Selegiline action

The mechanism of action of amantadine (Symmetrel) and selegiline (Eldepryl) in die treatment of parkinsonism is not fully understood. 

Monoamine oxidase exists in two forms, MAOa and MAOb. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like S-phenylethylamine, it is more affected by MAOb. H seems likely that MAOb is the dominant enzyme in human brain and inhibitors of it, such as selegiline, have some value in the treatment of Parkinson s disease by prolonging the action of the remaining endogenous DA as well as that formed from administered levodopa. 

Selegiline (deprenyl Eldepryl) is an irreversible MAO-B inhibitor that blocks dopamine breakdown and can modestly extend the duration of action of L-dopa (up to 1 hour). It often permits reduction of L-dopa dose by as much as one-half. 

Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson s disease, is a selective, irreversible inhibitor of MAO-B. 

Pharmacology Selegiline hydrochloride is a levorotatory acetylenic derivative of phenethylamine. Although the mechanism of action is not fully understood, inhibition of monoamine oxidase (MAO) type B activity is of primary importance and selegiline... 

Another drug used in the treatment of Parkinson s disease is selegiline (also known as deprenyl, or Eldepryl). It is an irreversible inhibitor of MAO-B, an important enzyme in the metabolism of dopamine (Fig. 33.2). Blockade of dopamine metabolism makes more dopamine available for stimulation of its receptors. Selegiline, as monotherapy, may be effective in the newly diagnosed patient with parkinsonism because its pharmacological effect enhances the actions of endogenous dopamine. 

Most of the adverse reactions to selegiline are related to actions of increased levels of dopamine, as discussed earlier. At recommended doses, and unlike the nonselective MAO inhibitors used in the treatment of depression, selegiline has little effect on MAO-A and therefore generally does not cause the hypertension associated with the ingestion of tyramine-enriched foods (see Chapter 20). However, at doses higher than those usually recommended, MAO-A may be inhibited, which increases the risk of a tyramine reaction. 

Ebadi M, Sharma S, Shavah S, El Refaey H. Neuro-protective actions of selegiline. J Neurosci Res. 2002 67 285-289. 

Selegiline possesses neurotrophic-like actions and rescues axotomized motomeurons independent of monoamine oxidase B (MAO-B) inhibition. 

Selegiline stimulates the biosynthesis of interleukin-lb and interleukin-6, is an immu-noenhancing substance, possesses antiapoptotic action, and is a neuroprotectant. 

Desmethylselegiline is also an irreversible inhibitor of monoamine oxidase B in humans. There is evidence that the 1-stereoisomers of 1-amphetamine and 1-methamphetamine may have some qualitatively different actions from their d-isomer counterparts, which might result in beneficial clinical effects and could complement any beneficial clinical actions of selegiline itself. Food has no effect on the pharmacokinetics of desmethylselegiline, methamphetamine, and amphetamine. At a dose of 10 mg per day, selegiline is devoid of the cheese effect that is, it does not cause hypertension when taken with tyramine-containing foods such as cheese. 

NEUROTROPHIC-LIKE ACTION OF SELEGILINE RESCUE OF AXOTOMIZED MOTORNEURONS INDEPENDENT OF MONOAMINE OXIDASE INHIBITION... 

FIGURE 13.5 Selegiline enhances the release of dopamine and inhibits its metabolism. In addition, it has neurotrophic-like action capable of repairing damaged neurons. 

Selegiline reduces neuronal death even after neurons have sustained seemingly lethal damage at concentrations too small to inhibit MAO-B and the rescuing action is related to antiapoptotic action of selegiline. 

Irreversible MAO-B inhibitors, namely, banisterine and selegiline, are efficacious in the treatment of Parkinson s disease, and selegiline prolongs the action of L-dopa and enhances the life expectancy of patients suffering from Parkinson s disease. 

Banisterine and selegiline promote accumulation of phenylethylamine, which potentiates the action of dopamine. 

Banisterine and selegiline might elicit an antidepressant action by inhibiting MAO. 

Extensive data, gathered by using tissue and experimental animals, suggest that selegiline possesses a plethora of actions that may be outlined under at least three separate major categories ... 

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