Abstract
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.
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Abbreviations
- MPTP:
-
mitochondrial permeability transition pore
- ANT:
-
adenine nucleotide translocator
- BKA:
-
Bongkrekic acid
- CsA:
-
cyclosporin A
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Acknowledgements
We thank Dr. David Park and Dr. Stephen Crocker for critical review of this manuscript and Clarrie Lam and Jody Lecher for excellent technical assistance. This work was supported by grants to WT from the Natural Sciences and Engineering Research Council of Canada and from the British Columbia Neurotrauma Foundation, BCR04. WT is the recipient of the Rick Hansen Man in Motion Foundation Chair in Spinal Cord Research.
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Vanderluit, J., McPhail, L., Fernandes, K. et al. In vivo application of mitochondrial pore inhibitors blocks the induction of apoptosis in axotomized neonatal facial motoneurons. Cell Death Differ 10, 969–976 (2003). https://doi.org/10.1038/sj.cdd.4401258
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DOI: https://doi.org/10.1038/sj.cdd.4401258
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