MAO-B inhibitor

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Acute treatment with nonselective MAO inhibitors (iproniazid, tranylcypromine, phenelzine), as a consequence of inhibiting both forms of the enzyme, increase, brain levels of all monoamines (phenylethylamine, tryptamine, methylhistamine aminergic neurotransmitters (dopamine, noradr enaline, adrenaline and serotonin). By contrast MAO-A inhibitors (clorgyline) increase serotonin and noradrenaline, while MAO-B inhibitors (selegiline, rasagiline) increase brain levels... 

Selegiline A selective MAO-B inhibitor, also called L-deprenyl, used in the treatment of Parkinson s disease. 

Monotherapy usually begins with a monoamine oxidase-B (MAO-B) inhibitor, or if the patient is physiologically young, a dopamine agonist. 

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. 

Rasagiline, another MAO-B inhibitor, has similar effects as selegiline in enhancing L-dopa effects and modest beneficial effect as monotherapy. Early initiation is associated with better long-term outcomes. 

Estrogen agonists Estrogen replacement Brain targeted Dabelotine/S-12024 MAO-B inhibitors... 

Entacapone can be taken concomitantly with a selective MAO-B inhibitor (eg, selegiline). 

In Section 1.1.1, L-deprenyl (2) was discussed as a potent selective MAO B inhibitor. Its p-fluoro analogue, fludeprenyl (7), was shown to retain the irreversible and selective inhibitory effects of its parent compound, with similar potency in vitro in rat tissue and in vivo in mice [33]. Both compounds have also been reported to have similar protective actions against transient global cerebral ischemia in gerbils. With L-deprenyl (2), these effects occurred at doses below those which inhibit MAO B, while the effects of the p-fluoro analogue 7 occurred only at doses that also inhibit MAO B activity [33b,34]. 

Carbolines. Harmine (8.40) and related carboline alkaloids are reversible MAO-A inhibitors, but are not used therapeutically. Deprenyl (8.41) is a selective MAO-B inhibitor and produces an increase in DA levels, but does not influence NE or 5-HT concentrations. It has been proposed as an antidepressant in aging males. 

It is a selective MAO-B inhibitor, which is predominant in brain and blood platelets. It retards intracerebral degradation of dopamine. It is used with levodopa in early cases of parkinsonism. It prolongs levodopa action, attenuates motor fluctuations and decreases wearing off effect. But clinical benefits are short lived (6-24 months). 

Most presently available MAOIs are irreversible inhibitors of the enzyme, forming a chemical bond with part of the enzyme or the flavin adenine dinucleotide cofactor. When treatment is stopped, inhibition continues for a time until MAO levels return to normal as the new enzyme is synthesized. Thus, phenelzine, isocarboxazid, and tranylcypromine are all irreversible, nonselective MAOIs. Clorgyline, however, is an irreversible, selective MAO-A inhibitor moclobemide is a reversible, selective MAOI l-deprenyl and pargyline are relatively selective, irreversible MAO-B inhibitors. 

The MAO-B inhibitor, l-deprenyl, has been approved by the FDA for use in Parkinson s disease. At the lower dose range, it does not interact with tyramine. As mentioned earlier, there is preliminary evidence of antidepressant efficacy for a transdermal delivery system for selegiline. This formulation does not interact with tyramine to produce a hypertensive crisis (181). 

In the case of MAO B inhibitors, no significant amount of MAO A is inhibited, and there is very little risk of hypertension from dietary amines. Patients taking MAO B inhibitors to prevent progression of Parkinson s disease, for example, do not require any special diet. On the other hand, MAO B inhibitors are not effective antidepressants at doses that are selective for MAO B. 

The cerebrospinal fluid of patients with Parkinson s disease contains substances that inhibit the growth and function of dopaminergic neurons in culture. Moreover, selegiline, an MAO-B inhibitor (0.125 to 0.250 iM) enhances the number of tyrosine hydroxylase (TH)-positive neurons, augments the high-affinity uptake of dopamine, and averts the neurotoxic effects of the cerebrospinal fluid of patients with Parkinson s disease on rat mesencephalic neurons in culture. 

The effects of treatment with selegiline, an MAO-B inhibitor, on plasma levels of insulin-like growth factor I (IGF-I) (as indicator of GH secretion), levels of monoamines and their metabolites, and the activity and content of tyrosine hydroxylase — the rate-limiting enzyme in the biosynthesis of catecholamines — in the hypothalamus and hypophysis of old animals have been studied. It is believed that the antiaging effects of selegiline are due to restoration of hypothalamic hormones. 

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