Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal
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J S Fowler1, N D Volkow, J Logan
1Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973.
Abstract:
L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L-Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use.
Insights
L-Deprenyl (Selegeline) irreversibly inhibits monoamine oxidase B (MAO B). Researchers measured a 40-day half-time for MAO B synthesis in the human brain, suggesting current L-deprenyl doses may be excessive.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- L-Deprenyl (Selegeline) is an irreversible inhibitor of monoamine oxidase B (MAO B).
- It is a prescribed treatment for Parkinson's disease, with current dosing at 5 mg twice daily.
- Recovery of MAO B activity after L-deprenyl cessation necessitates new enzyme synthesis.
Purpose of the Study:
- To measure the half-time for brain MAO B synthesis in humans.
- To investigate the implications of MAO B turnover rate for L-deprenyl dosing in Parkinson's disease and potential Alzheimer's disease treatment.
Main Methods:
- Measurement of brain MAO B synthesis rate in Parkinson's disease patients and normal subjects after L-deprenyl withdrawal.
- This study represents the first quantification of a specific protein's synthesis rate in the living human brain.
Main Results:
- A 40-day half-time for brain MAO B synthesis was determined in both Parkinson's disease patients and normal subjects.
- This finding indicates a slow turnover rate for MAO B in the human brain.
Conclusions:
- The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be unnecessarily high.
- Further evaluation of reduced L-deprenyl dosing is warranted to assess clinical efficacy, mechanistic insights, and potential reduction in side effects and costs.