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Originally Posted by IBE
Selegiline, also known as l-deprenyl, is an irreversible and (relatively) selective MAO-B inhibitor. Meta-analysis of published clinical trials confirms it offers a cheap, safe and effective symptomatic treatment of early Parkinson's disease. Selegiline may also be neuroprotective and act as an antidepressant.
The enzyme monoamine oxidase has two main forms, type A and type B. They are coded by separate genes. MAO may be inhibited with agents that act reversibly or irreversibly; and selectively or unselectively. These categories are not absolute. MAO type-A preferentially deaminates serotonin and noradrenaline, 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 retains its 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 to unselective 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 of selegiline daily 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, cerebral nitric oxide and the production of key interleukins. Selegiline offers protection against DNA damage and oxidative stress by hydroxyl and peroxyl radical trapping; and against excitotoxic damage from glutamate. In addition, selegiline stimulates the release of superoxide dismutase (SOD). SOD is a key enzyme which helps to quench the production of damaging free-radicals. 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 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 the mitochondrial 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 elixir of eternal youth. But its current "off-label" use by life-extensionists prefigures the longevity-enhancing mitochondrial medicine of decades to come.
Taken consistently in low doses, 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 role against 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) in dogs.
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.
Selegiline protects the brain's dopamine cells from oxidative stress. 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 the treatment of Parkinson's disease in 1989.
Administered at low doses, selegiline is neuroprotective against possible damage to the serotonergic fine axon terminals caused by overconsumption of the popular drug MDMA (Ecstasy). Several competing theories exist that purport to explain MDMA-induced neurotoxicity. One theory blames the deamination by MAO-B of excessive dopamine taken up by the membrane-bound transporter into 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 compounds cause membrane lipid peroxidation and consequent fine terminal degeneration. Selegiline prevents such serotonergic damage, in theory at any rate. On the other hand, co-administering unselective selegiline dosages or unselective irreversible MAOIs like tranylcypromine (Parnate) or phenelzine (Nardil) with MDMA is potentially lethal.
Taken at MAO-B-selective dosages, selegiline is typically less effective as a mood-brightener than other dopaminergics such as amineptine (Survector) - though occasionally spectacular remission of depressive symptoms may occur even with minimal MAO-A inhibition. Taken at unselective dosages of 20mg a day or more, selegiline is typically an effectivee well-tolerated antidepressant. Selegiline at higher dosages may also be useful for "atypical" depressive symptoms of overeating, oversleeping, and hypersensitivity to rejection. An unselective dosage regimen would normally call for an MAOI diet (no cheese, red wine, fava beans, salami, etc).
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07-03-2006, 10:42 PM
SELEGILINE HCL - AKA Deprenyl
Linear Mode
