Background:

Z-DEVD-FMK is a tetrapeptide caspase inhibitor that is considered relatively selective for caspase-3^{1, 2}and has been widely used in in vitro and in vivo models of acute injury to delineate roles for caspase 3 in neuronal cell death. Intracerebroventricular injections of Z-DEVD-FMK improved function after LFP³. Intraparenchymal infusion of Z-DEVD-FMK over several days after combined CCI and hypoxia reduced lesion size, although functional outcome was not significantly improved in this model⁴(Clark et al., 2000).

Z-DEVD-FMK was a potent inhibitor of calpain and that improvement observed after treatment with Z-DEVD-FMK may reflect, at least in part, this action.

Early treatment with Z-DEVD-FMK improved neurologic function and reduced lesion volume. Z-DEVD-FMK reduces cell death and inhibits calpain in a model of in vitro necrosis and a cell free assay and Z-DEVD-FMK treatment inhibits calpain activity after TBIin vivo.

Z-DEVD-FMK improved neurologic function and reduced tissue damage at an injury severity that showed predominantly necrotic neuronal cell death with minimal evidence of caspase 3 activation. Moreover, effective treatment with Z-DEVD-FMK was associated with reduced calpain-mediated -spectrin degradation. Z-DEVD-FMK was also neuroprotective, at concentrations lower than those routinely used to inhibit caspase 3, in anin vitromodel of necrotic neuronal cell death induced by maitotoxin.

The present data show that treatment with Z-DEVD-FMK improves behavioral recovery, reduces tissue damage and prevents accumulation of calpain-mediated α-spectrin breakdown products when administered not later than 1 hour after injury in a TBI model that primarily shows necrosis. Z-DEVD-FMK also reduces necrotic neuronal cell death in vitro, and such neuroprotection is associated with inhibition of calpain, but not caspase 3 or cathepsin B. In addition, Z-DEVD-FMK reduces calpainmediated hydrolysis of casein, which indicates that Z-DEVD-FMK can directly inhibit calpain. This nonspecificproperty of Z-DEVD-FMK may account, at least in part, for its neuroprotective actions⁵.

参考文献:
1. Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW, Thornberry NA (1998) Inhibition of human caspases by peptidebased and macromolecular inhibitors.J Biol Chem273:32608–32613
2. Thornberry NA, Rano TA, Peterson EP, Rasper DM, Timkey T, Garcia-Calvo M, Houtzager VM, Nordstrom PA, Roy S, Vaillancourt JP, Chapman KT, Nicholson DW (1997) A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis.J Biol Chem272:17907–17911
3. Yakovlev AG, Knoblach SM, Fan L, Fox GB, Goodnight R, Faden AI (1997) Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury.J Neurosci17:7415–7424
4. Clark RS, Kochanek PM, Watkins SC, Chen M, Dixon CE, Seidberg NA, Melick J, Loeffert JE, Nathaniel PD, Jin KL, Graham SH (2000) Caspase-3 mediated neuronal death after traumatic brain injury in rats.J Neurochem74:740–753
5. S. M. Knoblach, D. A. Alroyet al, Caspase Inhibitor z-DEVD-fmk Attenuates Calpain and Necrotic Cell Death in Vitro and After Traumatic Brain Injury,Journal of Cerebral Blood Flow & Metabolism24:1119–1132.