Modulation of gene expression rather than monoamine oxidase inhibition

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.

R‐Deprenyl and R‐2‐Heptyl‐N‐Methylpropargylamine Prevent Apoptosis in Cerebellar Granule Neurons Induced by Cytosine Arabinoside but Not Low Extracellular Potassium

“…Although the antiapoptotic action of R-deprenyl is not affected by the protein synthesis dependency of the apoptotic process, it has been shown that the antiapoptotic action of R-deprenyl is dependent on altering gene expression (Tatton et al, 1994;Tatton and Chalmers-Redman, 1996). There is now considerable evidence that mitochondrial failure is an early event in apoptosis (Zamzami eta!., 1995;Tatton and ChalmersRedman, 1996) and may represent a commitment to the apoptotic death program.…”

“…More recently, a new action of R-deprenyl has been described: its ability to prevent apoptosis in neurons (for review, see Tatton and Chalmers-Redman, 1996). This antiapoptotic effect of R-deprenyl has been shown in vitro with PC12 cells (Tatton et al, 1994) and mesencephalic dopaminergic neurons (Roy and Bedard, 1993;Mytilineou et al, 1997a) and in vivo in the rat hippocampus following hypoxia-ischemia (Paterson et al, 1997a), dopaminergic neurons in the substratia nigra following MPTP treatment (Tatton and Greenwood, 1991;Yu et al, 1994), and facial motorneurons following facial nerve axotomy (Salo and Tatton, 1992;Ansari et al, 1993).…”

“…The antiapoptotic action of deprenyl is highly stereospecific: R-Deprenyl can prevent apoptosis of facial motorneurons at low doses, whereas S-deprenyl is without effect, even at high doses (Ansari et a!., 1993). It has been shown that R-deprenyl alters gene expression to exert its antiapoptotic action (Tatton et al, 1994;Tatton and Chalmers-Redman, 1996) and that this change in gene expression is selective, acting at least in part, to prevent loss of mitochondrial function (Tatton and Chalmers-Redman, 1996). Thus, R-deprenyl can prevent neuronal apoptosis by a novel mechanism.…”

Factors influencing neurotrophic effects of electrical stimulation in the deafened developing auditory system

“…Sinai School of Medicine, NY). The selegiline (−)-deprenyl has been used clinically for many years to treat Parkinson's disease (Tatton et al, 1999) and Alzheimer's disease (Tatton and Chalmers-Redman, 1996). Deprenyl has been reported to act as an MAO-B inhibitor, but Tatton et al suggested that it is actually the drug's primary metabolite, (−)-desmethyldeprenyl (DES) that reduces neuronal apoptosis by a mechanism that requires gene transcription and involves maintenance of the mitochondrial membrane potential (Tatton et al, 1999).…”

“…Deprenyl has been reported to act as an MAO-B inhibitor, but Tatton et al suggested that it is actually the drug's primary metabolite, (−)-desmethyldeprenyl (DES) that reduces neuronal apoptosis by a mechanism that requires gene transcription and involves maintenance of the mitochondrial membrane potential (Tatton et al, 1999). Mediated by GAPDH binding, DES was suggested to increase mitochondrial BCL-2 and BCL-x levels, decrease BAX levels, and thereby prevent the permeability transition pore from opening, thus preventing apoptosis (Carlile et al, 2000;Tatton and Chalmers-Redman, 1996).…”