Deprenyl administration in man: A selective monoamine oxidase B inhibitor without the ?cheese effect?

Elsworth, J. D.; Glover, Vivette; Reynolds, Gavin P.; Sandler, M.; Lees, Andrew J.; Phuapradit, P; Shaw, Kenneth; Stern, Gerald; Kumar, Parveen

doi:10.1007/bf00426954

Cited by 232 publications

(70 citation statements)

References 20 publications

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“…Its administration prevents the degradation of dopamine in human brain, where this is a substrate for MAO B (Glover, Sandier, Owen & Riley, 1977); however, it leaves the peripheral mechanisms normally preventing a hypertensive response following tyramine administration intact (Elsworth, Glover, Reynolds, Sandler, Lees, Phuapradit, Shaw, Stern & Kumar, 1978), although this amine interacts adversely with all other irreversible MAO inhibitors so far described. Because of this freedom from what has come to be called the 'cheese effect', deprenyl, in combination with L-dopa, provides both a rational and safe therapy for the treatment of Parkinson's disease (Birkmayer, Riederer Ambrozi & Youdim, 1977;Lees, Shaw, Kohout, Stem, Elsworth, Sandler & Youdim, 1977).…”

Section: Deprenyl Is Metabolized To Methamphetamine and Amphetamine Imentioning

confidence: 99%

Deprenyl is metabolized to methamphetamine and amphetamine in man.

Reynolds¹,

Elsworth²,

Blau³

et al. 1978

Brit J Clinical Pharma

276

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Section: Deprenyl Is Metabolized To Methamphetamine and Amphetamine Imentioning

confidence: 99%

Deprenyl is metabolized to methamphetamine and amphetamine in man.

Reynolds¹,

Elsworth²,

Blau³

et al. 1978

Brit J Clinical Pharma

276

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“…MAO-B inhibitors pose little or no risk of a cheese effect (Elsworth et al, 1978). Meanwhile, at relatively high but clinically used doses, the MAO-B inhibitor selegiline decreases plasma levels of MAO-A metabolites (Eisenhofer et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells

Goldstein

Jinsmaa

Sullivan

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson's disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The "cheese effect"-paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production is unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All three drugs also increased dopamine and norepinephrine, decreased 3,4-dihydroxyphenylalanine, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine spontaneous oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations, the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in Parkinson's disease.

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“…MAO-B rapidly metabolizes β -PEA, maintaining it at low levels in the CNS. Clinically relevant doses of the MAO-B inhibitor deprenyl can result in a nearly 100-fold increase in the concentration of β -PEA excreted in the urine, suggesting that the CNS concentration of β -PEA may rise markedly in the presence of MAO-B inhibitors (Elsworth et al 1978). Subconvulsant doses of β -PEA have been shown to elicit psychomotor stimulation and to facilitate seizing activity in the presence of deprenyl (Ukponmwan et al 1983;Bergman et al 2001).…”

Section: Discussionmentioning

confidence: 99%

.BETA.-Phenylethylamine Inhibits K+ Currents in Neocortical Neurons of the Rat: A Possible Mechanism of .BETA.-phenylethylamine-induced Seizures

Kitamura

Munakata

Haginoya

et al. 2008

Tohoku J. Exp. Med.

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β -Phenylethylamine (β -PEA), an endogenous amine synthesized in the brain, serves as a neuromodulator and is involved in the pathophysiology of various neurological disorders such as depression, schizophrenia, and attention-deficit hyperactivity disorder. β -PEA fully exerts the physiological effects within the nanomolar concentration range via the trace amine receptors, but β -PEA also causes convulsions at much higher concentrations via an as yet unknown mechanism. To investigate the electrophysiological mechanism by which β -PEA induces convulsions, we examined the effect of β -PEA on ionic currents passing through the cell membrane of dissociated rat cerebral cortical neurons, using a patch-clamp technique. The external application of β -PEA suppressed ionic currents which continuously flowed when the membrane potential was held at -25 mV. The suppression was in a concentration-dependent manner and a half-maximal effective concentration was 540 μ M. These currents suppressed by β -PEA consisted of two K + currents: a time-and voltagedependent K + current (M-current) and a leakage K + current. The suppression of the M-current reduces the efficacy of the current in limiting excessive neuronal firing, and the suppression of the leakage K + current can cause membrane depolarization and thus promote neuronal excitation. Reducing both of these currents in concert may produce neuronal seizing activity, which could conceivably underlie the convulsions induced by high-dose β -PEA.β -phenylethylamine; M-current; patch-clamp; seizure.

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Deprenyl administration in man: A selective monoamine oxidase B inhibitor without the ?cheese effect?

Cited by 232 publications

References 20 publications

Deprenyl is metabolized to methamphetamine and amphetamine in man.

Deprenyl is metabolized to methamphetamine and amphetamine in man.

Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells

.BETA.-Phenylethylamine Inhibits K+ Currents in Neocortical Neurons of the Rat: A Possible Mechanism of .BETA.-phenylethylamine-induced Seizures

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