Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity

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 vitr...

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Autores principales:	Hui-Ju Huang, Hsiang-Tsui Wang, Ting-Yu Yeh, Bo-Wei Lin, Young-Ji Shiao, Yu-Li Lo, Anya Maan-Yuh Lin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3f2aedffe9fe435480877ee74c6069a3
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spelling	oai:doaj.org-article:3f2aedffe9fe435480877ee74c6069a32021-12-02T17:41:31ZNeuroprotective effect of selumetinib on acrolein-induced neurotoxicity10.1038/s41598-021-91507-62045-2322https://doaj.org/article/3f2aedffe9fe435480877ee74c6069a32021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91507-6https://doaj.org/toc/2045-2322Abstract 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.Hui-Ju HuangHsiang-Tsui WangTing-Yu YehBo-Wei LinYoung-Ji ShiaoYu-Li LoAnya Maan-Yuh LinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hui-Ju Huang Hsiang-Tsui Wang Ting-Yu Yeh Bo-Wei Lin Young-Ji Shiao Yu-Li Lo Anya Maan-Yuh Lin Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity
description	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.
format	article
author	Hui-Ju Huang Hsiang-Tsui Wang Ting-Yu Yeh Bo-Wei Lin Young-Ji Shiao Yu-Li Lo Anya Maan-Yuh Lin
author_facet	Hui-Ju Huang Hsiang-Tsui Wang Ting-Yu Yeh Bo-Wei Lin Young-Ji Shiao Yu-Li Lo Anya Maan-Yuh Lin
author_sort	Hui-Ju Huang
title	Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity
title_short	Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity
title_full	Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity
title_fullStr	Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity
title_full_unstemmed	Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity
title_sort	neuroprotective effect of selumetinib on acrolein-induced neurotoxicity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3f2aedffe9fe435480877ee74c6069a3
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Neuroprotective effect of selumetinib on acrolein-induced neurotoxicity

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