Synergistic effects of caspase inhibitors and MK‐801 in brain injury after transient focal cerebral ischaemia in mice
J Ma, M Endres, MA Moskowitz - British journal of …, 1998 - Wiley Online Library
J Ma, M Endres, MA Moskowitz
British journal of pharmacology, 1998•Wiley Online LibraryExcitotoxic 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. Given alone as pretreatment, MK‐801 (1, 3 and 5 mg …
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. Given alone as pretreatment, MK‐801 (1, 3 and 5 mg …
- 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.
- 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 1 h after reperfusion.
- 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.
- 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.
- 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.
- 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.
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