Opening of the Mitochondrial Permeability Transition Pore by Reactive Oxygen Species is a Basic Event Neurodegeneration

摘要

This investigation focuses on mitochondrial injury in the brain and subsequent apoptosis, as a major factor in neurodegeneration. The animal model system involves the direct injection of Al maltolate directly into the brains of New Zealand white rabbits via the intracisternal route. Our hypothesis was that Al maltolate induced oxidative stress resulting in opening of the mitochondrial permeability transition pore (PTP) and release of cytochrome c. This event was predicted to induce apoptosis. Our original proposal was to emphasize the use of immunohistochemical techniques for this study with confirmation by Western blot analysis. We have now developed cell fractionation techniques to that we can obtain mitochondrial, cytoplasmic, endoplasmic reticulum and nuclear fractions, with appropriate markers, with confirmation by immunohistochemistry. We have shown, as originally proposed, that aged rabbits do indeed demonstrate opening of the PTP and cytochrome c release, whereas young adult rabbits are not affected. However, this event does not necessarily lead to caspase-3 activation and apoptosis. We have now demonstrated that the endoplasmic reticulum and caspase-12 is important in the overall process of neurodegeneration and have been able to demonstrate neuroprotection with GDNF. We have performed studies on 70 rabbits during the time period covered by this present report.