ATF5-Mediated Mitochondrial Unfolded Protein Response (UPR mt ) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia

The mitochondrial unfolded protein response (UPR ) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPR may be a potential therapeutic target for...

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Vydáno v:Stroke (1970) Ročník 55; číslo 7; s. 1904
Hlavní autoři: An, Hong, Zhou, Bing, Hayakawa, Kazuhide, Durán Laforet, Violeta, Park, Ji-Hyun, Nakamura, Yoshihiko, Mandeville, Emiri T, Liu, Ning, Guo, Shuzhen, Yu, Zhanyang, Shi, Jingfei, Wu, Di, Li, Wenlu, Lo, Eng H, Ji, Xunming
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.07.2024
Témata:
Animals
Brain Ischemia - metabolism
Cells, Cultured
Glucose - deficiency
Infarction, Middle Cerebral Artery - metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria - drug effects
Mitochondria - metabolism
Neurons - drug effects
Neurons - metabolism
Neuroprotective Agents - pharmacology
Oxygen - metabolism
Unfolded Protein Response - drug effects
meclizine
oligomycins
homeostasis
unfolded protein response
ischemic stroke
ISSN:1524-4628, 1524-4628
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Shrnutí:The mitochondrial unfolded protein response (UPR ) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPR may be a potential therapeutic target for ischemic stroke. We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPR . We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro. Inducing UPR with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPR could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPR with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPR in vivo, which reduced infarction and improved neurological outcomes. These findings suggest that the UPR is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPR mechanism may provide a new therapeutic avenue for ischemic stroke.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1524-4628
1524-4628
DOI:10.1161/STROKEAHA.123.045550