Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity

Hui-Ju Huang,Ting-Yu Yeh,Hsiang-Tsui Wang,Yu-Li Lo,Young-Ji Shiao,Bo-Wei Lin,Anya Maan-Yuh Lin

doi:10.1038/s41598-021-91507-6

Abstract

Abnormal accumulation of acrolein, an α, β unsaturated aldehyde has been reported as one pathological cause of the CNS neurodegenerative diseases. In the present study, the neuroprotective effect of selumetinib (a MEK–ERK inhibitor) on acrolein-induced neurotoxicity was investigated in vitro using primary cultured cortical neurons. Incubation of acrolein consistently increased phosphorylated ERK levels. Co-treatment of selumetinib blocked acrolein-induced ERK phosphorylation. Furthermore, selumetinib reduced acrolein-induced increases in heme oxygenase-1 (a redox-regulated chaperone protein) and its transcriptional factor, Nrf-2 as well as FDP-lysine (acrolein-lysine adducts) and α-synuclein aggregation (a pathological biomarker of neurodegeneration). Morphologically, selumetinib attenuated acrolein-induced damage in neurite outgrowth, including neuritic beading and neurite discontinuation. Moreover, selumetinib prevented acrolein-induced programmed cell death via decreasing active caspase 3 (a hallmark of apoptosis) as well as RIP (receptor-interacting protein) 1 and RIP3 (biomarkers for necroptosis). In conclusion, our study showed that selumetinib inhibited acrolein-activated Nrf-2-HO-1 pathway, acrolein-induced protein conjugation and aggregation as well as damage in neurite outgrowth and cell death, suggesting that selumetinib, a MEK–ERK inhibitor, may be a potential neuroprotective agent against acrolein-induced neurotoxicity in the CNS neurodegenerative diseases.

Highlights

Abnormal accumulation of acrolein, an α, β unsaturated aldehyde has been reported as one pathological cause of the CNS neurodegenerative diseases
One was to delineate the involvement of MEK–ERK signaling in the acrolein-induced neurotoxicity using primary cultured cortical neurons
We found that incubation of acrolein for 30 min significantly increased phosphorylated ERK levels (40 and 42 kDa) and maintained the elevated ERK phosphorylation for 8 h (Fig. 1A) and 24 h (Fig. 1B)

Summary

Introduction

An α, β unsaturated aldehyde has been reported as one pathological cause of the CNS neurodegenerative diseases. One was to delineate the involvement of MEK–ERK signaling in the acrolein-induced neurotoxicity using primary cultured cortical neurons. The involvement of MEK–ERK signalings in the acrolein-induced neuronal toxicity was delineated using primary cultured cortical neurons. Acrolein concentration-dependently increased ERK phosphorylation in primary cultured cortical neurons (Fig. 1B).

Results

Conclusion