Allyl Sulfide Counteracts 1-Bromopropane-Induced Neurotoxicity by Inhibiting Neuroinflammation and Oxidative Stress

摘要

Chronic exposure to 1-bromopropane (1-BP), an alternative to ozone-depleting solvents, produces potential neurotoxicity in occupational populations. However, no therapeutic strategy is available currently. Accumulating evidence suggests that cytochrome P4502E1 (CYP2E1) is critical for the active metabolism of 1-BP. The purpose of this study is aimed to test whether inhibition of CYP2E1 by allyl sulfide, a specific inhibitor of CYP2E1, could be able to protect against 1-BP-induced neurotoxicity. Male Wistar rats were intoxicated with 1-BP for 9 continuous weeks with or without allyl sulfide pretreatment. Results clearly demonstrated that 1-BP exposure induced decrease in NeuN(+) cells and increase in cleaved caspase-3 expression and TUNEL+ cells in motor cortex of rats, which was significantly ameliorated by allyl sulfide. Allyl sulfide treatment also recovered the motor performance of rats treated with 1-BP. Mechanistically, allyl sulfide-inhibited 1-BP-induced expression of CYP2E1 in microglia, which was associated with suppression of microglial activation and M1 polarization in motor cortex of rats. Reduced oxidative stress was also observed in rats treated with combined allyl sulfide and 1-BP compared with 1-BP alone group. Furthermore, we found that allyl sulfide abrogated 1-BP-induced activation of Nuclear factor(NF)-B and GSH/Thioredoxin/ASK1 pathways, the key factor for the maintenance of M1 microglial inflammatory response and oxidative stress-related neuronal apoptosis, respectively. Thus, our results showed that allyl sulfide exerted neuroprotective effects in combating 1-BP-induced neurotoxicity through inhibition of neuroinflammation and oxidative stress. Blocking CYP2E1 activity by allyl sulfide might be a promising avenue for the treatment of neurotoxicity elicited by 1-BP and other related neurotoxicants.