Opening of the Mitochondrial Permeability Transition Pore by Reactive Oxygen Species is a Basic Event in Neurodegeneration
Abstract
The role of mitochondrial injury and subsequent apoptosis in the process of neurodegeneration is gaining increasing attention and importance. The animal model system utilized in this project is the New Zealand white rabbit which is treated with an aluminum compound (Al maltolate)by direct injection into the brain cisterna. Early studies have shown that this treatment induces oxidative injury, presumably to mitochondria. Our early work suggested that the aging process increased susceptibility to this M-induced injury, as we have now confirmed by isolating brain tissue and obtaining cell fractions. We have demonstrated that the release of Cytochrome C through a megachannel in mitochondria, termed the mitochondrial permeability transition pore (MTP), is present in aged rabbits but not in young adults. By direct injection of Cyclosporin A into the brain cisterna of these experimental animals, we have shown that we can block the opening of this megachannel, and have observed blocking of the release of Cytochrome C from mitochondria into the cytosol. Young adult animals appear to be protected from this mitochonrial injury, but as yet we do not know by which mechanism. Cytochrome C release through the MTP is known to be the initial step in activating caspases, and eventually in leading to apoptosis and death of the neuron. Our initial work has centered around optimizing the dose of M maltolate and establishing that we can indeed inject Cyclosporin A directly, without apparent clinical problems. We have developed techniques for obtaining cell fractions which are providing us with important new information. We are employing immunohistochemistry as a confirmatory technique, although we anticipate that this approach will play an increasingly important role for our future studies. We have established almost all of our techniques and so far have performed studies on 6% rabbits.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA382802
Entities
People
- John Savory
Organizations
- University of Virginia