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Journal of Parkinson's Disease 2022Monoamine oxidase-B (MAO-B) inhibitors are commonly used for the symptomatic treatment of Parkinson's disease (PD). MAO-B inhibitor monotherapy has been shown to be... (Review)
Review
Monoamine oxidase-B (MAO-B) inhibitors are commonly used for the symptomatic treatment of Parkinson's disease (PD). MAO-B inhibitor monotherapy has been shown to be effective and safe for the treatment of early-stage PD, while MAO-B inhibitors as adjuvant drugs have been widely applied for the treatment of the advanced stages of the illness. MAO-B inhibitors can effectively improve patients' motor and non-motor symptoms, reduce "OFF" time, and may potentially prevent/delay disease progression. In this review, we discuss the effects of MAO-B inhibitors on motor and non-motor symptoms in PD patients, their mechanism of action, and the future development of MAO-B inhibitor therapy.
Topics: Dopamine Agents; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline
PubMed: 34957948
DOI: 10.3233/JPD-212976 -
Sub-cellular Biochemistry 2018Monoamine oxidases A and B (MAO A and B) are mammalian flavoenzymes bound to the outer mitochondrial membrane. They were discovered almost a century ago and they have... (Review)
Review
Monoamine oxidases A and B (MAO A and B) are mammalian flavoenzymes bound to the outer mitochondrial membrane. They were discovered almost a century ago and they have been the subject of many biochemical, structural and pharmacological investigations due to their central role in neurotransmitter metabolism. Currently, the treatment of Parkinson's disease involves the use of selective MAO B inhibitors such as rasagiline and safinamide. MAO inhibition was shown to exert a general neuroprotective effect as a result of the reduction of oxidative stress produced by these enzymes, which seems to be relevant also in non-neuronal contexts. MAOs were successfully expressed as recombinant proteins in Pichia pastoris, which allowed a thorough biochemical and structural characterization. These enzymes are characterized by a globular water-soluble main body that is anchored to the mitochondrial membrane through a C-terminal α-helix, similar to other bitopic membrane proteins. In both MAO A and MAO B the enzyme active site consists of a hydrophobic cavity lined by residues that are conserved in the two isozymes, except for few details that determine substrate and inhibitor specificity. In particular, human MAO B features a dual-cavity active site whose conformation depends on the size of the bound ligand. This article provides a comprehensive and historical review of MAOs and the state-of-the-art of these enzymes as membrane drug targets.
Topics: Animals; Catalytic Domain; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Oxidative Stress; Parkinson Disease; Protein Structure, Secondary
PubMed: 29464559
DOI: 10.1007/978-981-10-7757-9_5 -
L'Encephale Dec 2016Antidepressant therapy aims to reach remission of depressive symptoms while reducing the complications and risks of relapse. Even though they have proven their efficacy,... (Review)
Review
Antidepressant therapy aims to reach remission of depressive symptoms while reducing the complications and risks of relapse. Even though they have proven their efficacy, it takes several weeks for antidepressants to demonstrate full effectiveness, and adverse effects occur more quickly or (quicker) which can be a source of poor compliance. This latest aspect often leads to dose reduction and/or change of molecule that have the effect of delaying remission. This review attempts to present, from the pharmacological properties of the major classes of antidepressants (monoamine oxidase inhibitor [MAOI], tricyclic antidepressants [TCA], selective serotonin reuptake inhibitor [SSRI] and serotonin and noradrenaline reuptake inhibitor [SNRI]), to the pharmacological mechanisms involved in adverse effects by focusing on sexual dysfunction, nausea/vomiting, and weight changes and sleep disruption. If the activation of dopamine D or norepinephrine receptors through the autonomic nervous system controls and facilitates sexual desire, increasing serotoninergic transmission through 5-HT receptors activation inhibits this process. The pharmacological properties of drugs inducing nausea/vomiting activate opiate receptors μ, increase dopaminergic and serotoninergic transmission activating the dopamine D and serotonin 5-HT receptors, respectively. Among the causes responsible for weight gain under antidepressant therapy, monoamine neurotransmission still plays an important role. The blockade of serotonin 5-HT or histamine H receptors is directly responsible for weight gain. Finally, the activation of 5-HT serotoninergique receptors modulates wakefulness, raid eyes movement or sleep duration. In conclusion, if antidepressant activity of SERT or MAO inhibitors is an indirect consequence of postsynaptic 5-HT, DA, NA receptor activation, it is also responsible for side effects, causes of poor compliance and hence therapeutic failures. Finally, we need to take into account the key role of the nocebo effect in the occurrence of adverse effects. The next generation of antidepressant would aim to have a rapid efficacy in patients unresponsive or resistant to drugs currently available while improving certain effects of tolerance through an optimization of their psychopharmacological properties leading to a reduction of their side effects.
Topics: Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Humans; Monoamine Oxidase Inhibitors; Selective Serotonin Reuptake Inhibitors
PubMed: 27423475
DOI: 10.1016/j.encep.2016.05.006 -
Pharmacotherapy Apr 2015Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose... (Review)
Review
Treatment-resistant depression (TRD) is a major health concern. More than 40% of patients treated for major depressive disorder with an appropriate antidepressant dose for an adequate duration fail to respond. Further, approximately half of adults with major depressive disorder fail to achieve sustained remission despite various medication trials. The utilization of monoamine oxidase inhibitors (MAOIs) for the treatment of depression in clinical practice today is low due to their widely known adverse effects, some of which may be life threatening, and the risk for dietary and drug interactions. For these reasons, MAOIs are not recommended to be prescribed along with other antidepressants or certain prescription or nonprescription drugs. Pharmacologic options are limited for individuals with TRD, however, and there is a paucity of data on the efficacy of MAOIs in combination with other antidepressants for the management of TRD. We performed a search of the PubMed database (inception through January 25, 2015) to identify cases that illustrate the potential utility, as well as risks, of combination treatment with MAOIs and other antidepressants for the management of TRD; 18 articles met the criteria for our search. In addition, we performed a retrospective case series by reviewing the medical records of 29 adults treated for depression with an MAOI plus another psychotropic agent (an antidepressant or stimulant medication) between 2003 and 2012 at a large Midwestern teaching hospital. We compared the findings of the published experience with our local experience to allow for more informed decisions regarding pharmacotherapy in patients with TRD. We separated the local experience into two groups: 15 cases with the selective MAO type B inhibitor selegiline combined with medications presumed to increase the risk of serotonin syndrome and 14 cases with nonselective MAOIs (phenelzine and tranylcypromine) combined with other contraindicated medications. Although risks of combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants.
Topics: Antidepressive Agents; Central Nervous System Stimulants; Contraindications; Depression; Depressive Disorder, Major; Drug Interactions; Drug Therapy, Combination; Humans; Monoamine Oxidase Inhibitors; Treatment Failure
PubMed: 25884531
DOI: 10.1002/phar.1576 -
Journal of Neural Transmission (Vienna,... May 2020Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions... (Review)
Review
Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on-off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson's disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors.
Topics: Animals; Humans; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Parkinson Disease; Selegiline
PubMed: 31562557
DOI: 10.1007/s00702-019-02082-0 -
Bioorganic & Medicinal Chemistry Letters Dec 2022Monoamine oxidase (MAO) plays an important role in psychiatric and neurological disorders, such as depression and Parkinson's disease. As a result, MAO represents a key...
Monoamine oxidase (MAO) plays an important role in psychiatric and neurological disorders, such as depression and Parkinson's disease. As a result, MAO represents a key target for developing drugs to treat these conditions. The present study aimed to synthesise and discover compounds that inhibit the MAO enzymes and which may be relevant to the treatment of neurological disorders. A series of nine 2H-1,4-benzothiazin-3(4H)-ones were synthesised and evaluated as potential in vitro inhibitors of human MAO-A and MAO-B. The benzothiazinones bear structural similarity to a series of 3,4-dihydro-2(1H)-quinolinones that have been shown to be highly potent MAO-B inhibitors. The results show that the benzothiazinones inhibit both MAO isoforms but are more potent MAO-B inhibitors. The most potent inhibitors exhibit IC values of 0.0027 (1b), 0.0082 (1c), 0.0096 (1d), and 0.0041 µM (1h) for MAO-B, and 0.714 µM (1d) for MAO-A. These benzothiazinone derivatives exhibit promising MAO inhibition activities and may be developed into clinically useful agents for the treatment of Parkinson's disease. Interestingly, related 4H-3,1-benzothiazin-4-ones have previously been investigated as dual-target-directed drugs that inhibit MAO-B and antagonize adenosine A receptors for the treatment of Parkinson's disease. Based on an interest in d-amino acid oxidase (DAAO) as a target for the treatment for schizophrenia, the 2H-1,4-benzothiazin-3(4H)-ones were also evaluated as in vitro inhibitors of this enzyme. Among the study compounds, only 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one (IC = 4.20 µM) was an active DAAO inhibitor. Finally, molecular docking was employed to gain insight into the binding modes and interactions of the 2H-1,4-benzothiazin-3(4H)-ones with MAO.
Topics: Humans; Monoamine Oxidase Inhibitors; Parkinson Disease; Molecular Docking Simulation; Structure-Activity Relationship; Monoamine Oxidase
PubMed: 36307034
DOI: 10.1016/j.bmcl.2022.129038 -
Progress in Neuro-psychopharmacology &... Aug 2016Progress in understanding the role of monoamine neurotransmission in pathophysiology of neuropsychiatric disorders was made after the discovery of the mechanisms of... (Review)
Review
Progress in understanding the role of monoamine neurotransmission in pathophysiology of neuropsychiatric disorders was made after the discovery of the mechanisms of action of psychoactive drugs, including monoamine oxidase (MAO) inhibitors. The increase in monoamine neurotransmitter availability, decrease in hydrogen peroxide production, and neuroprotective effects evoked by MAO inhibitors represent an important approach in the development of new drugs for the treatment of mental disorders and neurodegenerative diseases. New drugs are synthesized by acting as multitarget-directed ligands, with MAO, acetylcholinesterase, and iron chelation as targets. Basic information is summarized in this paper about the drug-induced regulation of monoaminergic systems in the brain, with a focus on MAO inhibition. Desirable effects of MAO inhibition include increased availability of monoamine neurotransmitters, decreased oxidative stress, decreased formation of neurotoxins, induction of pro-survival genes and antiapoptotic factors, and improved mitochondrial functions.
Topics: Animals; Humans; Mental Disorders; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Synaptic Transmission
PubMed: 26944656
DOI: 10.1016/j.pnpbp.2016.02.012 -
Progress in Neuro-psychopharmacology &... Aug 2016Monoamine oxidases (MAO) influence the monoamine levels in brain by virtue of their role in neurotransmitter breakdown. MAO B is the predominant form in glial cells and... (Review)
Review
Monoamine oxidases (MAO) influence the monoamine levels in brain by virtue of their role in neurotransmitter breakdown. MAO B is the predominant form in glial cells and in platelets. MAO B structure, function and kinetics are described as a background for the effect of alterations in its activity on behavior. The need to inhibit MAO B to combat decreased brain amines continues to drive the search for new drugs. Reversible and irreversible inhibitors are now designed using data-mining, computational screening, docking and molecular dynamics. Multi-target ligands designed to combat the elevated activity of MAO B in Alzheimer's and Parkinson's Diseases incorporate MAO inhibition (usually irreversible) as well as iron chelation, antioxidant or neuroprotective properties. The main focus of drug design is the catalytic activity of MAO, but the imidazoline I2 site in the entrance cavity of MAO B is also a pharmacological target. Endogenous regulation of MAO B expression is discussed briefly in light of new studies measuring mRNA, protein, or activity in healthy and degenerative samples, including the effect of DNA methylation on the expression. Overall, this review focuses on examples of recent research on the molecular aspects of the expression, activity, and inhibition of MAO B.
Topics: Animals; Brain; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors
PubMed: 26891670
DOI: 10.1016/j.pnpbp.2016.02.005 -
Journal of Neural Transmission (Vienna,... Nov 2018Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including... (Review)
Review
Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including therapeutic drugs. While inhibition of MAO activity in the periphery removes protection from biogenic amines and so is undesirable, inhibition in the brain gives vital antidepressant and behavioural advantages that make MAO a major pharmaceutical target for inhibitor design. In neurodegenerative diseases, MAO inhibitors can help to maintain neurotransmitter levels, making it a common feature in novel multi-target combinations designed to combat Alzheimer's disease, albeit not yet proven clinically. Vital information for inhibitor design comes from an understanding of the structure, mechanism, and kinetics of the catalyst. This review will summarize the kinetic behaviour of MAO A and B and the kinetic evaluation of reversible inhibitors that transiently decrease catalysis. Kinetic parameters and crystal structures have enabled computational approaches to ligand discovery and validation of hits by docking. Kinetics and a wide variety of substrates and inhibitors along with theoretical modelling have also contributed to proposed schemes for the still debated chemical mechanism of amine oxidation. However, most of the marketed MAO drugs are long-lasting irreversible inactivators. The mechanism of irreversible inhibition by hydrazine, cyclopropylamine, and propargylamine drugs will be discussed. The article finishes with some examples of the propargylamine moiety in multi-target ligand design to combat neurodegeneration.
Topics: Drug Design; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors
PubMed: 29516165
DOI: 10.1007/s00702-018-1861-9 -
Journal of Clinical Psychopharmacology
Topics: Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors
PubMed: 37335191
DOI: 10.1097/JCP.0000000000001718