Necrotic death of neurons following an excitotoxic insult is prevented by a peptide inhibitor of c-jun N-terminal kinase.
Peptide inhibitors of c-Jun N-terminal kinase (JNK) have been shown to potently protect against cerebral ischemia. The protective effect has been ascribed to prevention of apoptosis, but cell death following cerebral ischemia is a consequence of both apoptotic and necrotic cell death. We evaluated whether a peptide inhibitor (TAT-TIJIP) of JNK could prevent necrotic cell death in an in vitro model of excitotoxic neuronal death. We find that TAT-TIJIP effectively prevented cell death by interfering with several processes which have been identified as leading to cell death by necrosis. In particular, reactive oxygen species production was reduced, as indicated by an 88% decrease in the rate of dihydroethidium fluorescence in the presence of TAT-TIJIP. Furthermore, TAT-TIJIP attenuated the increase in cytosolic calcium following the excitotoxic insult. The potent neuroprotective properties of JNK peptide inhibitors likely reflects their abilities to prevent cell death by necrosis as well as apoptosis.
Arthur
Peter G
PG
School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, Western Australia, Australia. parthur@cyllene.uwa.edu.au
Matich
Graeme P
GP
Pang
Wei Wei
WW
Yu
Dao-Yi
DY
Bogoyevitch
Marie A
MA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018846:Excitatory Amino Acids / Q000633:toxicity; D005456:Fluorescent Dyes; D018698:Glutamic Acid / Q000633:toxicity; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D009474:Neurons / Q000473:pathology*; D010101:Oxygen Consumption / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species; D013481:Superoxides / Q000378:metabolism
D004791:Enzyme Inhibitors; D018846:Excitatory Amino Acids; D005456:Fluorescent Dyes; D010455:Peptides; D017382:Reactive Oxygen Species; C521384:TAT-TIJIP; D013481:Superoxides; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D002118:Calcium