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Caspase inhibition selectively reduces the apoptotic component of oxygen-glucose deprivation-induced cortical
F J Gottron1, H S Ying, D W Choi
1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
Cultured mouse cortical neurons undergo apoptosis when exposed to staurosporine. The cell-permeable caspase inhibitor Z-Val-Ala-Asp fluoromethylketone (Z-VAD.FMK) attenuated this death, without altering overall protein synthesis. Z-VAD.FMK also attenuated cortical neuronal apoptosis induced by removal of serum. However, Z-VAD.FMK did not attenuate the excitotoxic necrosis induced by 5-min exposure to 100 microM NMDA, 24-h exposure to 100 microM kainate, or 90-min exposure to oxygen-glucose deprivation. We have previously shown that blockade of the excitotoxic component of oxygen-glucose deprivation-induced neuronal death with glutamate antagonists unmasks an apoptotic death. Treatment with Z-VAD.FMK, but not the cathepsin-B protease inhibitor Z-Phe-Ala fluoromethylketone (Z-FA.FMK), also attenuated this oxygen-glucose deprivation-induced neuronal apoptosis. These data support the idea that brain caspases mediate the apoptotic component of oxygen-glucose deprivation-induced neuronal death and raise the possibility that combining caspase inhibitors with glutamate antagonists might attenuate brain damage induced by hypoxic-ischemic insults in vivo.
Insights
Caspase inhibitors, like Z-Val-Ala-Asp fluoromethylketone (Z-VAD.FMK), reduce apoptosis in mouse neurons. Combining these inhibitors with glutamate antagonists may protect against brain damage from hypoxic-ischemic insults.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Cultured mouse cortical neurons undergo apoptosis when exposed to staurosporine.
- The cell-permeable caspase inhibitor Z-Val-Ala-Asp fluoromethylketone (Z-VAD.FMK) attenuated this death, without altering overall protein synthesis.
- Z-VAD.FMK also attenuated cortical neuronal apoptosis induced by removal of serum.
Purpose of the Study:
- To investigate the role of caspases in neuronal apoptosis and excitotoxicity.
- To determine if caspase inhibitors can attenuate neuronal death induced by oxygen-glucose deprivation.
- To explore the potential of combining caspase inhibitors with glutamate antagonists for treating hypoxic-ischemic brain damage.
Main Methods:
- Using cultured mouse cortical neurons.
- Exposing neurons to staurosporine, serum removal, NMDA, kainate, and oxygen-glucose deprivation (OGD).
- Treating neurons with caspase inhibitors (Z-VAD.FMK) and cathepsin-B protease inhibitor (Z-FA.FMK).
Main Results:
- Z-VAD.FMK attenuated staurosporine- and serum deprivation-induced apoptosis.
- Z-VAD.FMK did not affect excitotoxic necrosis induced by NMDA, kainate, or OGD.
- Z-VAD.FMK attenuated the apoptotic component of OGD-induced neuronal death, while Z-FA.FMK did not.
Conclusions:
- Brain caspases mediate the apoptotic component of oxygen-glucose deprivation-induced neuronal death.
- Combining caspase inhibitors with glutamate antagonists may attenuate brain damage from hypoxic-ischemic insults in vivo.