Metabolism of (‐) deprenyl to amphetamine and methamphetamine may be responsible for deprenyl's therapeutic benefit

Karoum, Farouk; Chuang, Lin-Whei; Eisler, Toomas; Calne, Donald B.; Liebowitz, Michael R.; Quitkin, F; Klein, Donald F.; Wyatt, Richard Jed

doi:10.1212/wnl.32.5.503

Cited by 124 publications

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“…Celada and Artigas (1993) reported that the irreversible MAO-A inhibitor clorgyline, together with the irreversible MAO-B inhibitor selegiline, increased extracellular serotonin levels more than clorgyline alone did. Selegiline is partly metabolized to L-amphetamine (Karoum et al, 1982). Therefore, another mechanism other than MAO inhibition might explain the enhancement of serotonin increase by selegiline in their study.…”

Section: Discussionmentioning

confidence: 78%

Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in β-phenylethylamine

Kitaichi

Inoue

Nakagawa

et al. 2010

European Journal of Pharmacology

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Section: Discussionmentioning

confidence: 78%

Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in β-phenylethylamine

Kitaichi

Inoue

Nakagawa

et al. 2010

European Journal of Pharmacology

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“…One explanation for the effect of L-deprenyl is that deprenyl is converted to L-amphetamine, and this in turn inhibits dopamine uptake via DAT or NET (Karoum et al, 1982;Tetrud and Langston, 1989;Okudo et al, 1992). However, all MAO inhibitors tested in the present study decreased the dopamine clearance rate.…”

Section: Processes Of Mpfc Dopamine Clearance In Vitromentioning

confidence: 99%

Characterization of Extracellular Dopamine Clearance in the Medial Prefrontal Cortex: Role of Monoamine Uptake and Monoamine Oxidase Inhibition

Wayment¹,

2001

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In vitro rotating disk electrode (RDE) voltammetry and in vivo microdialysis were used to characterize dopamine clearance in the rat medial prefrontal cortex (mPFC). RDE studies indicate that inhibition by cocaine, specific inhibitors of the dopamine transporter (DAT) and norepinephrine transporter (NET), and low Na ϩ produced a 50-70% decrease in the velocity of dopamine clearance. Addition of the monoamine (MAO) inhibitors, L-deprenyl, clorgyline, pargyline, or in vivo nialamide produced 30-50% inhibition. Combined effects of uptake inhibitors with L-deprenyl on dopamine clearance were additive (up to 99% inhibition), suggesting that at least two mechanisms may contribute to dopamine clearance. Dopamine measured extracellularly 5 min after exogenous dopamine addition to incubation mixtures revealed that most conditions of DAT/NET inhibition did not produce elevated dopamine levels above controls. Inhibition of MAO produced elevated dopamine levels only after long-term, but not short-term, incubation in vitro. Short-term incubation of L-deprenyl combined with DAT and NET uptake inhibitors increased dopamine above control levels, consistent with more than one mechanism of dopamine clearance. Local infusion of pargyline (100 or 300 M) into the mPFC or striatum via microdialysis produced more pronounced and immediate increases in mPFC dopamine levels compared with striatum. Furthermore, dopamine elevation in the mPFC was not accompanied by a decrease in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, as found in the striatum. These findings may have revealed a unique mechanism of mPFC dopamine clearance and therefore contribute to the understanding of multiple behaviors that involve mPFC dopamine transmission, such as schizophrenia, drug abuse, and working memory function.

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“…Hence MAO-A rather than MAO-B inhibition could cause increased dopamine levels with prolonged (-)-deprenyl treatment and might explain the apparent slowing found in clinical trials. ( -)-Deprenyl is mainly metabolized to (-)-desmethyldeprenyl, (-)-methamphetamine and (-)-amphetamine (Karoum et al, 1982). The (-)-enantiomers of amphetamine and methamphetamine have a 10 times weaker effect on attention than ( + )-methamphetamine and ( + )-amphetamine (Taylor and Snyder, 1974) so that concentrations of the (-)-enantiomers produced by a 10mg daily dose of (-)-deprenyl are considered too small to influence attention which could in turn account for improved cognitive performance in AD (Gerlach et al, 1992).…”

mentioning

confidence: 99%

(−)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase

Tatton

Wadia

et al. 1996

Deprenyl — Past and Future

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Summary. (-)-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 oneo-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 pr;opose 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.

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Metabolism of (‐) deprenyl to amphetamine and methamphetamine may be responsible for deprenyl's therapeutic benefit

Cited by 124 publications

References 0 publications

Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in β-phenylethylamine

Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in β-phenylethylamine

Characterization of Extracellular Dopamine Clearance in the Medial Prefrontal Cortex: Role of Monoamine Uptake and Monoamine Oxidase Inhibition

(−)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase

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