Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury

Evidence indicates that both necrotic and apoptotic cell death contribute to tissue injury and neurological dysfunction following spinal cord injury. Caspases have been implicated as important mediators of apoptosis following acute central nervous system insults. We investigated whether caspase-1 an...

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Bibliographic Details
Published in:Neuroscience 2000-01, Vol.99 (2), p.333-342
Main Authors: Li, M., Ona, V.O., Chen, M., Kaul, M., Tenneti, L., Zhang, X., Stieg, P.E., Lipton, S.A., Friedlander, R.M.
Format: Article
Language:English
Subjects:
Amino Acid Chloromethyl Ketones - pharmacology
Amino Acid Chloromethyl Ketones - therapeutic use
Animals
apoptosis
Apoptosis - drug effects
Apoptosis - physiology
Biological and medical sciences
Caspase 1 - metabolism
Caspase 3
Caspase Inhibitors
Caspases - metabolism
Enzyme Activation
ICE
In Situ Nick-End Labeling
interleukin-1β
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity - drug effects
Motor Activity - physiology
Neurons - drug effects
Neurons - metabolism
Neuropharmacology
neuroprotection
Neuroprotective agent
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
Pharmacology. Drug treatments
Spinal Cord Injuries - drug therapy
Spinal Cord Injuries - enzymology
Spinal Cord Injuries - physiopathology
zVAD-fmk
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Summary:Evidence indicates that both necrotic and apoptotic cell death contribute to tissue injury and neurological dysfunction following spinal cord injury. Caspases have been implicated as important mediators of apoptosis following acute central nervous system insults. We investigated whether caspase-1 and caspase-3 are involved in spinal cord injury-mediated cell death, and whether caspase inhibition may reduce tissue damage and improve outcome following spinal cord injury. We demonstrate a 17-fold increase in caspase-1 activity in traumatized spinal cord samples when compared with samples from sham-operated mice. Caspase-1 and caspase-3 activation were also detected by western blot following spinal cord injury, which was significantly inhibited by the broad caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. By immunofluorescence or in situ fluorogenic substrate assay, caspase-1 and caspase-3 expression were detected in neuronal and non-neuronal cells following spinal cord injury. N-Benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone treated mice, and transgenic mice expressing a caspase-1 dominant negative mutant, demonstrated a significant improvement of motor function and a reduction of lesion size compared with vehicle-treated mice. Our results demonstrate for the first time that both caspase-1 and caspase-3 are activated in neurons following spinal cord injury, and that caspase inhibition reduces post-traumatic lesion size and improves motor performance. Caspase inhibitors may be one of the agents to be used for the treatment of spinal cord injury.
ISSN:0306-4522
1873-7544
DOI:10.1016/S0306-4522(00)00173-1