Frontiers in Natural Product Chemistry: Volume 5 -  - E-Book

Frontiers in Natural Product Chemistry: Volume 5 E-Book

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Frontiers in Natural Product Chemistry is a book series devoted to publishing monographs that highlight important advances in natural product chemistry. The series covers all aspects of research in the chemistry and biochemistry of naturally occurring compounds, including research on natural substances derived from plants, microbes and animals. Reviews of structure elucidation, biological activity, organic and experimental synthesis of natural products as well as developments of new methods are also included in the series.
The fourth volume of the series brings seven reviews covering these topics:
-natural antiamoebic medicines, analgesics and antimalarials
-essential oils and cognitive performance
-cannabis and drug development
-lectins in biosensors,
-brassinosteroids.

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Table of Contents
Welcome
Table of Content
Title
BENTHAM SCIENCE PUBLISHERS LTD.
End User License Agreement (for non-institutional, personal use)
Usage Rules:
Disclaimer:
Limitation of Liability:
General:
PREFACE
List of Contributors
Inhibition of Monoamine Oxidase (MAO) via Green Tea Extracts: Structural Insights of Catechins as Potential Inhibitors of MAO
Abstract
1. INTRODUCTION
1.1. The Potential of Green Tea for Health and Disease Prevention
2. CHARACTERIZATION OF CATECHINS
2.1. Characteristics and Types
2.2. Catechins as Inhibitors
2.3. Effects of Catechins on Depression
3. CHARACTERIZATION OF MONOAMINE OXIDASES
3.1. Functional Characteristics
3.2. Mechanistic Comparison of Monoamine Oxidases
3.3. Diseases of the Nervous System: Fluctuations in MAO Activity
3.4. Monoamine Oxidase Inhibitors: A Pharmaceutical Approach
3.5. Current Pharmacological Agents as MAOIs
3.6. Pharmacotherapy of Monoamine Oxidase-Associated Disorders
3.7. Monoamine Reuptake Inhibitors: Mechanisms of Inhibitor Action
3.8. MAOIs: Mechanisms of Inhibitor Action-Nonselective and Selective Inhibition
3.9. Adverse Effects of Conventional MAOIs: Clinical Considerations and Toxicity
3.10. The Need for Additional (natural) Inhibitors of MAO
3.11. The Proposed Benefits of Catechins as Natural Inhibitors of MAO
4. HIGH THROUGHPUT SCREENING STRATEGIES
4.1. Non-Fluorescence-based Assays
4.2. Fluorescence-based Assays: The Role of the Fluorescent Probe
4.3. Fluorescence-based Assays: Inhibition Assays
4.4. High Throughput Screening with Enzyme-Linked Fluorescent Assays
5. EGCG AS AN INHIBITOR OF MAOA AND MAOB
5.1. EGCG Content in Green Tea and Recommended Dosage
5.2. Preliminary Studies
5.3. Inhibition of MAO via Green Tea Extracts
5.4. Molecular Docking Studies
5.5. Molecular Docking of Control Inhibitors
5.6. Molecular Docking of Catechin EGCG
6. PHARMACOKINETICS AND ADVERSE EFFECTS OF GREEN TEA CATECHINS
6.1. Absorption, Distribution, Metabolism, and Excretion of Green Tea Catechins
6.2. Adverse Effects of Green Tea Consumption: Toxicity and Drug Interactions
CONCLUDING REMARKS
ABBREVIATIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Sesquiterpene Lactone Cynaropicrin as Novel Inhibitor of Bcr-Abl Fusion Oncogene Expression
Abstract
INTRODUCTION
Tyrosine Kinase Inhibitors (TKIs)
Sesquiterpene Lactone Cynaropicrin Extraction
Sesquiterpene Lactone Cynaropicrin Derivatives and Structure–Activity Relationship (SAR) Studies
Cynaropricrin as Co-adjuvant CML Therapy
CONCLUDING REMARKS
Consent for Publication
CONFLICT OF INTEREST
ACKNOWLEDGMENT
REFERENCES
Effects of Dietary Polyphenols on Chronic Diseases: Epidemiological Data and Molecular Mechanisms of Action
Abstract
1. INTRODUCTION
2. CHARACTERISTICS OF DIETARY POLYPHENOLS
2.1. Classification of Polyphenol
2.1.1. Phenolic Acids
2.1.2. Flavonoids
2.1.3. Stilbenes
2.1.4. Lignans
2.2. Protective Action of Polyphenols Against Reactive Oxygen Species (ROS)-Associated NCDs
2.3. Protective Action of Polyphenols Against Inflammation
3. BIOAVAILABILITY AND ABSORPTION OF POLYPHENOLS
4. PROTECTIVE EFFECT OF POLYPHENOLS AGAINST NCDs - EPIDEMIOLOGIC STUDIES
4.1. Cardiovascular Disease
4.2. Cancer
4.3. Type 2 Diabetes Mellitus
5. PROTECTIVE EFFECT OF POLYPHENOLS AGAINST OBESITY - EPIDEMIOLOGIC STUDIES
6. MOLECULAR MECHANISMS OF ACTION OF EGCG AND RESVERATROL INVOLVED IN THE PREVENTION OF OBESITY AND NCDs
6.1. Obesity
6.1.1. EGCG
6.1.2. Resveratrol
6.2. Cardiovascular Disease
6.2.1. EGCG
6.2.2. Resveratrol
6.3. Cancer
6.3.1. EGCG
6.3.2. Resveratrol
6.4. Type 2 Diabetes Mellitus
6.4.1. EGCG
6.4.2. Resveratrol
CONCLUSION
ABBREVIATIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGMENTS
REFERENCES
Overview of Past and Present Developments Towards Biotechnological and Molecular Approaches to Improve Taxol Production
Abstract
1. INTRODUCTION
2. TAXOL AND ITS SUCCESS STORY TO DRUG DEVELOPMENT
3. CELL AND TAXOL FIGHT
4. TOXICITY OF TAXOL
4.1. Hypersensitivity
4.2. Extravasation Reactions
4.3. Cutaneous Toxicities
4.4. Neurotoxicity
4.5. Cardiac Arrhythmias
4.6. Gastrointestinal Effects
4.7. Taxol-induced Alopecia
5. SOURCES AND PRODUCTION OF TAXOL
5.1. Taxus and Other Plant Sources of Taxol
5.2. Total Synthesis of Taxol
5.3. Semi-synthesis of Taxol
5.4. Production by Plant Cell Culture
5.5. Taxol Producing Endophytic Fungi
6. TAXOL BIOSYNTHESIS AND METABOLIC ENGINEERING FOR TAXOL PRODUCTION
6.1. Taxol Production by Transgenic Saccharomyces Cerevisiae
6.2. Taxol and its Precursor’s Production by E.Coli
6.3. Transformation of Taxus Cell Culture
6.4. Taxol and its Precursor Production in Heterologous Plants
7. MOLECULAR BASIS OF TAXOL BIOSYNTHESIS
7.1. Transcriptomic Studies for Genes Involved in Taxane Biosynthesis
7.2. TFs Involved in Taxanes Biosynthesis
SUMMARY
ABBREVIATIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Cytotoxicity Through Molecular Targets Involved in Apoptosis. Where Should We Further Search for Mushrooms Functionalities in Future Cancer Treatment?
Abstract
INTRODUCTION
Intrinsic Pathway
Extrinsic Pathway
Targeting Apoptosis in Cancer Treatment
Targeting Bcl-2 and Bax
Targeting Death Receptors
Caspase Activators
Modulation of the p53 Tumor Suppressor
Targeting Mutant p53 to Restore its Wild-Type Function
Reactivation of Wild-type p53 by Targeting Mdm2 and MdmX Inhibitors
Natural Bioactive Compounds from Fungi That Modulate p53 Activity
Mushrooms as Part of Regular Diet - Potential Role in Cancer Prevention
Mushrooms as Apoptosis Inducers in Cancer Cells
Inonotus obliquus (Ach. ex Pers.) Pilát (1942)
Inonotus taiwanensis Sheng H. Wu, Y.T. Lin & C.L. Chern (2018)
Phellinus igniarius (L.) Quél. (1886)
Ganoderma resinaceum Boud. (1889)
Ganoderma applanatum (Pers.) Pat. (1887)
Cantharellus cibarius Fr. (1821)
Pleurotus sajor-caju (Fr.) Singer (1951)
Lignosus rhinocerus (Cooke) Ryvarden (1972)
Morchella esculenta (L.) Pers. (1801)
Lentinus squarrosulus Mont. (1842)
Ramaria botrytis (Pers.) Ricken (1918)
Coprinus comatus (O.F.Müll.) Pers. (1797)
Grifola frondosa (Dicks.) Gray (1821)
Cyclocybe aegerita (V. Brig.) Vizzini 2014
Antrodia salmonea Chang & Chou (2004)
Antrodia cinnamomea Chang & Chou (1995)
Agaricus lanipes (F.H. Møller & Jul. Schäffer) Singer (1949)
Polyporus squamosus (Huds.) Quélet (1886)
Pulveroboletus ravenelii (Berk. & M.A. Curtis) Murrill (1909)
Trametes versicolor (syn. Coriolus versicolor) (L.) Lloyd (1920)
Ganoderma lucidum (Curtis) P. Karst. (1881)
Agaricus blazei Murill. (1945)
Fulviformes fastuosus
Ganoderma colossum (Fr.) C.F. Baker (1918)
Calvatia gigantea (Batsch) Lloyd (1904)
Termitomyces clypeatus R.Heim (1951)
Armillaria mellea (Vahl) P.Kumm. (1871)
Pyropolyporus fomentarius (L.) Teng (1963)
Leccinum vulpinum Watling (1961)
Tricholoma matsutake (S. Ito & S. Imai) Singer (1943)
Hericium erinaceum (Bull.) Persoon (1797)
Amauroderma rude (Berk.) Torrend (1920)
Cordyceps militaris (L.) Fr. (1818)
Cordyceps bassiana Z.Z. Li, C.R. Li, B. Huang & M.Z. Fan (2001)
Pleurotus eryngii var. ferulae (Lanzi) Sacc. 1887
Lentinus crinitus (L.) Fr. (1825)
Sarcodon aspratus (Berk.) S. Ito (1955)
Meripilus giganteus (Pers.) Karst. (1882)
Where Should We Further Search for Mushrooms Functionalities?
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Health Related Enzyme Inhibiting Natural Products from Medicinal Plants
Abstract
INTRODUCTION
Naturally Occurring α-Glucosidase Inhibitors
Naturally Occurring Acetylcholinesterase Inhibitors
Naturally Occurring Glutathione S-Transferase (GST) Inhibitors
Naturally Occurring Renin Inhibitors
CONCLUDING REMARKS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
Acknolwdgements
REFERENCES

Frontiers in Natural Product Chemistry

(Volume 5)

Edited by

Atta-ur-Rahman, FRS

Kings College
University of Cambridge
Cambridge
UK

BENTHAM SCIENCE PUBLISHERS LTD.

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PREFACE

Frontiers in Natural Product Chemistry presents recent advances in the chemistry and biochemistry of naturally occurring compounds. It covers a range of topics including important researches on natural substances. The book is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information on bioactive natural products.

The chapters in this volume are written by eminent authorities in the field and are mainly focused on inhibition of monoamine oxidase (MAO) via green tea extracts, cynaropicrin as an inhibitor of Bcr-Abl fusion oncogene expression, effects of dietary polyphenols on chronic diseases, taxol production, mushroom functionalities in cancer treatment, and health related enzyme inhibiting natural products.

I hope that the readers will find these reviews valuable and thought provoking so that they may trigger further research in the quest for the new and novel therapies against various diseases. I am grateful for the timely efforts made by the editorial personnel, especially Mr. Mahmood Alam (Director Publications), and Mr. Shehzad Iqbal Naqvi (Editorial Manager Publications) at Bentham Science Publishers.

Atta-ur-Rahman, FRS Kings College University of Cambridge Cambridge UK

List of Contributors

Athar AtaDepartment of Chemistry, Richardson College for the Environmental and Science Complex, The University of Winnipeg, 599 Portage Avenue, Winnipeg, Manitoba R3B 2G3, CanadaAstrid MarchBiotechnology Division, Roxbury Community College, Boston, MA02120, USABilal Ahmad AsadState Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, 100081, ChinaBilge SenerDepartment of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, TurkeyChun-Tao HeState Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Xingang Xi Road 135, Guangzhou, 510275, ChinaDanijela StanisavljevićInstitute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, PO Box 23, 11010, Belgrade, SerbiaDejan StojkovićDepartment of Plant Physiology, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Bulevar Despota Stefana 142, 11000, Belgrade, SerbiaErika CioneDepartment of Pharmacy Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, ItalyFrancesca AielloDepartment of Pharmacy Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, ItalyGemma R. TopazBiotechnology Division, Roxbury Community College, Boston, MA02120, USA Department of Biology, Boston University, Boston, MA02215, USAJasmina GlamočlijaDepartment of Plant Physiology, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Bulevar Despota Stefana 142, 11000, Belgrade, SerbiaJelena PopovićInstitute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, PO Box 23, 11010, Belgrade, SerbiaJelena ŽivkovićInstitute for Medicinal Plant Research “Dr. Josif Pančić”, Tadeuša Košćuška 1, 11000, Belgrade, SerbiaKazuo YamagataLaboratory of Molecular Health Science of Food, Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), Fujisawa, JapanKenneth FriesenDepartment of Chemistry, Richardson College for the Environmental and Science Complex, The University of Winnipeg, 599 Portage Avenue, Winnipeg, Manitoba R3B 2G3, CanadaKimberly A. StieglitzBiotechnology Division, Roxbury Community College, Boston, MA02120, USAMaria Cristina CaroleoDepartment of Pharmacy Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, ItalyMaria Luisa Di GioiaDepartment of Pharmacy Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, ItalyMarija SmiljkovićDepartment of Plant Physiology, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Bulevar Despota Stefana 142, 11000, Belgrade, SerbiaMilena StevanovićInstitute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, PO Box 23, 11010, Belgrade, Serbia Faculty of Biology, University of Belgrade, Studentski trg 16, PO box 43, 11000, Belgrade, Serbia Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11001, Belgrade, SerbiaSamavia MubeenState Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Xingang Xi Road 135, Guangzhou, 510275, ChinaSamina NazDepartment of Chemistry, Richardson College for the Environmental and Science Complex, The University of Winnipeg, 599 Portage Avenue, Winnipeg, Manitoba R3B 2G3, CanadaVictor Epiter-SmithBiotechnology Division, Roxbury Community College, Boston, MA02120, USAZhong-Yi YangState Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Xingang Xi Road 135, Guangzhou, 510275, China

Inhibition of Monoamine Oxidase (MAO) via Green Tea Extracts: Structural Insights of Catechins as Potential Inhibitors of MAO

Gemma R. Topaz1,2,Astrid March1,Victor Epiter-Smith1,Kimberly A. Stieglitz1,*
1 Biotechnology Division, Roxbury Community College, Boston, MA 02120, USA
2 Department of Biology, Boston University, Boston, MA 02215, USA

Abstract

MAOs perform deamination of amines, are present at high-concentration in neuronal cells, and are found bound to the outer mitochondrial membrane. MAOA oxidizes serotonin, noradrenaline, and adrenaline; and MAOB oxidizes dopamine, β-phenylethylamine (β-PEA), and benzylamine. Abnormal MAOA activity has been implicated in depression, anxiety, and other psychological or psychiatric disorders, while heightened MAOB activity in the brain occurs in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and normal aging. Drugs have been developed and continue to be developed with both MAOA and MAOB as targets. However, MAO inhibitors (MAOIs) have adverse side effects and serious drug interactions with some over the counter medications. MAOA is inhibited by Clorgyline and MAOB is potently inhibited by both Deprenyl and Pargyline. In addition, polyphenol green tea catechins may also target the MAO enzymes. Using these inhibitors as controls, fluorescent activity assays were performed with commercially available catechins from green tea extracts primarily composed primarily of EGCG. MAOs were utilized as targets to investigate and confirm recent studies suggesting that green tea catechin polyphenols may be preventative for certain degenerative diseases, psychiatric disorders, and emotional disabilities. Of the tested green tea extracts (confirmed EGCG), commercial catechins exhibited half-maximal inhibitory concentration (IC50) values in the low-to-mid µM range, at approximately 50-750 µM. Molecular docking of specific catechins into the MAOA and MAOB active sites resulted in binding constants in the low µM range. Docking studies as such provide structural insights into possible binding models of EGCG catechin to MAOs. Efforts to understand the effect of catechins on MAO targets are currently underway, and a survey of the literature is provided.

Keywords: Catechins, EGCG, Green tea extracts, MAOA, MAOB, NDRIs, SNRIs.
*Corresponding author Kimberly A. Stieglitz: Biotechnology Division, Roxbury Community College, Boston, MA 02120, USA; E-mail: [email protected]

1. INTRODUCTION

1.1. The Potential of Green Tea for Health and Disease Prevention

Investigation of Traditional Chinese Medicine is fairly recent within the scope of interest to comparative studies in Western Medicine. Chinese botanical medicine in the form of green tea continues to be a highly desired good for consumption. Green tea as an herbal medicine supports long-standing theories regarding the potential benefits of green teas for improved physical health. Tea is generally consumed not only for its taste but also for its reliable alleviative properties. Catechins, bioactive compounds known to possess medicinal benefits [1], are found in high quantities in green tea, more so than any other consumable. Previous research pertaining to green tea catechins and their potential medicinal properties has spanned many areas of study including cancer, obesity, atherosclerosis, diabetes, and gum disease, with a special emphasis on certain disorders affecting the central nervous system, notably, neurodegenerative diseases [2-4].

The primary motivation for this study stems from an increased interest in exploring the possible benefits of green tea to better understand its potential impact on health and disease prevention. This chapter not only seeks to gain structural insights of catechins, but also to survey literature focusing on the various mechanisms of MAO activity and inhibitor actions for the purpose of providing functional knowledge of how catechins may act as potent inhibitors of MAO.

2. CHARACTERIZATION OF CATECHINS

2.1. Characteristics and Types

On a molecular level, catechin compounds are comprised of four groups of polyphenols (flavonoid compounds) and are commonly found in plants. The primary catechin flavonoids focused herein are epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG) [5]. Polyphenols as such are further characterized as flavan-3-ols, or flavanols. Catechins are secondary metabolites (not essential for survival) with a 15-carbon skeleton containing two phenyl rings and a heterocyclic ring (Fig. 1). In green tea, plant polyphenols (of catechins) are of special significance due to their antioxidant properties [6].

Polyphenolic plant compounds display scavenger-like behavior. This scavenging activity is important for the removal of potentially toxic chemical products or reactants, thereby enabling the elimination of molecular impurities. Nakagawa and Yokozawa [7] found that flavan-3-ols-which serve as antioxidants and aid in the process of reduction-enhance the scavenging activity of polyphenolic plant compounds (gallic acids) compared to the scavenging activity of gallic acids independently. A study by Hirun and Roach [8] found that the structure of EGCG is consistent with the type of molecule that performs scavenging activity. EGCG was also evaluated for its ability to act as a neuroprotecting agent and was found to have the highest protection values against the process of DNA excision, compared to other catechin compounds [5]. In contrast, however, ECG was evaluated for having the highest potential for its scavenging abilities [9].

Fig. (1))Structure of Catechins. The four major types of catechins and their structures, from top-left to top-right and bottom-left to bottom-right. (A) Structure of Epicatechin (EC). (B) Structure of Epigallocatechin (EGC). (C) Structure of Epicatechin Gallate (ECG). (D) Structure of Epigallocatechin Gallate (EGCG).

2.2. Catechins as Inhibitors

Green tea catechins (especially (-) Epigallocatechin-3-gallate (EGCG)), exert multiple effects on signaling pathways and cellular proteins [1]. A study by Dulloo et al. [10] found that green tea catechins can inhibit Catechol-O- methyltransferase (COMT), an enzyme responsible for the degradation of neurotransmitters including norepinephrine. Similarly, EGCG has demonstrated high inhibition levels of pure catalase inhibition and increased suppression of viable cell types such as cancer cells, with IC50 levels of 54.5 µM [4]. This study proposes a great potential for patenting the use of gallated catechins such as EGCG, in anticancer drug treatment against the spread of cancerous cells. Moreover, studies conducted in vitro found that EGCG exhibits an inhibitory effect on certain signal transduction pathways such as Notch, Wnt, JAK/STAT, MAPK and P13K/Akt, where the disruption of these pathways may prevent carcinogenesis (the initiation of cancer formation) from occurring [11]. Additionally, Singh and his colleagues [11] also found that the prevention of sequential damage which occurs in response to oxidation could serve as a promising first defense mechanism against carcinogens, thereby combatting cancer progression. Some general mechanisms proposed for the biological activities of EGCG include cell cycle arrest, apoptosis, modulation of cell signaling, inhibition of DNA methylation, altered miRNA expression, protease activity, and telomerase activity [11]. Furthermore, the study in focus [11] also examines the effect of EGCG on several signal transduction pathways including the inhibition of protein kinase.

As previously mentioned, EGCG inhibits mitogen-activated protein kinase (MAPK) pathways, though it has also been shown to have an inhibitory effect on other molecular mechanisms including cyclin-dependent kinases (CDKs) which contribute to the cell cycle, DNA methyltransferase (with epigenetic applications), proteosomes (significant to proteases and the ubiquitin pathway), and the pathway for receptor tyrosine kinase (RTK) [12]. Moreover, EGCG prevents the spread of several malignant conditions (e.g., cancer) as it targets mechanisms such as those aforementioned, and specifically RTK pathways [12].

2.3. Effects of Catechins on Depression

Depression can be debilitating in many ways, however, when present in combination with other underlying and thus, overlapping psychiatric and/or emotional or affective disorders, can greatly impact one’s quality of life. In this circumstance, depression can be extremely dangerous and may drastically increase patient vulnerability to the risk of suicide. Furthermore, neuronal tissue is particularly prone to oxidative damage compared to other tissues in the body. Catechins serve as natural antioxidants which aid in the prevention of neuronal damage and therefore, protect neurons during increased oxidative stress-which, notably, is higher during depressive states [13]. Interestingly, oxidative stress has previously been ascribed a contributor not only to cardiovascular disease, but is also implicated in the development of certain psychiatric disorders [13].

A recent study examining post-stroke depression identified the antioxidant activity of polyphenol catechins as the active ingredient of green tea that helps aid in the regulation of depressive symptoms, thereby reducing oxidative stress, restoring proper functioning, and partially repairing antioxidant endogenous defense mechanisms [13]. Similarly, another study found that green tea reduces symptoms of depression in non-human animal subjects by inhibiting monoamine oxidase (MAO) [14]. Likewise, a study conducted by Mähler et al. [15] found that neurotransmitter activity in rats decreases with age. Additionally, researchers found that upon the administration of EGCG, rats showed an increase in neurotransmitter activity, specifically of acetylcholine (ACh), dopamine, and serotonin, thereby exhibiting fewer depressive symptoms [15]. Furthermore, a meta-analysis involving 11 cohorts demonstrated that in 13 cases covering upwards of 22 thousand participants, a negative correlation existed between tea consumption and the risk of depression, resulting in a 37% reduction in symptoms among participants who drank 3 or more cups of green tea per day [16]. These findings further elucidate the potential medicinal benefits of green tea catechins and present a promising approach to the therapeutic treatment of depression and associated psychiatric disorders by means of natural products.

3. CHARACTERIZATION OF MONOAMINE OXIDASES

3.1. Functional Characteristics

Monoamine oxidase (MAO) performs deamination of amines by catalyzing the oxidation/inactivation of primary monoamines (Fig. 2). MAOs are bound to the outer mitochondrial membrane with higher activity localized in neuronal cells, and are active in the CNS, PNS, and peripheral organs. MAO oxidizes freely accessible monoamine neurotransmitters that have not already been taken up and stored in vesicles in a presynaptic cell. In the brain, MAO primarily targets serotonin, dopamine, and norepinephrine for functional removal. Consequently, several psychological, psychiatric, and/or mental health disorders may develop as a result of the function of MAOs in brain activity.

Fig. (2))The Monoamine Oxidase Mechanism. Monoamine oxidases are a group of enzymes that catalyze the oxidative deamination of monoamines. The above mechanism illustrates the oxidation of a secondary amine (into an imine) followed by hydration, resulting in the generation of an aldehyde and a primary amine.

3.2. Mechanistic Comparison of Monoamine Oxidases

MAOs are a type of amine-oxidizing flavoenzyme that serve as catalysts in the enzyme-catalyzed reaction of flavin-dependent amine oxidation. There are two forms of the MAO enzyme, collectively known as isozymes. These include type A which is further characterized as MAOA, and type B, characterized as MAOB [17]. Both monoamine oxidase isoenzymes contain highly conserved active sites and demonstrate 70% homogeneity. Substrates for MAOA predominantly include epinephrine, norepinephrine, and serotonin, whereas substrates for MAOB include phenylethylamine, phenylethanolamine, tyramine, and benzylamine [18]. However, there are substances that are metabolized by both enzymes, such as dopamine and tryptamine. Although each MAO isozyme is abundantly expressed in the brain, MAOA is also present in the liver, heart, and pancreas, while MAOB is found in the liver, posterior pituitary, renal tubules, and endocrine pancreas [17]. MAOA is a gene found in catecholaminergic neurons, in this case norepinephrine and dopamine [19]. MAOA metabolizes several different monoamine neurotransmitters and is selectively inhibited by Clorgyline, an MAO inhibitor (MAOI) that is structurally similar to the antidepressant Pargyline (Table 1) [19]. Li and his colleagues [19] reveal that MAOB is found mostly in astrocytes as well as in some serotonergic neurons that specifically act on dopamine and β-phenylethylamine (β-PEA) monoamines, and is selectively, and irreversibly, inhibited by Selegiline (Deprenyl) (Table 1) [19-21]. Both MAOA and MAOB enzymes maintain homoeostasis in the brain, with functional roles in the regulation of neurotransmitters to ensure proper neurological and psychological functioning [19]. Li and colleagues [19] also found that the excessive activation of MAOA and/or MAOB produces neurotoxic byproducts which, in turn, can trigger the development of psychiatric disorders, and may ultimately result in irreversible neurodegeneration.

3.3. Diseases of the Nervous System: Fluctuations in MAO Activity

Altered MAO activity was found to be an occurrence of some central and peripheral nervous system diseases. For instance, elevated levels of MAOA leading to heightened MAOA activity has found to be associated with episodes of major depressive disorder [22]. Interestingly, these occurrences have shown to persist even after treatment with a Selective Serotonin Reuptake Inhibitor (SSRI), a substance which functions to inhibit the reuptake of the neurotransmitter serotonin [22].

In contrast, heightened MAOB activity in the brain has been shown to occur in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and is a result of normal aging. Medical intervention, treatment, and therapy for these disorders is widely available, although a common form of intervention includes routine dosing of pharmaceutical agents using MAOA, MAOB, or both isozymes as targets. Alternatively, some studies have demonstrated that catechins may serve as potent inhibitors of MAO [18]. This is of special importance in that catechins, and particularly green tea catechins-using MAOs as targets-may present a new therapeutic approach to treating MAO-associated disorders using natural products as a substitute for synthetic pharmaceutical medications. These findings further suggest that, with the use of MAOs as targets, catechins may also be preventative for certain disease progression with respect to degenerative diseases and emotional disorders [19].

3.4. Monoamine Oxidase Inhibitors: A Pharmaceutical Approach

Monoamine oxidase inhibitors (MAOIs) are a class of drugs generally used as antidepressants and are effective in treating depression, although they are also used to treat Bipolar disorder as well as various Panic disorders. MAOIs functionally inhibit the actions of the MAO enzymes. As the MAO isoenzymes catalyze the breakdown of monoamine neurotransmitters through the process of oxidative deamination, methods of inhibition as such enable a steady increase in the level of monoamine neurotransmitter accumulation at the synapse, thereby enhancing the docking potential of monoamines onto postsynaptic cells. This activity ultimately results in the steady firing of action potentials which, in turn, maintains neuronal amine homeostasis.

3.5. Current Pharmacological Agents as MAOIs

As presented in Table 1 below, the most common MAO inhibitors (from DrugBank.com) are shown. There are many types of pharmacological agents currently on the market as MAOIs. Despite molecular variations, these drugs share similar function in that they mimic monoamine neurotransmitters such as dopamine, serotonin, epinephrine (adrenaline), norepinephrine (noradrenaline), and β-phenylethylamine (β-PEA), for inhibition and inactivation of the target MAO enzymes. However, the effects of these drugs are not solely confined to the central nervous system. In fact, pharmaceutical agents in the form of MAOIs are often administered in the treatment of neurodegenerative diseases for the purpose of targeting the peripheral nervous system. As previously mentioned, the overall objective of MAOIs is to regulate the accumulation of neurochemicals (specifically, monoamine neurotransmitters) between presynaptic and postsynaptic cells. As certain neurochemicals, neurotransmitters, and neuromodulators, such as those aforementioned, are primarily responsible for many aspects pertaining to emotion (including the perception of mood and feelings) and are crucial for proper cognitive functioning, an imbalance of any such chemical can play a critical role in the pathogenesis of many psychological and/or neurological conditions. MAOIs therefore serve as a means to offset the impact of chemical imbalances on mood and behavior, while also temporarily restoring impaired cognitive functioning in response to neurodegeneration as a result of such imbalances.

3.6. Pharmacotherapy of Monoamine Oxidase-Associated Disorders

Table 1 presents a display for elements of (or pertaining to) current, developmental, experimental, and investigational pharmacological treatments for MAOA- and MAOB-related disorders by means of monoamine oxidase inhibitors. The table details various properties of MAOIs in terms of chemical classification, pharmacological classification, their known side effects, and current status, in accordance with the Food and Drug Association (FDA). Depending on whether the drug is an inhibitor of MAOA or MAOB can determine the way in which the inhibitor treats the condition for the patient.

Table 1Pharmacotherapy of Monoamine oxidase-related disorders via MAOIs [20, 21].Inhibitors of MAOAMedicationChemical ClassificationPharmacological ClassificationCommentsSide EffectsStatusBEFLOXATONEUnclassifiedSuper Class: N/AClass: N/ASub Class: N/ANeuropsychiatric agent and Antidepressant-used to mitigate panic disorders.Selective. Prescription information currently unavailable.Increased sleep latency (REM sleep), decreased sleep duration (SEM sleep).ExperimentalBROFAMINEBenzenofuransSuper Class: Organoheterocyclic compoundsClass: BenzenofuransSub Class: N/ANo further information is available at this time.Used to make Abediterol, Acarbose, and Accebutolol.N/AExperimentalCLORGILINE (CLORGYLINE)DichlorobenzenesSuper Class: BenzenoidsClass: Benzene & Substitute Derivatives (SDs)Sub Class: HalobenzenesAntidepressant.Related to Pargyline. Used to make Clorgiline Hydrochloride and Moclobemide.Anxiety, dizziness, headache, nausea, vomiting, dry mouth, sleep disturbances, constipation, liver damage, sexual dysfunction.ExperimentalMINAPRINEPhenylpyridazinesSuper Class: Organoheterocyclic compoundsClass: DiazinesSub Class: Pyridazines and derivativesPsychoactive drug. Also used as an antidepressant to treat depression.Used to make Cantor and Minaprine Dihydro-chloride.N/AApprovedMOCLOBEMIDE4-halobenzoic acids & DerivativesSuper Class: BenzenoidsClass: Benzene & SDsSub Class: Benzoic acids & derivativesAntidepressant-used to treat depression (Major Depressive Disorder) and is more effective in the acute form.Selective and reversible. Used to make Manerix; also used to make Moclobemide 100 and PMS Moclobemide.Agitation, dizziness, drowsiness, muscle rigidity, headache, confusion, seizures, and hypertension.Approved, Under InvestigationPHENELZINEBenzeneSuper Class: BenzenoidsClass: Benzene & SDsSub Class: N/AAntidepressant and anxiolytic agent used to treat depression and social anxiety disorder. Also used as a panic disorder treatment option.Nonselective and irreversible. Used to make Nardil and Phenelzine Sulfate.Elevation in aminotransferase levels; injury to liver.ApprovedPIRLINDOLECarbazolesSuper Class: Organoheterocyclic compoundsClass: Indoles & DerivativesSub Class: CarbazolesAntidepressant. Also used to treat fibromyalgia.Reversible. Elevates mood by regulating levels of available catecholamines and norepinephrine.Seizures, agitation, and hyperthermia. Tremors and death when coupled with SSRIs, TCAs, tyramine-rich foods, and sympathomimetic drugs.ApprovedPYRAZOLINE DERIVATIVESAlkaloids / PyrazolesSuper Class: Organoheterocyclic compoundsClass: AzolesSub Class: PyrazolesAnticancer, antipyretic, antiviral, anticonvulsant, anti-inflammatory, and analgesic agent.Reversible.N/AExperimentalTOLOXATONEToluenesSuper Class: BenzenoidsClass: Benzene & SDsSub Class: ToluenesAntidepressant.Selective and reversible.Constipation, dysuria, nausea, insomnia, vertigo and fulminant hepatitis.ApprovedTRANYL-CYPROMINE(PARNATE)AralkylaminesSuper Class: Organic Nitrogen CompoundsClass: Organo-nitrogen compoundsSub Class: AminesPsychoactive drug used as an antidepressant or anxiolytic agent to treat major and atypical depression, panic and phobia-based disorders, and dysthymic disorder.Nonselective and irreversible. Used to make Tranyl-cypromine Sulfate and Parnate.Anxiety, mental incoherence, insomnia, feeling of drowsiness or dizziness, and hypotension.Approved, Under InvestigationTYRIMAUnclassifiedSuper Class: N/AClass: N/ASub Class: N/AUsed to treat anxiety and depression.Catalyzes biogenic and xenobiotic amines.N/AUnder Investigation3,5-DIARYL PYRAZONEAlkaloids / PyrazolesSuper Class: Organoheterocyclic CompoundsClass: AzolesSub Class: PyrazolesPotential anticancer and anti-inflammatory agent. Potential tyrosinase inhibitor.Selective and reversible.N/AExperimentalInhibitors of MAOBMedicationChemical ClassificationPharmacological ClassificationCommentsSide EffectsStatus3,5-DIARYL PYRAZONEAlkaloids / PyrazolesSuper Class: Organoheterocyclic CompoundsClass: AzolesSub Class: PyrazolesPotential anticancer and anti-inflammatory agent. Potential tyrosinase inhibitor.Selective and reversible.N/AExperimentalCATECHIN / EPICATECHINSCatechinsSuper Class: Phenylproponoids & PolyketidesClass: FlavonoidsSub Class: FlavansUnclassified.Used in studies for pre-diabetes treatment.N/AUnder InvestigationCHALCONE DERIVATIVESDerivatives: HesperidinChalcanoidsSuper Class: PolyphenolsClass: ChalcanoidsSub Class: N/APotential anticancer agent.Potential MAOB inhibitor.Hepa, Nephra, neuro and ototoxicity.Under InvestigationCOURAMINEDerivatives: Photovoltaic sensitizers, Warfarin, laser dye gain medium, edema modifier.Phenylpropanoids(see Geiparvarin)Super Class: BenzopyronesClass: LactonesSub Class: CoumarinAntidepressant.Potential anti- inflammatory, antibacterial, anticoagulant, antifungal and antitumor properties.Anxiety, nausea, vomiting, dry mouth, dizziness, headache, sleep disturbances, constipation, sexual dysfunction, and liver damage.Under InvestigationDESMETHOXY-YANGONINKavalactonesSuper Class: N/AClass: N/ASub Class: N/APotential MAOB inhibitor.Used to make Kava.Liver damage, apoptosis.ExperimentalGEIPARVARINDerivatives: Couramin-derived treatments.PhenylpropanoidsSuper Class: BenzopyronesClass: LactonesSub Class: CoumarinUsed to treat lymphedema and is under study for its antitumor properties.Sometimes used to make organic blue-green laser dyes.Moderate toxicity in humans, mainly liver and kidneys.Under InvestigationISATINIndolinesSuper Class: Organoheterocyclic compoundsClass: Indoles & DerivativesSub Class: IndolinesPotential MAOB inhibitor. Biosynthesizes pigments, hormones, and neurotransmitters.Found in Schiff bases and certain plants. Used to make Isatin-based derivatives.N/AExperimentalPARGYLINEPhenylmethylaminesSuper Class: BenzenoidsClass: Benzene & Substitute DerivativesSub Class: PhenylmethylamineAntidepressant. Also used to reduce hypertension and hypertensive properties.Used to make Abediterol, Acarbose, and Acebutolol.Increased hypertension, increased blood pressure, increased heart rate, and increased levels of glucose in the bloodstream.Approved, Under InvestigationPHTHALIMIDES/ THALIDOMIDEPhthalimidesSuper Class: Organoheterocyclic compoundsClass: Isoindoles & DerivativesSub Class: IsoindolinesNon-barbiturate hypnotic-used for treatment of immunological and inflammatory disorders. Potential tumor suppressive properties.Used to make Thalomid and Thalidomide Celgene.Teratogenic side effects.Approved, Under Investigation, WithdrawnPYRAZOLINE DERIVATIVESAlkaloids / PyrazolesSuper Class: Organoheterocyclic compoundsClass: AzolesSub Class: PyrazolesAnticancer, antipyretic, antiviral, anticonvulsant, anti-inflammatory, and analgesic agent.Reversible.N/AExperimentalRASAGILINEPropargylamineSuper Class: BenzenoidsClass: IndanesSub Class: UnavailableMAOB Inhibitor used to treat Parkinson’s disease. Treatments also available for Alzheimer’s disease, ALS and MSA.Irreversible. Used to make aporasagiline, Rasagiline Mesylate, and Azilect.Irregular pulse, agitation, feeling of drowsiness or dizziness, coma, hyperactivity, convulsions, migraines, irritability.ApprovedSAFINAMIDEAlpha amino acid aminesSuper Class: Organic Acids & DerivativesClass: Carboxylic Acid & DerivativesSub Class: Analogues, Amino acids & PeptidesAmino acid amide used to treat Parkinson’s disease.Used to make Xadago.Insomnia, involuntary movement, high blood pressure, hallucinations, nausea, vomiting.Approved, Under InvestigationSELEGILINE (DEPRENYL)Amphetamines & DerivativesSuper Class: BenzenoidsClass: Benzene & Substitute DerivativesSub Class: PhenylethylaminesMAOB inhibitor used towards making treatments for Parkinson’s Disease.Selective and irreversible. Prolongs dopamine. Used to make Atapryl, Carbex, and Eldepryl.Heartburn, nausea, dry-mouth, insomnia, dizziness. Confusion, nightmares, hallucinations, headaches.Approved, Under Investigation, Vet-Approved

3.7. Monoamine Reuptake Inhibitors: Mechanisms of Inhibitor Action

Although synthetic drugs employ a variety of different mechanistic approaches for the ways in which they exert their effects, the pharmacological agents discussed herein primarily alter-e.g., enhance (by means of activation), disrupt (through methods of interference), or inhibit (via inactivation)-synaptic transmission (i.e., neurotransmission) by targeting either neurotransmitter-receptor interactions or neurotransmitter-transporter interactions on pre- and postsynaptic cells. Monoamine reuptake inhibitors (MARIs), in particular, constitute a category of inhibitory agents which act on monoamine transporters directly, and functionally prevent the reuptake of monoamine neurotransmitters by blocking access of transporters to their respective neurotransmitters [23]. In other words, MARIs block the transporters for monoamine neurotransmitters. This action further prevents the transport of neurotransmitters from pre- to postsynaptic cells. Examples of monoamine transporters include serotonin transporters (SERT), noradrenaline/norepinephrine transporters (NET), and the selective dopamine transporter (DAT). Upon the inhibition of such transporters, an increase in the amount of neurotransmitter able to accumulate in the synapse is observed [24]. As more neurotransmitters accumulate, they are redistributed further along the synapse before being metabolized [24]. Moreover, upon the binding of neurotransmitters to transporters such as SERT or DAT, an event known as colocalization typically occurs, generally with PICK1 (Protein Interacting with C Kinase-1; a protein encoded by the PICK1 gene in humans) via a PDZ domain [24]. The PDZ domain serves as an anchoring protein bound to the membrane which colocalizes the SERT or DAT neurotransmitter-transporter complex to the metabotropic glutamate receptor (mGluR7a), which then mediates endocytosis on the postsynaptic cell [25, 26]. However, the binding of an inhibitor to the transporters SERT or DAT functionally prevents this mechanistic sequence of events.

There are selective and nonselective MARIs, where the former selectively binds a single, specific type of transporter, and the latter binds two or more different kinds of monoamine transporters. Examples of pharmaceutical MARIs include Tricyclic Antidepressants (TCAs), Tetracyclic Antidepressants, Selective Serotonin Reuptake Inhibitors (SSRIs), Noradrenaline Reuptake Inhibitors (NARIs), Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs), Noradrenaline-Dopamine Reuptake Inhibitors (NDRIs), and Nonselective MARIs [27, 28].

3.8. MAOIs: Mechanisms of Inhibitor Action-Nonselective and Selective Inhibition

MAOIs act on both mitochondrial-bound MAO isozymes adjacently located to receptor sites for neurotransmitters in postsynaptic cells. While MAOs function in the catabolism of ingested monoamines, they are also responsible for the inactivation of monoamine neurotransmitters through a process of deamination in which the amine group of an incoming monoamine neurotransmitter is oxidized by an MAO enzyme.

MAOIs, however, serve to inhibit the actions of MAOs which, in turn, prevent the process of deamination. As a result, receptors become saturated with neurotransmitters. These actions enable neurotransmitters to remain in the synapse for longer durations, thereby maintaining psychological homeostasis. The development and use of MAOIs marks an important feat in pharmacology as the first pharmacological treatment to combat symptoms of depression. MAOIs provide a means to correct an imbalance of neurotransmitters (due to insufficiency, deficiency, or excessive levels) in response to MAO activity, and synthetic MAOIs have been manufactured as antidepressants for decades. As with MARIs, MAO enzyme inhibitors can also be selective or nonselective. Nonselective MAOIs are irreversible, while selective MAOIs can be either reversible or irreversible. Examples of nonselective MAOIs include Phenelzine, and Tranylcypromine (Table 1), although these are traditionally used as MAOA inhibitors rather than MAOB inhibitors. These nonselective MAOIs interact with the flavin N5 atom in the active site of each MAO enzyme.

Previous structural studies of inhibitor-MAOB complexes provide electron density maps which show that various clinically used inhibitors of MAOB may also interact with the flavin N5 atom of the FAD cofactor [27]. The active site of MAOB consists of a hydrophobic substrate cavity interconnected to an entrance cavity in the active site by Ile199 which acts like a ‘hinge’ connecting these two sites. The recognition site for the substrate amino group(s) is an aromatic cage partly formed by Tyr398 and Tyr435 [27].

Moreover, of the selective inhibitors, there are also two types of MAOIs: reversible and irreversible. Selective, reversible MAOIs for the MAOA isozyme include MoclobemideBlue; and examples of irreversible MAOIs for the MAOB isoenzyme are Rasagiline and Selegiline (Deprenyl) (Table 1) [20, 21, 27]. Selective, irreversible drugs which act on MAOB are typically used for the treatment of neurological disorders (e.g., Parkinson’s disease) as they target cells in the PNS, thereby prolonging the presence of dopamine in the synapse [28]. Drugs of this type therefore serve as a reliable means to combat symptoms brought on by the progression of the disease. In contrast, drugs which inhibit MAOA are more commonly used to treat psychological disorders, such as depression and anxiety, by targeting neuronal cells in the CNS [29].

3.9. Adverse Effects of Conventional MAOIs: Clinical Considerations and Toxicity

Selective MAOIs are currently used more frequently than nonselective MAOIs as they pose less risk for the occurrence of adverse side effects. Nonselective MAOIs display a broader systemic effect, while selective MAOIs exhibit more specificity. However, MAOIs have a higher degree of toxicity compared to other forms of antidepressants, as apparent by the increased risk of adverse side effects for which these drugs impose. The more pronounced side effects of MAOIs generally include dry mouth, nausea, diarrhea, constipation, headache, drowsiness, insomnia, and dizziness (or lightheadedness) from possible postural hypotension [28].

In addition to the adverse reactions caused by the drugs themselves, MAOIs tend to be less favorable compared to other forms of antidepressants, as they are often accompanied by many hazardous food-drug and drug-drug interactions. The most common side effect of a food-drug interaction with MAOIs is the inhibition of tyramine breakdown. This results in a buildup of tyramine, increasing tyramine toxicity, and may ultimately cause increased hypertension and possible hypertensive crisis. Tyramine is derived from the amino acid tyrosine, which helps regulate blood pressure. Tyramine is often found in foods such as aged cheese, cured/smoked meats, fish, beer, red wines, certain beans, pickles, olives, some soy products, teriyaki sauce, and is sometimes found in chocolate, caffeine, yogurt, avocados, and raspberries. Because of this, the consumption of these food types with the use of MAOIs is usually prohibited. Consequently, dietary limitations as extensive and restrictive as these typically result in lower patient compliance [29].

Concerning drug-drug interactions, the action of MAOIs in conjunction with any other drug affecting the metabolism, release, synthesis, or reuptake of monoamine neurotransmitters, can cause an increase in MAOI toxicity by increasing the risk of potentially dangerous side effects. Examples of drugs that pose such risks include Dextromethorphan, SSRIs, and serotonergic agents [29]. Furthermore, because pharmacological agents are metabolized more effectively over time, an increase in metabolism (or tolerance) generally requires a subsequent-and perhaps continuous-increase in dosage to compensate for diminishing effects, thereby maintaining the overall efficacy of the drug. Although a constant increase in dosage may seem like an easy solution in a therapeutic context, indeed such increases actually pose great risk to patients in a clinical setting. For example, in addition to the many possible harmful interactions as well the various negative side effects associated with MAOIs, the need for frequent dosage increases can also introduce an array of complications and other concerning factors which contribute to the overall toxicity of the drug and ultimately affect one's overall health. These risks can include drug dependency as well as overdose, but when taken in considerable amounts over particularly extended durations, may also pose significant threat to physiological systems and individual organs such as the heart, liver, and kidneys, and may result in chronic disease-possibly accompanied by organ failure-all of which can be a contributor to premature death [29-34].

With respect to potentially life-threatening adverse reactions, there is also the possibility, although rather uncommon and somewhat rare, of developing various potentially fatal conditions, such as Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS), which arise in response to excessive and prolonged use of, for example, antidepressants or antipsychotics-used in the treatment of depression, manic depressive disorder, and bipolar disorder, among many other debilitating neurological disorders. Such conditions arise unexpectedly and can take the form of an unintentional drug-induced overdose, regardless of the appropriate and responsible use of the prescription medication.

3.10. The Need for Additional (natural) Inhibitors of MAO

Although MAOIs are continuously reliable for their intended purpose, particularly for atypical symptoms associated with certain disorders, the popularity and use of MAOIs has waned for decades. As previously mentioned, the most common reasons for not prescribing MAOIs include drug-drug interactions, drug-food interactions, negative adverse effects, preference for alternative treatment, and dietary restrictions [29-34]. Therefore, substantial research efforts have been set forth to investigate the potential medicinal benefits of natural products-a widely explored topic recently-as natural products may demonstrate comparable impact and effectiveness as MAOIs on neurotransmitters and surrounding mechanisms, but without the increased probability of harsh adverse effects. A natural inhibitor of MAO can have the same impact as a synthetic pharmaceutical agent, yet with minimal side effects and far fewer, if any, restrictions due to potentially harmful interactions. Thus, a significant amount of research has been conducted with efforts currently underway for the purpose of identifying additional natural methods to treat psychological disorders and neurodegenerative diseases.

3.11. The Proposed Benefits of Catechins as Natural Inhibitors of MAO

For the above reasons, catechins could serve as potentially powerful, minimal-to- no-risk alternatives to MAOIs. For instance, the aforementioned meta-analysis of 11 studies involving over 22 thousand participants concluded that an inverse, linear relationship exists between routine tea consumption and the risk of depression [16, 35]. However, these studies account for only a small fraction of the many available studies which demonstrate a pharmacological potential for the bioactive constituents found in various natural products. Catechins, for example, have been shown to display similar actions as a multitude of synthetic drugs used in the treatment of certain neurological disorders. Likewise, catechins have shown to exert the same inhibitory actions as MAOIs, and can be a safer alternative to the medications which hinder the lives of many individuals Each year, studies continue to confirm the effectiveness of green tea catechins as natural, yet potent substitutes for certain pharmaceutical drugs that are frequently accompanied by hazardous drug-drug and drug-food interactions, in addition to unwanted side effects [36]. These findings are in further support of the notion that green tea may serve as a safer alternative to MAOIs.

4. HIGH THROUGHPUT SCREENING STRATEGIES

4.1. Non-Fluorescence-based Assays

There are many different types of assays that use various techniques to monitor and measure the progress of the MAOA and MAOB reactions. As shown in Fig. (2), an imine is generated from the oxidative deamination of monoamines, and the following hydration produces an aldehyde and hydrogen peroxide. This provides several efficient approaches to monitor MAO activity using various detection methods: either by tracking the absence of substrate or by probing the presence of specific products in the reaction. One of the original approaches to high throughput assays utilized radiolabeling (14C labeling) of selective substrates Serotonin (for MAOA) and Benzylamine (for MAOB) [37]. Another approach (developed by Promega) called the MAO-GLOTM Assay makes use of a bioluminescent-coupled assay. This is particularly advantageous in that it is not susceptible to interference, as fluorescent assays may be due to endogenous fluorescent molecules in cell lysate and tissue homogenates. Promega developed an assay that couples the activity of MAO to the production of light by luciferase. Briefly, the non-selective substrate aminopropyl ether (analog of luciferin methyl ester) is cleaved to generate light.

This occurs in a two-step process. Once the MAO enzyme oxidizes the amine of the substrate to an imine––which is quickly hydrolyzed to an aldehyde––the specific aldehyde product in the MAO-GLOTM assay undergoes a spontaneous β- elimination reaction to form luciferin methyl ester. In the second step of the assay, the luciferin detection reagent inactivates the MAO enzyme, and the esterase and luciferase enzymes in the reagent hydrolyze the methyl ester, thus oxidizing the luciferin to produce light. The reactions are rapid and the amount of light produced in the second step is proportional to the activity of MAO in the first part of the reaction [38].

4.2. Fluorescence-based Assays: The Role of the Fluorescent Probe

A fluorescent probe is introduced to the reaction where it reacts with either a reactant, product, or byproduct of the initial reaction and fluoresces. These probes are generally designed to exhibit a high-degree of specificity for a target molecule (the stimulus). Upon interaction with the target, fluorescence emission (the signal) is generated and released by a fluorophore, thereby becoming measurable. Because of this, fluorescent assays serve as a useful method to detect and quantify the presence of specific components within a reaction. Redox-sensitive probes are one of several examples in which a probe can be sensitized to different stimuli, but react and respond via the same process of fluorescence. These assays thus serve as effective methods to not only measure the presence of a known reactant or product within a reaction, but also to study certain aspects of a reaction itself, with the ability to monitor specific enzymatic activity of a given reaction.

Fluorescent probes have therefore played a crucial role in the study of biological reactions and have greatly expanded the ways in which reactions can be quantitatively assessed-through the use of kinetic studies. Furthermore, the convenience of using fluorescence as a means to study kinetics has largely enabled the ease of drug design in addition to the study of natural products, but has also proven quite useful in studying the particular pharmacokinetics of proposed medications within the scope of pharmacology. This is largely due to the ability to not only measure enzymatic activity, but to also examine specific enzymatic activity in response to pharmacological agents which modulate this activity, such as an inhibitor.

As indicated by Youdim and a multitude of fellow colleagues who have since referenced him [39-43], the use of fluorescence-based methods to probe for the detection of MAO activity is most beneficial. Fluorescent assays now include (but are by no means limited to) bioimaging with either near-infrared or two-photon techniques [19], as well a plethora of assays performed in combination with ELISA methods, fluorescent probe kits (example: Amplex Red kit), and a multitude of synthetic MAOA and MAOB substrates that cleave to fluorescent molecules such as kynuramine assays which utilize kynuramine to form 4-hydroxyquinoline (a fluorescent product) [41].

4.3. Fluorescence-based Assays: Inhibition Assays

Fluorescent assays provide a reliable means to assess certain components of a reaction, such as the effectiveness of an inhibitor and its effect on enzymatic activity. The ability of reaction-sensitive probes to sense changes in enzymatic activity (assessed via concentration levels) as a result of pharmacological manipulation has proven most valuable when investigating the pharmacokinetics of potential drug inhibitors.