Current Topics in Medicinal Chemistry - Volume 18, Issue 21, 2018

Background: Monoamine oxidase inhibitors are potential drug candidates within therapeutics of different neuropsychological and neurodegenerative disorders including anxiety, depression and Parkinson’s disease. Objective: We investigated the MAO inhibitory effects of the umbelliferone based derivatives for the treatment of neurological disorders. The potential antioxidant effects of the derivatives were evaluated by DPPH and H2O2 scavenging methods. Method: A series of different umbelliferone derivatives was designed and synthesized, and the derivatives were screened for hMAO-A and hMAO-B inhibition. Moreover, the mechanistic insight for enzyme- compound infractions was achieved by docking simulation. The antioxidant potential was dually assessed by two spectrophotometric titrations methods. Results: Compound 5 with bromo 5-bromo-isatin exhibited a remarkable hMAO-A inhibitory potential (7.473±0.035 μM and the selectivity index of 0.14) revealing the impact of hybrid coumarin and 5- bromo-2-oxoindolin-3-yl ring with hydrazine linker on the hMAO-A active site. Compound 13 exhibited significant hMAO-B inhibition with an IC50 value of 10.32±0.044μM with an exceptional selectivity index of 8.55. Incorporation of 2-hydroxy-2-phenylacetate moiety on 2-oxo-2H-chromen ring led the important binding infractions within the hMAO active site. Conclusion: Our findings revealed a good correlation between experimental MAO inhibition and docking score by computational studies. Notably, the compounds with remarkable MAO inhibitory potential were also observed as potential antioxidants.

Background: Most neurodegenerative and other brain disorders, especially Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and autism spectrum disorder (ASD) continue to elude objective biomarkers and effective treatments. Increasing evidence indicates that such diseases involve focal inflammation of the brain. Objective: To review the role of cytokine-neuropeptide interactions in the pathogenesis of inflammation of the brain and the beneficial role of natural flavonoids. Methods: Medline search was conducted (2000-2017) for articles using the terms allergy, amygdala, atopy, autism, brain, chemokines, cytokines, hypothalamus, immunity, inflammation, mast cells, microglia, neurotensin, peptides, substance P, and TNF. Results: Neuropeptides and cytokine stimulation of mast cells and microglia can result in focal inflammation in the hypothalamus and amygdala, thus explaining most of the symptoms at least in ME/CFS and ASD. Some of the triggers may be corticotropin-releasing hormone (CRH), neurotensin (NT), and substance P (SP), which have synergistic action on IL-33. The natural flavonoids luteolin and tetramethoxyluteolin inhibit these processes and have neuroprotective actions. Tetramethoxyluteolin is also more metabolically stable and has greater oral absorption. Conclusion: Inhibition of inflammatory processes unique to the brain with intranasal formulations of tetramethoxyluteolin could provide new possibilities for the understanding and treatment of neurodegenerative diseases.

New brain technologies including neuroimaging studies are powerful means for providing new insights into clinical and cognitive neuroscience. Bipolar disorder is a severe chronic phasic mental disease characterized by various cognitive dysfunctions. Working memory is one prominent domain of cognitive impairment in bipolar disorder. Disruptions in working memory are observed even in euthymic bipolar patients which makes it a potential endophenotypic marker for the disorder. Finding such markers may help in providing firm neurobiological basis for psychiatric nosologies and symptomatic presentations. This review aims to summarize some of the important aspects of findings from functional magnetic resonance imaging studies on the activation of brain structures in relation to working memory paradigms.

MicroRNAs are endogenous small non-coding RNAs that regulate gene expression by means of partial complementarity to microRNA binding sites at their target genes. These molecules have emerged as key regulators of almost every biological process including accurate control of neuronal gene expression. The authors discuss the current state of microRNA research, including studies of psychiatric disorders (schizophrenia, autism spectrum disorder and affective disorders). Stress has also been shown to have a critical role in the development of psychiatric disorders, at least partially, through mechanisms related to neural plasticity. Synaptic connections in the brain undergo experience-dependent functional or morphological changes through complex pathways that are not yet fully understood, but for which microRNAs might have a critical role. The focus is on the role that microRNAs play in the development of psychiatric disorders and their potential to serve as biomarkers of disease as well as targets for pharmacological treatment.

Magnetic Resonance Spectroscopy (MRS) has become a valuable tool for investigating the biochemical bases of both normal processes in the healthy brain and elucidating the pathophysiology of neuropsychiatric disorders. As a rapidly advancing field, new developments in pulse sequence design have seen new possibilities arise in terms of what can be done with in vivo spectroscopy. While the applications of MRS are numerous, this review has been confined to the use of single voxel spectroscopy in the assessment of five key metabolites and their roles in schizophrenia: N-acetylaspartate (NAA), glutamate (Glu) and glutamine (Gln), γ-aminobutyric acid (GABA) and glutathione (GSH). This article will briefly cover the roles they play in schizophrenia, review current methods being used in their assessment and highlight new approaches that may potentially overcome some of the limitations current methods pose.