A comprehensive review of monoamine oxidase inhibitors as Anti-Alzheimer’s disease agents: A review

Manzoor, Shoaib; Hoda, Nasimul

doi:10.1016/j.ejmech.2020.112787

Cited by 155 publications

(90 citation statements)

References 262 publications

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“…MAO inhibitors, theoretically useful in increasing extracellular NE levels, have shown mixed results in clinical trials. 225,226 Selegiline, a MAO-B inhibitor with proven neuroprotective benefits in Parkinson's, has exhibited very few significant treatment effects, though the studies have been small and a subsequent meta-analysis has revealed a possible benefit on memory function. 226 MAO inhibitors also come with a range of undesirable side-effects and non-selectively alter multiple other neurotransmitter systems.…”

Section: Targeted Noradrenergic Therapiesmentioning

confidence: 99%

“…227,228 This limits the maximum therapeutic efficacy, but, given the promise of norepinephrine in improving Aβ clearance and limiting cognitive decline, a tremendous amount of research is now being done to formulate better MAO inhibitors and design more rigorous clinical trials. 225 It is likely, though, that these new efforts will continue to be plagued by the lack of MAO inhibitor specificity for the systems most strongly implicated in AD dysfunction, especially if NE misbalances between different regions of the brain prove clinically significant. This work does leave open, however, the idea that region-specific NE stimulation, possibly through a combination of approaches to be discussed later in this review, may prove more effective.…”

Section: Targeted Noradrenergic Therapiesmentioning

confidence: 99%

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Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies

Slater

Wang

2021

Clinical & Translational Med

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In this review, we provide a brief overview of several of the most thoroughly researched pathogenic hypotheses for Alzheimer's disease (AD) and assess their clinical impact to-date. We focus specifically on recent research into the role of the locus coeruleus norepinephrine (LC-NE) system, in both AD pathogenesis and symptom exacerbation, as well as the potential to use advanced neural stimulation techniques as a novel therapeutic option in the earliest stages of neuropathology.

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Section: Targeted Noradrenergic Therapiesmentioning

confidence: 99%

Section: Targeted Noradrenergic Therapiesmentioning

confidence: 99%

Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies

Slater

Wang

2021

Clinical & Translational Med

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“…A well-known aspect of monoamine oxidases (MAOs) is their role in metabolizing various types of biogenic amines, which can impart a crucial role in modulating the central nervous system (CNS) neurotransmitter functions [1]. The malfunctioning of these neurotransmitters by the oxidative deamination process by MAOs leads to a variety of neurodegenerative disorders (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) [2][3][4]. Among the MAO family, selective inhibitors of MAO-A can be employed for managing various depressive states, and at the same time, inhibitors of MAO-B can be widely used for the adjuvant therapy for NDDs [5,6] Subsequently, MAOs have been extensively researched, with over 23,000 publications dealing with their properties, enzymology, functions, and specific inhibitors from various classes, according to the PubMed database [7].…”

Section: Introductionmentioning

confidence: 99%

Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders

Vishal

Khames

et al. 2021

Pharmaceutics

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Six halogenated trimethoxy chalcone derivatives (CH1–CH6) were synthesized and spectrally characterized. The compounds were further evaluated for their inhibitory potential against monoamine oxidases (MAOs) and β-secretase (BACE-1). Six compounds inhibited MAO-B more effectively than MAO-A, and the 2′,3′,4′-methoxy moiety in CH4–CH6 was more effective for MAO-B inhibition than the 2′,4′,6′-methoxy moiety in CH1–CH3. Compound CH5 most potently inhibited MAO-B, with an IC50 value of 0.46 µM, followed by CH4 (IC50 = 0.84 µM). In 2′,3′,4′-methoxy derivatives (CH4-CH6), the order of inhibition was –Br in CH5 > -Cl in CH4 > -F in CH6 at the para-position in ring B of chalcone. CH4 and CH5 were selective for MAO-B, with selectivity index (SI) values of 15.1 and 31.3, respectively, over MAO-A. CH4 and CH5 moderately inhibited BACE-1 with IC50 values of 13.6 and 19.8 µM, respectively. When CH4 and CH5 were assessed for their cell viability studies on the normal African Green Monkey kidney cell line (VERO) using MTT assays, it was noted that both compounds were found to be safe, and only a slightly toxic effect was observed in concentrations above 200 µg/mL. CH4 and CH5 decreased reactive oxygen species (ROS) levels of VERO cells treated with H2O2, indicating both compounds retained protective effects on the cells by antioxidant activities. All compounds showed high blood brain barrier permeabilities analyzed by a parallel artificial membrane permeability assay (PAMPA). Molecular docking and ADME prediction of the lead compounds provided more insights into the rationale behind the binding and the CNS drug likeness. From non-test mutagenicity and cardiotoxicity studies, CH4 and CH5 were non-mutagenic and non-/weak-cardiotoxic. These results suggest that CH4 and CH5 could be considered candidates for the cure of neurological dysfunctions.

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“…Thus, the inhibitors of MAOs are considered as prophylactic and therapeutic agents for NDDs such as PD, Alzheimer's disease (AD), schizophrenia, anxiety, and depression. These conditions are characterized by elevated levels and activities of MAOs, which lead to decreased levels of neurotransmitters, increased oxidative stress resulting from the oxidoreductase activity of the enzymes, and the subsequent degeneration of neurons [3,[5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M4 Receptor Antagonism by Tanshinone I

et al. 2021

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Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson’s disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dopaminergic neurotoxins and the inhibition of MAO-A. Since MAO-B inhibition is considered an effective therapeutic strategy for PD, we tested the inhibitory activities of three abundant tanshinone congeners against recombinant human MAO (hMAO) isoenzymes through in vitro experiments. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone, with an IC50 less than 10 µM. They also suppressed hMAO-B activity, with an IC50 below 25 µM. Although tanshinones are known to inhibit hMAO-A, their enzyme inhibition mechanism and binding sites have yet to be investigated. Enzyme kinetics and molecular docking studies have revealed the mode of inhibition and interactions of tanshinones during enzyme inhibition. Proteochemometric modeling predicted mAChRs as possible pharmacological targets of 1, and in vitro functional assays confirmed the selective M4 antagonist nature of 1 (56.1% ± 2.40% inhibition of control agonist response at 100 µM). These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD.

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A comprehensive review of monoamine oxidase inhibitors as Anti-Alzheimer’s disease agents: A review

Cited by 155 publications

References 262 publications

Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies

Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies

Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders

Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M4 Receptor Antagonism by Tanshinone I

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