Caspase inhibition has been proposed as a target to attenuate ischemia-induced neurodegeneration and behavioral dysfunction. The present study evaluated the pharmacological effects of a single dose of an irreversible cell permeant general (nonselective) caspase inhibitor, Boc-D-fluoromethylketone (BDFMK) administered intrathecally (i.t.) in a reversible spinal cord ischemia model (RSCIM). Quantal analysis indicated that the P-50 (represents the duration of ischemia that produces permanent paraplegia in 50% of the animals in a group) of the control group was 25.08+/-4.71 min. Using the RSCIM, neuroprotection is observed if a drug significantly prolongs the P-50 compared to the control group. The P-50 values for the BDFMK-treated groups were 27.21+/-2.62, 27.28+/-3.29 and 28.98+/-2.32 min, for the three dose groups studied. There were no statistically significant changes when measured 18 or 48 h following ischemia. Biochemical analysis of cell extracts from the caudal lumbar spinal cord indicated that there was increased production of the 120-kDa fragment of fodrin suggesting enhanced caspase-3 activity, an increase that was reduced by i.t. BDFMK administration. Moreover, in caudal lumbar spinal cord extracts from a set of paraplegic rabbits (25-50 min occlusion), we measured a 32-42% decrease of caspase-3 activity in BDFMK-treated rabbits. The present study shows that i.t. administration of BDFMK reduced caspase-3 activity, but the inhibition did not translate into a significant behavioral improvement. Our results suggest that administration of a single dose of the caspase inhibitor BDFMK is insufficient to attenuate ischemia-induced behavioral deficits following aortic occlusion. (C) 2002 Elsevier Science B.V. All rights reserved.
|Article number||PII S0006-8993(02)03739-3|
|Number of pages||8|
|Publication status||Published - 10 Jan 2003|
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