cells exposed to LPS (1 |ìg/mL) or acrolein (30 |ìM) these increases were blocked by AZD6244 (10 |ìM). Simultaneously, AZD6244 attenuated LPS-caused TNF-|á (a professional-inflammatory cytokine) and cyclooxygenase-II (COX II, a professional-inflammatory enzyme). Consistently, AZD6244 reduced acrolein-caused elevations in COX-II mRNA and COX-II protein expression. Additionally, AZD6244 inhibited acrolein-caused increases in activated caspase 1 (a biomarker of inflammasome activation) and heme oxygenase-1 (a redox-controlled chaperone protein) in BV-2 cells. Utilizing a transwell migration assay, AZD6244 attenuated acrolein (5 |ìM)-caused migration of BV-2 cells and first cultured microglia. To conclude, our study implies that acrolein is capable of doing inducing neuroinflammation which involved ERK activation in microglia. In addition, AZD6244 is capable of doing inhibiting acrolein-caused neuroinflammation. Our study shows that ERK inhibition can be a neuroprotective target against acrolein-caused neuroinflammation within the CNS neurodegenerative illnesses.