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Title: Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain

Journal Article · · Neuropsychopharmacology
DOI:https://doi.org/10.1038/npp.2014.214· OSTI ID:1183284
 [1];  [2];  [3];  [4];  [5];  [6];  [4];  [4];  [1];  [4];  [1];  [1];  [1];  [6];  [4];  [1];  [1];  [4]
  1. Brookhaven National Lab. (BNL), Upton, NY (United States)
  2. New York Univ., NY (United States)
  3. National Inst. on Drug Abuse, Bethesda, MD (United States); National Inst. on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)
  4. National Inst. on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)
  5. Targeted Medical Pharma Inc., Los Angeles, CA (United States)
  6. Columbia Univ., New York, NY (United States)
+ Show Author Affiliations

Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson’s disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar®) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared to equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using PET and the MAO-A radiotracer [¹¹C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9 ± 19.7%, range 11–70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2 ± 28.9 (range 9-68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
SC00112704
OSTI ID:
1183284
Report Number(s):
BNL-107759-2015-JA; R&D Project: MO-085; KP1602010
Journal Information:
Neuropsychopharmacology, Vol. 40, Issue 3; ISSN 0893-133X
Publisher:
NatureCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 41 works
Citation information provided by
Web of Science

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Cited By (14)

90 years of monoamine oxidase: some progress and some confusion journal April 2018
Selegiline: a molecule with innovative potential journal September 2019
N-Acetylcysteine Prevents the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells journal August 2017
Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration journal January 2017
Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells journal November 2015
Monoamine Oxidases (MAOs) as Privileged Molecular Targets in Neuroscience: Research Literature Analysis journal May 2019
(E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates MPTP-Induced Dopaminergic Neurodegeneration by Inhibiting the STAT3 Pathway journal May 2019
Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs journal July 2017
Current trends in formulation and application of pharmaceutical preparations in therapy of depression in children and adults [Savremeni trendovi u formulaciji i primeni lekova u terapiji depresije kod dece i odraslih] journal January 2017
Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration text January 2017
Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs journal July 2017
Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration text January 2017
Close Correlation of Monoamine Oxidase Activity with Progress of Alzheimer’s Disease in Mice, Observed by in Vivo Two-Photon Imaging journal December 2016
A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer’s Disease journal January 2020

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Related Subjects

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY
brain MAO-A
MAO inhibitors
PET
selegiline
Zydis selegiline
Emsam
selegiline transdermal system
buccal mucosa absorption
positron emission tomography (PET) facility