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Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness.

ABSTRACT: A few years after the foundation of the British Pharmacological Society, monoamine oxidase (MAO) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine (and, later, 5-hydroxytryptamine, as well). Within the next decade, the therapeutic value of inhibitors of MAO in the treatment of depressive illness was established. Although this first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two isoforms, MAO-A and -B, and isoform-selective inhibitors. Selective inhibitors of MAO-B have found a therapeutic role in the treatment of Parkinson's disease and further developments have provided reversible inhibitors of MAO-A, which offer antidepressant activity without the serious side effects of the earlier inhibitors. Clinical observation and subsequent pharmacological analysis have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress in the brain may be critical for the initiation and progress of neurodegeneration and selective inhibition of brain MAO could contribute importantly to lowering such stress. There are complex interactions between free iron levels in brain and MAO, which may have practical outcomes for depressive disorders. These aspects of MAO and its inhibition and some indication of how this important area of pharmacology and therapeutics might develop in the future are summarized in this review.

SUBMITTER: Youdim MB

PROVIDER: S-EPMC1760741 | biostudies-other | 2006 Jan

REPOSITORIES: biostudies-other

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Monoamine reuptake inhibitors in Parkinson's disease.

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Project description:PURPOSE:To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson's disease. METHODS:We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson's disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug. RESULTS:Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment. CONCLUSIONS:Dopamine agonists were found to be effective as treatment for Parkinson's disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson's disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.

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Project description:BACKGROUND:Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. METHODS:Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. RESULTS:Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]. CONCLUSIONS:These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.

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Project description:Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with abnormal dopamine metabolism by MAO-B (monoamine oxidase-B) and intracellular ?-Synuclein (?-Syn) aggregates, called the Lewy body. However, the molecular relationship between ?-Syn and MAO-B remains unclear. Here, we show that ?-Syn directly binds to MAO-B and stimulates its enzymatic activity, which triggers AEP (asparagine endopeptidase; legumain) activation and subsequent ?-Syn cleavage at N103, leading to dopaminergic neurodegeneration. Interestingly, the dopamine metabolite, DOPAL, strongly activates AEP, and the N103 fragment of ?-Syn binds and activates MAO-B. Accordingly, overexpression of AEP in SNCA transgenic mice elicits ?-Syn N103 cleavage and accelerates PD pathogenesis, and inhibition of MAO-B by Rasagiline diminishes ?-Syn-mediated PD pathology and motor dysfunction. Moreover, virally mediated expression of ?-Syn N103 induces PD pathogenesis in wild-type, but not MAO-B-null mice. Our findings thus support that AEP-mediated cleavage of ?-Syn at N103 is required for the association and activation of MAO-B, mediating PD pathogenesis.

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Project description:Neuropsychiatric disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and depression, have seriously inconvenienced the lives of patients. Growing evidence indicates that these diseases are closely related to the monoamine oxidase (MAO) enzyme, making it an attractive target for the exploitation of potent MAO inhibitors (MAOIs) with high selectivity and low side effects. Although various MAOIs have been discovered, the discovery of an ideal MAOI is not an easy task. In this review, we discuss the currently available rational design strategies for obtaining ideal MAOIs, including ligand-based and receptor-based design strategies, and these strategies were further illustrated with the aid of specific examples from the recent literature. To better understanding the biological activity of MAO, we also highlight the binding modes of typical inhibitors against MAO. Besides, advanced strategies for finding upcoming potent MAOIs were prospected.

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Project description:Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective therapy is then available. Monoamine Oxidase A (MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. This study shows that MAO A expression is increased in human glioma tissues and cell lines. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. NMI was localized specifically to the tumor. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. NMI can also be used as a non-invasive imaging tool. Thus has a dual function for both therapy and diagnosis.

| S-EPMC4924682 | biostudies-literature

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