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Abstract
(-)-Deprenyl has been used to irreversibly inhibit monoamine oxidase B (MAO-B) in Parkinson's disease (PD) and Alzheimer's disease (AD) as a possible means of improving dopaminergic neurotransmission or of reducing neuronal necrosis caused by oxidative radical damage. Recent research in tissue culture and animal models has shown that (-)-deprenyl can reduce neuronal apoptosis caused by a variety of agents, in a variety of neuronal subtypes through a mechanism(s) that does not require MAO-B inhibition. Studies using general P450 blockers have shown that one of the principal metabolites of (-)-deprenyl, (-)-desmethyldeprenyl, mediates the antiapoptotic action. Other research has shown that (-)-deprenyl can induce altered expression of a number of genes in preapoptotic neurons both in vitro and in vivo, including the genes for superoxide dismutase (SOD) 1 and 2, BCL-2 and BCL-xL, nitric oxide synthase, c-JUN, and nicotinamide adenine dinucleotide dehydrogenase. Antiapoptosis by (-)-deprenyl is associated with a prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons, which has been shown to occur early in apoptosis and is likely an initiating factor. The above changes in gene expression appear to reduce oxidative radical damage to mitochondria and maintain mitochondrial permeability, thereby blocking mitochondrial "signals" that initiate apoptosis. In situ evidence suggests that apoptosis contributes to neuronal death in a number of neurodegenerative diseases. If apoptosis is critical to the progression of one or more human neurodegenerative diseases, then transcriptionally active agents such as (-)-desmethyldeprenyl may be of value in treating the diseases. The kinetics of (-)-deprenyl metabolism, however, and its biodistribution after oral administration, make it unlikely that the antiapoptotic action has played a major role in benefits found for the drug in PD and AD to date.
NEUROLOGY 1996;47(Suppl 3): S171-S183
- Copyright 1996 by Advanstar Communications Inc.
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- Abstract
- The hypothetical basis for the benefits of MAO-B inhibition in Parkinson's disease.
- Clinical benefits of (-)-deprenyl.
- (-)-Deprenyl can increase neuronal survival in vivo and in vitro without inhibiting MAO-B.
- Apoptosis may be involved in neurodegeneration.
- Genes and proteins that promote or retard apoptosis.
- Evidence that mitochondria contribute to the initiation of apoptosis and that (-)-deprenyl alters apoptosis through a mitochondrial mechanism.
- (-)-Deprenyl alters the expression of genes that influence mitochondrial viability.
- Do the selective changes in gene expression explain the capacity of (-)-deprenyl to maintain mitochondrial membrane potential and reduce neuronal apoptosis?
- Do the actions of (-)-deprenyl on gene expression contribute to the benefits reported for (-)-deprenyl treatment in human neurodegenerative diseases?
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