William G. Tatton

Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase.

(-)-Deprenyl stereospecifically reduces neuronal death even after neurons have sustained seemingly lethal damage at concentrations too small to cause monoamine oxidase-B (MAO-B) inhibition. (-)-Deprenyl can also influence the process growth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with the earlier work of others, we showed that (-)-deprenyl alters the expression of a number mRNAs or proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial ATP production depends on mitochondrial membrane potential (MMP) and mitochondrial failure has been shown to be one of the earliest events in apoptosis, we used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl are accompanied by a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and to decrease cytoplasmic oxidative radical levels and thereby to reduce apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may contribute to the development of new therapies for neurodegenerative diseases.

Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription.

Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimers disease, Parkinsons disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.

Chapter 1 Mechanisms of Nerve Cell Death: Apoptosis or Necrosis After Cerebral Ischaemia

Publisher Summary Nerve cell death in human stroke was believed to be necrotic. In the 1970s and early 1980s, evidence of a different form of cell death termed “apoptosis” was found. Apoptosis seemed particularly important as a counterbalance to overexuberant cell replication but seemed to have little to do with nerve cells that were postmitotic and unable to replicate. About the same time, it was recognized that the massive death of neurons that occurred as part of vertebrate prenatal and postnatal brain development depended on competition for trophic factors. Death due to neurotrophic insufficiency was termed “programed cell death” as it was thought that it depended on the activation of an intrinsic program leading to self-destruction. Numerous studies have now reported apoptosis as contributing to the neuronal death found in experimental models of ischemia. The extent of apoptosis versus that of necrosis under specific conditions and in relation to regional changes in arterial perfusion remains uncertain.

Reduction of neuronal apoptosis by small molecules: Promise for new approaches to neurological therapy

Publisher Summary Several members of the neurotrophin, mitogen, and cytokine/neurokine families have the capacity to reduce or slow neuronal apoptosis. Each of these neurotrophic factors act on specific receptors, which activate a number of cellular processes, some of which lead to a reduction in neuronal death. Deprenyl was synthesized as a psychoenergizer that combined (−)-metham–phetamine with a pargene chain and was subsequently found to selectively inhibit the B form of monoamine oxidase (MAO-B). Levodopa and (−)-deprenyl were used in combination to treat Parkinsons disease in the hope that levodopa would be converted to dopamine by nigrostriatal neurones, and (−)-deprenyl would cause an acute decrease in dopamine metabolism, thereby increasing dopamine availability in the striatum. The celebrated finding that MAO-B inhibition protected nigrostriatal neurones from damage caused by the toxin MPTP, presumably by blocking the conversion of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) to 1-methyl-4-phenylpyridinum (MPP + ) in astroglia, reinforced the view that (−)-deprenyl could have clinical utility as an MAO-B inhibition-dependent neuroprotectant. The results indicate that three of the four MAO-independent actions of (−)-deprenyl result from selective alterations in gene expression induced by (−)-desmethyldeprenyl.