selegiline ( l-deprenyl )

8/11/2019 Selegiline ( L-Deprenyl )

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From

THE GOOD DRUG GUIDE

"..... Selegiline

, also known as l-deprenyl

, is an irreversible and

(relatively) selective MAO-Binhibitor. Meta-analysis of published

clinical trials confirms it offers a cheap, safe and effective

symptomatic t reatment of early Parkinson's disease. Selegiline may

also be neuroprotec tive and act as an antidepressant.

The enzyme monoamine oxidase has two main forms, type A

andtype B. They are coded by separate genes. MAOmay be

inhibited with agents that act reversibly or irreversibly; andselectively or unselectively. These categories are not absolute. MAO

type- A preferentially deaminates serotoninandnoradrenaline

, and

also non-selectively dopamine. Type B metabolises dopamine

,phenylethylamine (the chocolate amphetamine) and various trace

amines.

At dosages up to around 10 mg or so daily, selegiline retainsits selectivity for the type-B MAO iso-enzyme; but it is also a weak

reversible inhibitor of the type-A MAO iso-enzyme. In contrast tounselective and irreversible MAO inhibitors such as tranylcypromine

(Parnate) and phenelzine (Nardil), both of which strongly potentiate

the catecholamine-releasing effect of tyramine

, selegiline inhibits it.

This ensures that low-dosage selegiline does not induce the

hypertensive "cheese effect". A regimen of 2 x 5 mg daily ofselegiline irreversibly inhibits over 90% of MAO-B in the basal ganglia,

the location of over 80% of dopamine in the human brain. This level

of MAO-B inhibition leads to a 40%-70% increase in synaptic

dopamine.

Selegiline has immune-system-boosting and anti-

neurodegenerative effects. Its use increases the level of tyrosine

hydroxylase

, growth hormone

, cerebralnitric oxideand the

production of key interleukins. Selegiline offers protection against

DNA damage and oxidative stress by hydroxyl and peroxyl radical

trapping; and against excitotoxic damage fromglutamate. In

addition, selegiline stimulates the release of superoxide dismutase

(SOD). SOD is a key enzyme which helps to quench the productionof damagingfree-radic als. Potentially, selegiline may prevent or

reverse iron-induced memory impairment. The deposition of excess

iron in the brain is implicated several neurodegenerative diseases.

Selegiline protects the mitochondria via its effects on


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mitochondrial membrane permeability: it directly interacts with the

pore-forming structures. Mitochondria are the energy powerhouses

of the eukaryotic cell where oxygen respiration occurs. If themitochondrial theory of aging is correct, then the root cause of

aging is damage to mitochondrial DNA by free radical leakage from

adjacent respiratory proteins. Alas selegiline itself is not an elixirof

eternal youth. But its current "off-label" use by life-extensionists

prefigures the longevity-enhancing mitochondrial medicine of

decades to come.

Taken consistently at low dosage, selegiline tends to extend

the life-expectancy of rats by some 20%; enhances drive, libido and

endurance; and independently improves cognitive performance in

Alzheimer's patients and in some healthy normals. Its protective roleagainst age-related memory decline derives at least in part from its

protection of hippocampal neurons in the aging brain. Aging drug-

free rats have poorer spatial memories and fewer hippocampal

neurons than their counterparts on selegiline. Selegiline is already

used successfully to treat canine cognitive dysfunction syndrome

(CDS) indogs.

Selegiline retards the metabolism not just of dopamine but also

of phenylethylamine

, a trace amine also found in chocolate and

released when we're in love.

Selegilineprotects the brain's dopamine cells from oxidativestress. The brain has only about 30-40 thousand dopaminergic

neurons in all. We tend to lose perhaps 13% a decade in adult life.

An eventual 70%-80% loss leads to the dopamine-deficiency

disorder Parkinson's disease, frequently foreshadowed by depression.

Selegiline in pill form was approved by the FDA as an adjunct in thetreatment of Parkinson's disease in 1989. In June 2006, the FDA

approved once-daily orally disintegrating tablets of selegiline HCl

branded as Zelapar from Valeant Pharmac eutic als. Zelapar is used as

an adjunct therapy for Parkinsonians on levodopa/carbidopa(Sinemet) whose response is deteriorating. The cocktail allegedly

reduces "off" time by an average of2.2 hours per day.

Administered at low doses, selegiline is neuroprotec tive against

possible damage to the serotonergic fine axon terminals c aused by

overconsumption of the popular drugMDMA (Ecstasy). Several

competingtheories exist that purport to explain MDMA-inducedneurotoxicity. One theory blames the deamination by MAO-Bof

excessive dopaminetaken up by the membrane-bound transporterinto the depleted serotonin terminals. This abnormal uptake follows

MDMA-induced reversal of the serotonin reuptake pump. In the

absence of MAO-B inhibition, deamination by MAO-B of excess

dopamine taken up into the serotonergic axon terminals is liable to

generate a glut of toxic free radicals. These highly reactive


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selegiline ( l-deprenyl )

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