Repurposing steroidogenesis inhibitors for the therapy of neuropsychiatric disorders: Promises and caveats.

Steroids exert a profound influence on behavioral reactivity, by modulating the functions of most neurotransmitters and shaping the impact of stress and sex-related variables on neural processes. This background - as well as the observation that most neuroactive steroids (including sex hormones, glucocorticoids and neurosteroids) are synthetized and metabolized by overlapping enzymatic machineries - points to steroidogenic pathways as a powerful source of targets for neuropsychiatric disorders. Inhibitors of steroidogenic enzymes have been developed and approved for a broad range of genitourinary and endocrine dysfunctions, opening to new opportunities to repurpose these drugs for the treatment of mental problems. In line with this idea, preliminary clinical and preclinical results from our group have shown that inhibitors of key steroidogenic enzymes, such as 5α-reductase and 17,20 desmolase-lyase, may have therapeutic efficacy in specific behavioral disorders associated with dopaminergic hyperfunction. While the lack of specificity of these effects raises potential concerns about endocrine adverse events, these initial findings suggest that steroidogenesis modulators with greater brain specificity may hold significant potential for the development of alternative therapies for psychiatric problems. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'.

Telomerase activity and its association with psychological stress, mental disorders, lifestyle factors and interventions: A systematic review.

OBJECTIVE: To summarise and discuss the association between telomerase activity and psychological stress, mental disorders and lifestyle factors. METHOD: A systematic review was carried out to identify prospective or retrospective studies and interventions published up to June 2015 that reported associations between telomerase activity and psychological stress, mental disorders and lifestyle factors. Electronic data bases of PubMed, ProQuest, CINAHL and Google Scholar were searched. RESULTS: Twenty six studies on humans measured telomerase activity in peripheral blood mononuclear cells (PBMCs) or leukocytes and examined its association with psychological stress, mental disorders and lifestyle factors. Of those studies, three reported significantly decreased telomerase activity in individuals under chronic psychological stress. Interestingly, one of the three studies found that acute laboratory psychological stress significantly increased telomerase activity. Nine studies reported mixed results on association between mental disorders and telomerase activity. Of the nine studies, five reported that major depressive disorder (MDD) was associated with significantly increased telomerase activity. In thirteen out of fourteen studies on lifestyle factors, it was reported that physical exercise, diet micronutrient supplementation, mindfulness meditation, Qigong practice or yoga mediation resulted in increase in telomerase activity. In addition, two studies on animal models showed that depression-like behaviour was associated with decreased hippocampus telomerase activity. Five animal studies showed that physical exercise increased telomerase activity by cell-type-specific and genotype-specific manners. CONCLUSION: Although multi-facet results were reported on the association between telomerase activity and psychological stress, mental disorders and lifestyle factors, there were some consistent findings in humans such as (1) decreased telomerase activity in individuals under chronic stress, (2) increased telomerase activity in individuals with MDD, and (3) increased telomerase activity in individuals under lifestyle interventions. Animal studies showed that physical exercise increased telomerase activity in specific cell-types. However, the exact mechanisms for the changes in telomerase activity have not been elucidated. We propose conglomerate models connecting chronic psychological stress, depression, mediation and physical exercise to telomerase activation. Several areas for future research are suggested.

Synthetic and natural inhibitors of phospholipases A2: their importance for understanding and treatment of neurological disorders.

Phospholipases A2 (PLA2) are a diverse group of enzymes that hydrolyze membrane phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is metabolized to eicosanoids (prostaglandins, leukotrienes, thromboxanes), and lysophospholipids are converted to platelet-activating factors. These lipid mediators play critical roles in the initiation, maintenance, and modulation of neuroinflammation and oxidative stress. Neurological disorders including excitotoxicity; traumatic nerve and brain injury; cerebral ischemia; Alzheimer's disease; Parkinson's disease; multiple sclerosis; experimental allergic encephalitis; pain; depression; bipolar disorder; schizophrenia; and autism are characterized by oxidative stress, inflammatory reactions, alterations in phospholipid metabolism, accumulation of lipid peroxides, and increased activities of brain phospholipase A2 isoforms. Several old and new synthetic inhibitors of PLA2, including fatty acid trifluoromethyl ketones; methyl arachidonyl fluorophosphonate; bromoenol lactone; indole-based inhibitors; pyrrolidine-based inhibitors; amide inhibitors, 2-oxoamides; 1,3-disubstituted propan-2-ones and polyfluoroalkyl ketones as well as phytochemical based PLA2 inhibitors including curcumin, Ginkgo biloba and Centella asiatica extracts have been discovered and used for the treatment of neurological disorders in cell culture and animal model systems. The purpose of this review is to summarize information on selective and potent synthetic inhibitors of PLA2 as well as several PLA2 inhibitors from plants, for treatment of oxidative stress and neuroinflammation associated with the pathogenesis of neurological disorders.

The neuroprotective effects of apocynin.

The recognition of health benefits of phytomedicines and herbal supplements lead to an increased interest to understand the cellular and molecular basis of their biological activities. Apocynin (4-hydroxy-3-methoxy-acetophenone) is a constituent of the Himalayan medicinal herb Picrorhiza kurroa which is regarded as an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, a superoxide-producing enzyme. NADPH oxidase appears to be especially important in the modulation of redox-sensitive signaling pathways and also has been implicated in neuronal dysfunction and degeneration, and neuroinflammmation in diseases ranging from stroke, Alzheimer's and Parkinson's diseases to psychiatric disorders. In this review, we aim to give an overview of current literature on the neuroprotective effects of apocynin in the prevention and treatment of neurodegenerative disorders. Particular attention is given to in vivo studies.

5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders.

There is evidence of an association between depression and anxiety and cardio- cerebro-vascular conditions, but the mechanisms of this association are unknown. Here we review a possible role for the 5-lipoxygenase (5-LOX) pathway. 5-LOX is an enzyme that, in association with 5-LOX-activating protein (FLAP), leads to the synthesis of leukotrienes from omega-6 arachidonic acid. Production of active leukotrienes can be reduced by dietary omega-3 fatty acids, which also are beneficial in cardiac and psychiatric (e.g., depression) pathologies. Human 5-LOX and FLAP gene polymorphisms are a risk factor in atherosclerosis and cardio-cerebro-vascular pathologies; an overactive 5-LOX pathway is found in these diseases. Studies with 5-LOX-deficient transgenic mice suggest that 5-LOX activity may contribute to anxiety- and depression-like behaviors. Future research should characterize the role of the 5-LOX pathway in comorbid cardio-cerebro-vascular and psychiatric disorders and in the therapeutic actions of dietary omega-3 fatty acids.