Insights into the Mechanism of the Therapeutic Potential of Herbal Monoamine Oxidase Inhibitors in Neurological Diseases

: Monoamine oxidase (MAO) is an enzyme that catalyzes the deamination of monoamines and other proteins. MAO’s hyperactivation results in the massive generation of reactive oxygen species, which leads to a variety of neurological diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and depression-like disorders. Although synthetic MAO inhibitors are clinically available, they are associated with side effects such as hepatotoxicity, cheese reaction, hypertensive crisis, and so on, necessitating the investigation of alternative MAO inhibitors from a natural source with a safe profile. Herbal medications have a significant impact on the prevention of many diseases; additionally, they have fewer side effects and serve as a precursor for drug development. This review discusses the potential of herbal MAO inhibitors as well as their associated mechanism of action, with an aim to foster future research on herbal MAO inhibitors as potential treatment for neurological diseases.

Effects of Natural Monoamine Oxidase Inhibitors on Anxiety-Like Behavior in Zebrafish

Monoamine oxidases (MAO) are a valuable class of mitochondrial enzymes with a critical role in neuromodulation. In this study, we investigated the effect of natural MAO inhibitors on novel environment-induced anxiety by using the zebrafish novel tank test (NTT). Because zebrafish spend more time at the bottom of the tank when they are anxious, anxiolytic compounds increase the time zebrafish spend at the top of the tank and vice versa. Using this paradigm, we found that harmane, norharmane, and 1,2,3,4-tetrahydroisoquinoline (TIQ) induce anxiolytic-like effects in zebrafish, causing them to spend more time at the top of the test tank and less time at the bottom. 2,3,6-trimethyl-1,4-naphtoquinone (TMN) induced an interesting mix of both anxiolytic- and anxiogenic-like effects during the first and second halves of the test, respectively. TIQ was unique in having no observable effect on general movement. Similarly, a reference MAO inhibitor clorgyline—but not pargyline—increased the time spent at the top in a concentration-dependent manner. We also demonstrated that the brain bioavailability of these compounds are high based on the ex vivo bioavailability assay and in silico prediction models, which support the notion that the observed effects on anxiety-like behavior in zebrafish were most likely due to the direct effect of these compounds in the brain. This study is the first investigation to demonstrate the anxiolytic-like effects of MAO inhibitors on novel environment-induced anxiety in zebrafish.

Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action

Chronic inflammatory diseases are debilitating, affect patients’ quality of life, and are a significant financial burden on health care. Inflammation is regulated by pro-inflammatory cytokines and chemokines that are expressed by immune and non-immune cells, and their expression is highly controlled, both spatially and temporally. Their dysregulation is a hallmark of chronic inflammatory and autoimmune diseases. Significant evidence supports that monoamine oxidase (MAO) inhibitor drugs have anti-inflammatory effects. MAO inhibitors are principally prescribed for the management of a variety of central nervous system (CNS)-associated diseases such as depression, Alzheimer’s, and Parkinson’s; however, they also have anti-inflammatory effects in the CNS and a variety of non-CNS tissues. To bolster support for their development as anti-inflammatories, it is critical to elucidate their mechanism(s) of action. MAO inhibitors decrease the generation of end products such as hydrogen peroxide, aldehyde, and ammonium. They also inhibit biogenic amine degradation, and this increases cellular and pericellular catecholamines in a variety of immune and some non-immune cells. This decrease in end product metabolites and increase in catecholamines can play a significant role in the anti-inflammatory effects of MAO inhibitors. This review examines MAO inhibitor effects on inflammation in a variety of in vitro and in vivo CNS and non-CNS disease models, as well as their anti-inflammatory mechanism(s) of action.

Developing a Multi-target Model to Predict the Activity of Monoamine Oxidase A and B Drugs

Introduction: Monoamine oxidase inhibitors (MAOIs) are compounds largely used in the treatment of Parkinson’s disease (PD), Alzheimer’s disease and other neuropsychiatric disorders since they are closely related to the MAO enzymes activity. The two isoforms of the MAO enzymes, MAO-A and MAO-B, are responsible for the degradation of monoamine neurotransmitters and due to this, relevant efforts have been devoted to finding new compounds with more selectivity and less side effects. One of the most used approaches is based on the use of computational approaches since they are time and money-saving and may allow us to find a more relevant structure-activity relationship. Objectives: In this manuscript, we will review the most relevant computational approaches aimed at the prediction and development of new MAO inhibitors. Subsequently, we will also introduce a new multitask model aimed at predicting MAO-A and MAO-B inhibitors. Methods: The QSAR multi-task model herein developed was based on the use of the linear discriminant analysis. This model was developed gathering 5,759 compounds from the public dataset Chembl. The molecular descriptors used was calculated using the Dragon software. Classical statistical tests were performed to check the validity and robustness of the model. Results: The herein proposed model is able to correctly classify all the 5,759 compounds. All the statistical performed tests indicated that this model is robust and reproducible. Conclusion: MAOIs are compounds of large interest since they are largely used in the treatment of very serious illness. These inhibitors may lose efficacy and produce severe side effects. Due to this, the development of selective MAO-A or MAO-B inhibitors is crucial for the treatment of these diseases and their effects. The herein proposed multi-target QSAR model may be a relevant tool in the development of new and more selective MAO inhibitors.