Acrylamide and its metabolite induce neurotoxicity via modulation of protein kinase C and AMP-activated protein kinase pathways

Acrylamide is known as a neurotoxicant found in commonly consumed food as well as in human body. However, the underlying mechanisms involved in neurotoxicity by acrylamide and its metabolite, glycidamide remain largely unknown. In this study, we have examined the interplay between CYP2E1, AMPK, ERK...

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Bibliographic Details
Published in:Toxicology in vitro 2021-04, Vol.72, p.105105, Article 105105
Main Authors: Triningsih, Dahlia, Yang, Jae-Ho, Sim, Kyeong Hwa, Lee, Chuhee, Lee, Youn Ju
Format: Article
Language:English
Subjects:
Acrylamide
AMP
AMP-activated protein kinase
AMPK
Autophagy
Cell death
Chloroquine
Cytotoxicity
Extracellular signal-regulated kinase
Glycidamide
Kinases
Metabolites
Mortality
Neuromodulation
Neurotoxicity
p62 Protein
Phagocytosis
Pheochromocytoma cells
PKC
Protein kinase C
Proteins
siRNA
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Summary:Acrylamide is known as a neurotoxicant found in commonly consumed food as well as in human body. However, the underlying mechanisms involved in neurotoxicity by acrylamide and its metabolite, glycidamide remain largely unknown. In this study, we have examined the interplay between CYP2E1, AMPK, ERK and PKC in acrylamide-induced neurotoxicity associated with autophagy in PC12 cells. Acrylamide-induced cell death was mediated by CYP2E1 expression and the activation of ERK, PKC-ɑ and PKC-δ, whereas AMPK knockdown exacerbated the acrylamide-induced neurotoxic effects. PKC-ɑ, but not PKC-δ, plays an upstream regulator of ERK and AMPK. Moreover, AMPK activation suppressed ERK, and CYP2E1 and AMPK bilaterally inhibit each other. Furthermore, acrylamide increased autophagy with impaired autophagic flux, evidenced by the increased beclin-1, LC3-II and p62 protein. Acrylamide-induced neuronal death was ameliorated by 3-methyladenine, an autophagy inhibitor, whereas neuronal death was exacerbated by chloroquine, a lysosomal inhibitor. Interestingly, PKC-δ siRNA, but not PKC-ɑ siRNA, dramatically reduced acrylamide-induced beclin-1 and LC3-II levels, whereas AMPK siRNA further increased beclin-1, LC3-II and p62 protein levels. Glycidamide, a major metabolite, mimicked acrylamide only with a higher potency. Taken together, acrylamide- and glycidamide-induced neurotoxicity may involve cytotoxic autophagy, which is mediated by interplay between PKCs and AMPK pathways. •Acrylamide induces neurotoxicity via activation of PKCs (α, δ) and ERK and inhibition of AMPK.•PKCα regulates ERK and AMPK in positive and negative manner, respectively.•PKCδ-induced cell death involves cytotoxic autophagy, which is counteracted by AMPK.•Glycidamide, a metabolite of acrylamide, induced neurotoxicity with a higher potency.
ISSN:0887-2333
1879-3177
DOI:10.1016/j.tiv.2021.105105