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Spine (Phila Pa 1976). 2008 Oct 1;33(21):2269-77. doi: 10.1097/BRS.0b013e3181831f7e.

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

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1
Neurobiology Research Laboratory, Veterans Affairs Medical Center, Kansas City, MO 64128, USA.

Abstract

STUDY DESIGN:

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.

OBJECTIVE:

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.

SUMMARY OF BACKGROUND DATA:

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).

METHODS:

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).

CONCLUSION:

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.

PMID:
18827691
DOI:
10.1097/BRS.0b013e3181831f7e
[Indexed for MEDLINE]
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