Neuroprotective effects of caspase-3 inhibition on functional recovery and tissue sparing after acute spinal cord injury

• Published in: Spine (Philadelphia, Pa. 1976) Vol. 33; no. 21; p. 2269
• Main Authors: Citron, Bruce A, Arnold, Paul M, Haynes, Neal G, Ameenuddin, Syed, Farooque, Mohammed, Santacruz, Karen, Festoff, Barry W
• Format: Journal Article
• Language: English
• Published: United States 01.10.2008
• Subjects: Acute Disease; Animals; Caspase 3 - metabolism; Caspase Inhibitors; Enzyme Activation - drug effects; Female; Motor Neurons - drug effects; Motor Neurons - enzymology; Motor Neurons - pathology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Protease Inhibitors - pharmacology; Protease Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; Recovery of Function - drug effects; Recovery of Function - physiology; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - enzymology; Spinal Cord Injuries - pathology
• ISSN: 1528-1159
• DOI: 10.1097/BRS.0b013e3181831f7e

We used gene microarrays and found that caspase-related death genes were upregulated. We tested caspase inhibition and evaluated its effect on the spinal cord after traumatic injury. The logical extension of previous studies was to determine whether downstream CASP genes might also be involved and whether inhibition might prevent injury-induced cell death. Apoptotic cell death occurs in all endogenous cellular compartments of the spinal cord, peaking at 3 days after injury in neurons, astrocytes, and microglia. The downstream effector caspase-3 cleaves several important cellular sites after being activated by upstream initiator caspases. Along with others, we have previously identified caspase signature cleavage of PARP, alpha-fodrin, and DFF45/ICAD in the injured rat spinal cord. We also showed rapid upregulation of caspase-3 gene expression along with localization of active caspase-3 in neurons and activated microglia after SCI. Others have reported that a more general active-site mimetic peptide ketone, benzylocarbonyl-Val-Ala-Asp-fluromethylketone (zVAD-fmk) was neuroprotective after rat spinal cord injury (SCI). In this study, we administered the caspase-3 subfamily tetrapeptide cell permeable inhibitor Z-Asp(O-Me)-Glu(O-Me)-Val-Asp(O-Me) fluoromethyl ketone (DEVD-fmk) intraperitoneally 1 hour after laminectomy and moderate (25 g cm force) SCI in rats. RESULTS.: We used the open field locomotor rating (LRS) over a 14-day course and found statistically significant improvement in DEVD-fmk-treated rats, LRS, 9.8 +/- 0.93 SEM, compared with vehicle, 6.6 +/- 0.4 (P < 0.05). Histologic analysis of percent spinal cord tissue volume spared was 50% greater for DEVD-fmk versus control (P < 0.5). These results indicate neuroprotection at both the cellular level and with substantial functional recovery, suggesting caspase-3 inhibition may be a viable therapy in the early hours after experimental SCI.