In vivo application of mitochondrial pore inhibitors blocks the induction of apoptosis in axotomized neonatal facial motoneurons.
Axotomy induces apoptosis in motoneurons of neonatal rodents. To identify the key players in motoneuron apoptosis, we assessed the progression of apoptosis at 4 h intervals following facial motoneuron axotomy. The mitochondrial release of cytochrome c, caspase-3 activation and nuclear condensation were first observed in the motoneuron cell bodies 16 h postaxotomy. In vivo application of inhibitors of the mitochondrial permeability transition pore, Bongkrekic acid and cyclosporin A prevented cytochrome c release as well as caspase-3 activation and attenuated motoneuron apoptosis. Similarly, in vivo application of RU360, an inhibitor of the mitochondrial calcium uniporter, also protected axotomized motoneurons from apoptosis. Taken together, our results show that cytochrome c release and subsequent caspase-3 activation are critical events that precipitate the apoptotic death of axotomized neonatal motoneurons in vivo. In addition, these results provide evidence that application of mitochondrial pore inhibitors in vivo can block the induction of apoptosis following motoneuron axotomy.
Vanderluit
J L
JL
ICORD (International Collaboration on Repair Discoveries), University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4.
McPhail
L T
LT
Fernandes
K J L
KJ
Kobayashi
N R
NR
Tetzlaff
W
W
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D019771:Axotomy; D001865:Bongkrekic Acid / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D005154:Facial Nerve / Q000254:growth & development / Q000601:surgery; D005260:Female; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D001865:Bongkrekic Acid; D016572:Cyclosporine; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases