Neuroprotective effect of A20 on TNF-induced postischemic apoptosis.
Focal cerebral ischemia causes apoptosis in neural cells during the postischemia period. TNF is critically involved in such neuronal apoptosis mediated by caspase pathways. A20 can inhibit TNF-induced apoptosis in many cell types. However, little work has been carried out in central nervous system. In the present study, gene transfer of A20 resulted in reduction of infarct volume and improvement of neurological deficit in ischemia rats. Results of flow cytometry, TUNEL and DNA fragmentation assay all indicated A20 could inhibit TNF-induced apoptosis both in primary rat hippocampal neurons and SH-SY5Y cells. Moreover, we found A20 targeted the TNF apoptotic pathway by inhibiting proteolytic cleavage of caspase 8 and 3 in SH-SY5Y cells. These data demonstrated A20 could effectively protect neurons from postischemic apoptosis and may function partly on death receptor caspase pathway. Gene transfer of A20 may be a promising approach to gene therapy for cerebral ischemia in the future.
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Room 901, Cell Biology Building, No. 320 Yueyang Road, Shanghai 200031, China.
Luyang
L
Yu
Hongsheng
H
Miao
Yanan
Y
Hou
Bao
B
Zhang
Lihe
L
Guo
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002545:Brain Ischemia / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005260:Female; D018014:Gene Transfer Techniques; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery; D047908:Intracellular Signaling Peptides and Proteins; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D020169:Caspases