Effects of intrathecal administration of a cell permeant caspase inhibitor, boc-D-fluoromethylketone (BDFMK), on behavioral deficits following spinal cord ischemia: a dose-response analysis.
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.
Lapchak
Paul A
PA
University of California San Diego, Department of Neuroscience, La Jolla, CA 92093-0624, USA. plapchak@ucsd.edu
Araujo
Dalia M
DM
Weir
Christopher J
CJ
Wei
Jiandong
J
Zivin
Justin A
JA
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007278:Injections, Spinal; D007511:Ischemia / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D010539:Permeability / Q000187:drug effects; D011817:Rabbits; D013116:Spinal Cord / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; D020169:Caspases