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Amelioration of Ischemic Mitochondrial Injury and Bax‐Dependent Outer Membrane Permeabilization by Mdivi‐1

CNS neuroscience & therapeutics, 2014-06, Vol.20 (6), p.528-538 [Peer Reviewed Journal]

2014 John Wiley & Sons Ltd ;2015 INIST-CNRS ;2014 John Wiley & Sons Ltd. ;Copyright © 2014 John Wiley & Sons Ltd ;ISSN: 1755-5930 ;EISSN: 1755-5949 ;DOI: 10.1111/cns.12266 ;PMID: 24712408

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Title:
Amelioration of Ischemic Mitochondrial Injury and Bax‐Dependent Outer Membrane Permeabilization by Mdivi‐1
Author: Zhao, Yan‐Xin ; Cui, Mei ; Chen, Shu‐Fen ; Dong, Qiang ; Liu, Xue‐Yuan
Subjects: Animals ; Apoptosis ; Apoptosis - drug effects ; Bax oligomerization ; bcl-2-Associated X Protein - metabolism ; Biological and medical sciences ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - physiopathology ; Brain Edema - drug therapy ; Brain Edema - etiology ; Capillary Permeability - drug effects ; Cell Hypoxia - drug effects ; Cell Line, Tumor ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Disease Models, Animal ; Drp1 ; Gene Expression Regulation - drug effects ; Glucose - deficiency ; Humans ; Infarction, Middle Cerebral Artery - complications ; Infarction, Middle Cerebral Artery - drug therapy ; Infarction, Middle Cerebral Artery - metabolism ; Infarction, Middle Cerebral Artery - pathology ; Injuries of the nervous system and the skull. Diseases due to physical agents ; Ischemia ; Male ; Mdivi‐1 ; Medical sciences ; Membrane Potential, Mitochondrial - drug effects ; Membrane Potential, Mitochondrial - physiology ; Mice ; Mice, Inbred C57BL ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria - ultrastructure ; Mitochondrial DNA ; Mitochondrial dynamics ; Neuroblastoma - pathology ; Neurology ; Neurons ; Original ; Quinazolinones - pharmacology ; Quinazolinones - therapeutic use ; Traumas. Diseases due to physical agents ; Vascular diseases and vascular malformations of the nervous system
Is Part Of: CNS neuroscience & therapeutics, 2014-06, Vol.20 (6), p.528-538
Description: Summary Aims Disturbance of the balance between mitochondrial fission and fusion has been implicated in cerebral ischemia and several neurodegenerative diseases, whereas the underlying mechanisms remain poorly understood. In the present study, we attempted to investigate the role of dynamin‐related protein 1 (Drp1), a key mitochondrial fission protein, in the pathogenesis of cerebral ischemia. Methods Using Drp1 siRNA or Mdivi‐1, a small molecule inhibitor of Drp1, we examined the effect of Drp1 knockdown or inhibition on oxygen‐glucose deprivation (OGD)‐induced mitochondrial dysfunction and death of SH‐SY‐5Y cells. Cell death and viability were evaluated with LDH and MTT assays, respectively, and mitochondrial morphology, mitochondrial membrane potential (Δψm), and ATP production were assessed using epifluorescence microscopy, flow cytometry, and HPLC, respectively. Moreover, to examine the effect of Drp1 inhibition on ischemic brain injury, middle cerebral artery occlusion (MCAO) mice were injected (i.p.) with Mdivi1, and blood–brain barrier permeability, brain water content, and cell apoptosis were assessed. Results Knockdown or inhibition of Drp1 by Mdivi‐1 significantly attenuated OGD‐induced cell death in SH‐SY‐5Y cells, associated with reduced morphological change of mitochondria and attenuated Bax insertion,oligomerization. Moreover, treatment of the MCAO mice with Mdivi‐1 remarkably reduced the infarct volume and neurological deficits in a dose‐dependent manner, associated with marked reduction of mitochondrial fragmentation and BAX expression. Conclusions Down‐regulation or inhibition of Drp1 may reduce cerebral ischemic damage through maintaining normal mitochondrial morphology and function, and decreasing Bax insertion and oligomerization in mitochondria.
Publisher: Oxford: Wiley-Blackwell
Language: English
Identifier: ISSN: 1755-5930
EISSN: 1755-5949
DOI: 10.1111/cns.12266
PMID: 24712408
Source: Journals@Ovid Open Access Journal Collection Rolling
MEDLINE
PubMed Central

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Amelioration of Ischemic Mitochondrial Injury and Bax‐Dependent Outer Membrane Permeabilization by Mdivi‐1

2014 John Wiley & Sons Ltd ;2015 INIST-CNRS ;2014 John Wiley & Sons Ltd. ;Copyright © 2014 John Wiley & Sons Ltd ;ISSN: 1755-5930 ;EISSN: 1755-5949 ;DOI: 10.1111/cns.12266 ;PMID: 24712408

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