Synergistic effects of caspase inhibitors and MK‐801 in brain injury after transient focal cerebral ischaemia in mice

Abstract

1. Excitotoxic and apoptotic mechanisms have been implicated in the pathophysiology of cerebral ischaemia. Both MK-801, an NMDA receptor antagonist, or peptide inhibitors of the caspase family (z-VAD.FMK and z-DEVD.FMK), protect mouse brain from ischaemic cell damage. In this study, we examined whether these drugs which act via distinct mechanisms, afford even greater neuroprotection when given in combination following 2 h MCA occlusion (filament model) and 18 h reperfusion. 2. Given alone as pretreatment, MK-801 (1, 3 and 5 mg kg(-1), but not 0.3 mg kg(-1), i.p.) decreased infarct size by 34-75%. When injected 1 h after occlusion and before reperfusion, 3 mg kg(-1) reduced injury but not when administered I h after reperfusion. 3. Pretreatment with a subthreshold dose of MK-801 (0.3 mg kg(-1)) plus a subthreshold dose of z-VAD.FMK (27 ng) or z-DEVD (80 ng) significantly decreased infarct size by 29 and 30%, respectively, and enhanced neurological function. 4. Administering a subthreshold dose of z-VAD.FMK (27 ng) or z-DEVD.FMK (80 ng) as pretreatment extended the time window for MK-801 (3 mg kg(-1)) by 2 h from 1 h before reperfusion to at least 1 h after reperfusion. 5. Pretreating with a subthreshold dose of MK-801 (0.3 mg kg(-1)) extended the time window for z-DEVD.FMK (480 ng) from 1 h after reperfusion to at least 3 h after reperfusion. 6. We conclude that caspase inhibitors which putatively block apoptotic cell death and inhibit cytokine production and the NMDA antagonist MK-801 act synergistically and prolong their respective therapeutic windows in cerebral ischaemia.

BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: A promising neuroprotective strategy

“…Acting at several sites in the neurotoxic cascade is likely to be more effective, as suggested by several studies in which different treatments have been associated (5,(37)(38)(39). Our results suggest that a better efficacy may be obtained with the use of a dual inhibitor.…”

Vasoconstrictive Neurovascular Coupling during Focal Ischemic Depolarizations

“…Regardless of its mechanism, this secondary hemodynamic benefit conferred by CSD inhibitors is a novel mechanism that might be shared by other neuroprotective drugs. Although PIDs are known to occur for up to 24 h (Hartings et al, 2003), the therapeutic window for neuroprotective drugs is relatively brief (e.g., approximately 1 h for MK-801) (Hatfield et al, 1992;Lyden et al, 1995;Ma et al, 1998;Margaill et al, 1996). Therefore, attenuation of vasoconstrictive coupling, as a relevant neuroprotective mechanism in vivo, appears to be effective only during the acute phase of ischemia.…”

Cellular and Molecular Pathways of Ischemic Neuronal Death

“…In addition, a prolonged deprivation of oxygen and glucose undergoes slowly-evolving apoptosis through the activation of caspases under the blockade of excitotoxicity Gottron et al, 1997). Accordingly, the combined treatment with a NMDA antagonist and a caspase inhibitor results in synergetic neuroprotection against hypoxic-ischemic injury in vitro and in vivo (Ma et al, 1998;Schulz et al, 1998;Allen et al, 1999;Choi, 2001).…”