Biological Sciences: Human Brain Monoamine Oxidase: Multiple Forms and Selective Inhibitors

Youdim, Moussa B. H.; Collins, G.G.S.; Sandler, M.; Jones, Adele; Pare, C. M. B.; Nicholson, W. J.

doi:10.1038/236225b0

Cited by 118 publications

(29 citation statements)

References 17 publications

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“…When deprenil is given, of course, Type A MAO is only partially inhibited. These findings strengthen the view (Youdim, 1973) (Youdim, Collins, Sandler, Bevan-Jones, Pare & Nicholson, 1972).…”

Section: Discussionsupporting

confidence: 79%

Effects of Monoamine Oxidase Inhibition by Clorgyline, Deprenil or Tranylcypromine on 5‐hydroxytryptamine Concentrations in Rat Brain and Hyperactivity Following Subsequent Tryptophan Administration

Green¹,

Youdim²

1975

British J Pharmacology

149

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1 The effect of various doses of tranylcypromine on the degree of inhibition of rat brain monoamine oxidase (MAO) using 5-hydroxytryptamine (5-HT), dopamine and phenylethylamine as substrates has been examined 120 min after injection of the inhibitor. The concentration of brain 5-HT was also examined both after tranylcypromine alone and also when L-tryptophan (100 mg/kg) had been given 30 min after the tranylcypromine. 2 All doses of tranylcypromine greater than 2.5 mg/kg totally inhibited MAO oxidation of 5-HT, phenylethylamine and dopamine as measured in vitro and produced a similar rise of brain 5-HT in vivo. When tryptophan was also given, there was a further rise of brain 5-HT, which was comparable after all doses of tranylcypromine above 2.5 mg/kg and the characteristic syndrome of hyperactivity made its appearance. 3 Clorgyline (a 'Type A' MAO inhibitor), in doses up to 10 mg/kg, did not totally inhibit MAO activity towards phenylethylamine although it did inhibit 5-HT oxidation by 100%. Deprenil (a 'Type B' MAO inhibitor) at doses up to 10 mg/kg did not fully inhibit 5-HT oxidation although phenylethylamine oxidation was inhibited almost completely. Administration of either compound alone did not produce as great an accumulation of brain 5-HT as that seen after tranylcypromine (2.5 mg/kg) and subsequent administration of tryptophan did not cause hyperactivity or the rise of brain 5-HT seen after tranylcypromine (2.5 mg/kg) plus tryptophan. 4 Administration of clorgyline plus deprenil (2.5 mg/kg of each) almost totally inhibited oxidation of both 5-HT and phenylethylamine; subsequent tryptophan administration resulted in a rise of brain 5-HT nearly as great as that seen fQllowing tranylcypromine (2.5 mg/kg) plus tryptophan and the animals became hyperactive. 5 No evidence was found pointing to the formation of any other 5-substituted indole in the brain following tranylcypromine plus L-tryptophan administration as suggested by others. 6 It is concluded that while 5-HT may normally be metabolized in the brain by 'Type A' MAO in vivo, when this form is inhibited, 5-HT can still be metabolized by 'Type B' enzyme. It is only when both forms are almost totally inhibited that the largest rise of brain 5-HT is seen and subsequent tryptophan administration produces the hyperactivity syndrome.

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Section: Discussionsupporting

confidence: 79%

Effects of Monoamine Oxidase Inhibition by Clorgyline, Deprenil or Tranylcypromine on 5‐hydroxytryptamine Concentrations in Rat Brain and Hyperactivity Following Subsequent Tryptophan Administration

Green¹,

Youdim²

1975

British J Pharmacology

149

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“…Similarly, Mese et al (22) and Robinson et al (33) found that patients tended to improve only when the dose of phenelzine was sufficient to inhibit platelet MAO activity, a finding not confirmed by Murphy et al (21). Such studies are in agreement with the animal work of Green and Youdim (10) who found that their 'specific hyperactivity' in rats could only be produced when MAO activity was re duced by over 70%, a reduction which was not generally attained in man (38).…”

Section: Dosagesupporting

confidence: 80%

Monoamine Oxidase Inhibitors in Resistant Depression

Pare¹

1979

Int Pharmacopsychiatry

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“…67 Because the MAO-B isoform appears to be predominantly responsible for dopamine metabolism in the human basal ganglia, 10,11 inhibitors of MAO-B have been used in the therapy of PD. Furthermore, MAO-B activity, as well as density, 15,16,73 has been shown to increase with age in most brain regions, including the basal ganglia.…”

Section: Mao-b Inhibitors In the Symptomatic Treatment Of Pdmentioning

confidence: 99%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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Summary:Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A 2A receptor is one such target. Antagonists of this receptor (A 2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A 2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A 2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A 2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

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Biological Sciences: Human Brain Monoamine Oxidase: Multiple Forms and Selective Inhibitors

Cited by 118 publications

References 17 publications

Effects of Monoamine Oxidase Inhibition by Clorgyline, Deprenil or Tranylcypromine on 5‐hydroxytryptamine Concentrations in Rat Brain and Hyperactivity Following Subsequent Tryptophan Administration

Effects of Monoamine Oxidase Inhibition by Clorgyline, Deprenil or Tranylcypromine on 5‐hydroxytryptamine Concentrations in Rat Brain and Hyperactivity Following Subsequent Tryptophan Administration

Monoamine Oxidase Inhibitors in Resistant Depression

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

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