Commentary

Monoamine oxidase, brain ageing and degenerative diseases

Parkinson’s disease is the most prevalent chronic neurodegenerative disease. Neurological conditions for PD were influenced by a variety of epigenetic factors and SNPs in some of the coexisting genes that were expressed. This article focused on nutrigenomics of PD and the prospective highlighting of how these genes are regulated in terms of nutritive factors and the genetic basis of PD risk, onset, and progression. Multigenetic associations of the following genetic alterations in the genes of SNCA, LRRK2, UCHL1, PARK2, PINK1, DJ-1, and ATP13A2 have been reported with the familial and de novo genetic origins of PD. Over the past two decades, significant attempts have been made to understand the biological mechanisms that are potential causes for this disease, as well as to identify therapeutic substances for the prevention and management of PD. Nutrigenomics has sparked considerable interest due to its nutritional, safe, and therapeutic effects on a variety of chronic diseases. In this study, we summarise some of the nutritive supplements that have an impact on PD.

This tutorial review provides a summary and discussion of recent advances in chemosensors that fluorescently respond to the enzyme systems involved in Phase I xenobiotic metabolism, including in vitro and in vivo imaging applications on biomedical models. This review includes Phase I enzyme systems such as cytochrome P450, monoamine oxidase, nitroreductases, aldehyde dehydrogenases, esterases, amidases, glycosidases. The enzymatic activities belong to oxidation, reduction, and hydrolysis reactions and show metabolic ability to diverse chemicals. These activities may be closely related to alterations in various pathophysiological processes in the human body, and their roles in drug metabolism are well known. Therefore, the enzyme-directed imaging techniques toward both in vitro and in vivo living systems have emerged as promising diagnostic modalities. In particular, fluorescent chemosensors activated through xenobiotic metabolism would serve as useful tools to study live biosystems, such as in situ monitoring and high-throughput drug screening, owing to their spatiotemporal responses with high sensitivity, selectivity, and rapidity. Current advances in detection strategies and validated in vitro and in vivo biomedical models for xenobiotic metabolism are highlighted. A brief discussion of the current and future challenges follows.

Oxidases and peroxidases are two subclasses of oxidoreductases. The abnormal expression of oxidases (such as tyrosinase, cytochrome P450 oxidases, and monoamine oxidases) and peroxidases (such as glutathione peroxidase, myeloperoxidase, and eosinophil peroxidase) is relative with some diseases. Therefore, the analysis of oxidases and peroxidases is great important for disease diagnosis and treatment. Fluorescent probes present simple protocol, high sensitivity and good stability in sensing field. Molecule fluorescent probes are constructed with chemical groups that tunes their fluorescence emission in response to binding events, chemical reactions, and the surrounding environment. A fluorescent probe is an efficient tool for visualizing the activity of enzymes in living organisms on the basis of its high specificity, sensitivity, and noninvasiveness characteristics. In this review, we focus on the sensing of oxidases and peroxidases by molecule fluorescent probes, and hope to bring new insight to wide researchers about oxidases and peroxidases in biological samples.

Monoamine oxidases (MAO-A and MAO-B) are mammalian flavoenzyme, which catalyze the oxidative deamination of several neurotransmitters like norepinephrine, dopamine, tyramine, serotonin, and some other amines. The oxidative deamination produces several harmful side products like ammonia, peroxides, and aldehydes during the biochemical reaction. The concentration of biochemical neurotransmitter alteration in the brain by MAO is directly related with several neurological disorders like Alzheimer’s disease and Parkinson’s disease (PD). Activated MAO also contributes to the amyloid beta (Aβ) aggregation by two successive cleft β-secretase and γ-secretase of amyloid precursor protein (APP). Additionally, activated MAO is also involved in aggregation of neurofibrillary tangles and cognitive destruction through the cholinergic neuronal damage and disorder of the cholinergic system. MAO inhibition has general anti-Alzheimer’s disease effect as a consequence of oxidative stress reduction prompted by MAO enzymes. In this review, we outlined and addressed recent understanding on MAO enzymes such as their structure, physiological function, catalytic mechanism, and possible therapeutic goals in AD. In addition, it also highlights the current development and discovery of potential MAO inhibitors (MAOIs) from various chemical scaffolds.

In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC₅₀ values of 0.012 μM and 0.011 μM and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound.

The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results of biological studies revealed that the majority of compounds exhibited potent to moderately potent activity and among them, 12 displayed potency comparable to that of the imipramine with %DID of 37.95 and 44.84 in the FST and TST, respectively. At the same time, imipramine showed %DID of 43.62 and 50.64 in the FST and TST, correspondingly. In the MAO-A inhibition assay, 12 showed an IC₅₀ of 18.27 μmol, whereas the reference drug moclobemide displayed an IC₅₀ of 13.1 μmol. The SAR study disclosed that the presence of bromo atom at the phenyl/furanyl or thienyl moiety in the oxindole derivatives was critical for the antidepressant activity.