The monoamine oxidase inhibitory activity of essential oils obtained from Eryngium species and their chemical composition

Context Monoamine oxidase (MAO) inhibitors are used in the treatment of depression, anxiety disorders, and the symptomatic treatment of Parkinson's disease. Eryngium, the most representative of the Apiaceae family, is well known for the presence of essential oils (EOs), which have already demonstrated MAO inhibitory potential.

Objective The objective of this study is to evaluate the MAO inhibitory capacity of the EOs obtained from Eryngium floribundum Cham. & Schlecht. (EF), E. eriophorum Cham. & Schlecht. (EE), E. nudicaule Lam. (EN), E. horridum Malme (EH), and E. pandanifolium Cham. & Schlecht. (EP).

Materials and methods EOs were obtained from fresh whole plants by hydrodistillation (3?h). Chemical analyses were performed by GC/MS using apolar and polar columns, with oven temperature from 60 to 300?°C at 3?°C/min. The MAO-A and -B activities were evaluated in vitro by an end-point method using kynuramine as the substrate and mitochondrial suspension or human recombinant enzymes as the enzymatic source. DMSO 2%, clorgyline 10^?7 M, and pargyline 10^?6 M were used as controls.

Results and discussion EFEO, EEEO, ENEO, EHEO, and EPEO GC/MS analysis showed (E)-caryophyllene (4.9–10.8%), germacrene D (0.6–35.1%), bicyclogermacrene (10.4–17.2), spathulenol (0.4–36.0%), and globulol (1.4–18.6%) as main constituents. None of the EOs inhibited MAO-A activity (4 and 40?μg/mL). However, EHEO inhibited MAO-B activity with an IC₅₀ value of 5.65?μg/mL (1–200?μg/mL). Pentadecane (10?μM), its major constituent (53.5%), did not display significant MAO-B inhibition.

Conclusion The study demonstrates the promising application of Eryngium species as a source of potential central nervous system bioactive secondary metabolites, specially related to neurodegenerative disorders.     

Monoamine oxidase A and B inhibitors

This patent update relates to monoamine oxidase inhibitors, covers the patent activity in this field for the last 3 - 5 years and focuses on the most relevant filings. Patents are classified according to the type of MAO inhibition: selective MAO-A and MAO-B inhibitors, and mixed and reversible MAO-A and MAO-B inhibitors.     

Anorexic properties of three monoamine oxidase inhibitors

The anorexic properties of 3 monoamine oxidase (MAO) inhibitors, pargyline, tranylcypramine and nialamide were determined 24 hr after their intra-peritoneal administration. The duration of anorexia occuring after the peripheral administration of the dose of pargyline commonly used in conjunction with 6-hydroxydopamine (6-OHDA) to enhance its dopamine-depleting properties was also determined. Body weight regulation and the control of food and water intake were severely impaired 24 hr after the administration of the three highest doses of pargyline, tranylcypramine and nialamide employed. Impairment in the ability to regulate body weight lasted for as long as 6 days in some animals injected with 50 mg/kg of pargyline. These findings bring to light the problems in interpretation of results from studies which employ MAO inhibitors and 6-OHDA simultaneously to enhance dopamine depleting properties of 6-OHDA.     

Effects of three monoamine oxidase inhibitors on ethanol preference in mice

These experiments investigated the effects of pargyline, N-[2-(o-Chlorophenoxy)-ethyl]-cyclopropylamine (Lilly 51641), and nialamide on voluntary ethanol consumption of C57BL/6J mice. Both pargyline and Lilly 51641 reduced ethanol preference; in contrast, nialamide did not affect preference, despite the fact that it inhibited MAO activity by more than 90%. A subsequent experiment determined that both pargyline and Lilly 51641 produced substantially greater elevations in acetaldehyde levels than did nialamide. It is suggested that increased acetaldehyde is the mechanism responsible for the reduction in ethanol preference observed with pargyline and Lilly 51641.     

The effect of monoamine oxidase A and B inhibitors on rat serum prolactin

Serum prolactin levels were assayed in rats treated with specific inhibitors of monoamine oxidase (MAO) A or B. Monoamine oxidase A was inhibited by MD780515, clorgyline and Lilly 51641, and MAO B by pargyline and deprenyl (all at 10 mg/kg, p.o.). Serum prolactin levels were significantly reduced 1 hour after treatment with MAO A inhibitors, but were unaltered by MAO B inhibitors. The time-course of the reduction in serum prolactin did not correspond to that of MAO A inhibition. When rats were treated with clorgyline, serum prolactin returned to control values by 6 hr after treatment, whereas MAO A was inhibited by 92–94% over the whole period. At a time when MAO A inhibitors produced no change in serum prolactin (5 hr after treatment) they abolished the rise in serum prolactin induced by reserpine (5 mg/kg, i.p.), indicating a continuing absence of MAO A activity in the neurones regulating prolactin release. Monoamine oxidase B inhibitors did not alter the effect of reserpine on serum prolactin. Possible reasons for the rapid recovery of serum prolactin levels are discussed.     

Synthesis and biological evaluation of tacrine-thiadiazolidinone hybrids as dual acetylcholinesterase inhibitors

The synthesis of tacrine-thiadiazolidinone hybrids is described. These compounds are designed as dual acetylcholinesterase inhibitors binding simultaneously to the peripheral and catalytic sites of the enzyme. All tested compounds exhibit significant AChE inhibitory activity. Competition assays using propidium as reference of selective ligand for the peripheral anionic site on acetylcholinesterase indicates the influence of the designed compounds over the peripheral site. They can be considered as new leads in the optimization of Alzheimer's disease modifying agents.     

Clinical pharmacology = disease progression + drug action

Clinical pharmacology is concerned with understanding how to use medicines to treat disease. Pharmacokinetics and pharmacodynamics have provided powerful methodologies for describing the time course of concentration and effect in individuals and in populations. This population approach may also be applied to describing the progression of disease and the action of drugs to change disease progress. Quantitative models for symptomatic and disease-modifying effects of drugs are valuable not only for describing drugs and diseases but also for identifying criteria to distinguish between types of drug actions, with implications for regulatory decisions and long-term patient care.     

Effects of zinc ion on type A monoamine oxidase in monkey brain mitochondria

The effects of ZnSO(4) on types A and B monoamine oxidase (MAO) isozymes in monkey brain mitochondria were investigated, in vitro. Type A MAO activity in monkey brain decreased to about 50% with 1 microM ZnSO(4) using serotonin as a substrate, and this inhibition was proportional to the concentration of ZnSO(4). ZnSO(4) had no effect, however, on type B MAO activity in monkey brain using beta-phenylethylamine as a substrate. The inhibition by ZnSO(4) of type A MAO activity was competitive and reversible. ZnSO(4) did not inhibit either type A or type B MAO activity in rat brain mitochondria. Almost similar results were also obtained when ZnCl(2) was used, in vitro. These results indicate that the inhibiting action of zinc ion differs depending on animal species and organ. Type A MAO in monkey brain mitochondria was highly sensitive to zinc ion, while type B activity was less sensitive.     

Synthesis and biological evaluation of enantiomerically pure pyrrolyl-oxazolidinones as a new class of potent and selective monoamine oxidase type A inhibitors

Due to the key role played by monoamine oxidases (MAOs) in the metabolism of neurotransmitters, MAO inhibitors (MAOIs) represent an useful tool for the treatment of several neurological diseases. Among selective MAOIs, MAO-A inhibitors (e.g. clorgyline) are used as antidepressant and antianxiety drugs and are claimed to protect neuronal cells against apoptosis, and selective MAO-B inhibitors (e.g. L-deprenyl) can be used in the treatment of Parkinson's disease either alone or in combination with L-DOPA. However, they engender covalent bonds with the active site of the enzyme and induce irreversible inhibition; moreover, they tend to lose their initial selectivity at high dosages or with repeated administrations. Phenyloxazolidinones belong to third-generation-MAOIs, characterized by a selective and reversible inhibition of the enzyme. Among these molecules, the most representative are toloxatone and befloxatone, two selective and reversible MAO-A inhibitors used in therapy as antidepressant drugs. Going on our searches on CNS potentially active compounds containing a pyrrole moiety we prepared 3-(1H-pyrrol-1-yl)-2-oxazolidinones (1) and isomeric 3-(1H-pyrrol-2-and -3-yl)-2-oxazolidinones (2 and 3) as anti-MAO agents. Such derivatives resulted selective and reversible MAO-A inhibitors. The most potent compound is (R)-5-methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone (1b), endowed with very high potency (K(iMAO-A) = 4.9 nM) and A-selectivity (A-selectivity = 10,200, about 116-fold greater than that of befloxatone).     

Antidepressants in states of cognitive dysfunction

Several approaches are described for the design of pharmacologic strategies for the manipulation of cognition. By a variety of criteria, it is concluded that antidepressants deserve a trial in some patients with cognitive dysfunction. Depression is an illness with prominent cognitive dysfunction that shares, to some extent, cognitive and biochemical impairments similar to those observed in cognitive dysfunction of organic etiology. Antidepressants appear to produce their beneficial effect on cognition in depression by inducing slow adaptive changes in catecholamine and indoleamine pathways, therein promoting alterations in the individual's central motivational state. Animal data supporting these ideas are reported. As reviewed, few satisfactory studies of antidepressants in cognitive dysfunction of organic etiology appear in the literature, perhaps as the result of the potent anticholinergic properties of the most popular antidepressant drugs.     

Enviromimetics: exploring gene environment interactions to identify therapeutic targets for brain disorders

There is a growing awareness of the central role played by environmental factors in many of the most debilitating neural disorders. Epidemiological studies have suggested a complex balance between genetic and environmental factors in the pathogenesis of neurological and psychiatric conditions. The use of accurate animal models, combined with experimental manipulations such as environmental enrichment, has shown that increased sensory, cognitive and motor stimulation has beneficial effects in a range of CNS disorders, including Huntington's, Alzheimer's, Parkinson's and other neurodegenerative diseases. Various studies have identified molecular, structural and functional correlates of this experience-dependent plasticity. The authors propose that the molecular systems which mediate the therapeutic effects of environmental enrichment may provide novel targets for pharmacotherapies. More specifically, they elaborate a theoretical framework for the development of ‘enviromimetics’, therapeutics that mimic or enhance the beneficial effects of environmental stimulation, targeted towards a wide range of nervous system disorders.     

Omega-3 fatty acid eicosapentaenoic acid. A new treatment for psychiatric and neurodegenerative diseases: a review of clinical investigations

Decreased n-3 fatty acid levels have been reported in patients with depression, schizophrenia or Alzheimer's disease. Recently, eicosapentaenoic acid (EPA) has been used to treat several psychiatric and neurodegenerative diseases due to its anti-inflammatory and neuroprotective effects. A total of six out of seven clinical trials have shown that EPA significantly improved depressive symptoms when compared with the placebo-treated populations. Several investigations have also reported that EPA could effectively treat schizophrenia. A case report and a clinical trial have shown that EPA was beneficial for the management of most symptoms of Huntington's disease, while a more extensive clinical investigation has demonstrated that EPA could only improve motor functions. Further clinical studies are required to fully explore the effects of EPA on other neurodegenerative diseases. The limitations of previous studies and further research directions have also been discussed.     

Effects of co-administration of a selective serotonin reuptake inhibitor and monoamine oxidase inhibitors on 5-HT-related behavior in rats

5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur in the case of co-administration of a monoamine oxidase (MAO) inhibitor and a serotonin reuptake inhibitor (SSRI). The goal of the present study was to investigate the effects of acute administration of MAO inhibitors and subchronic administration of fluvoxamine on 5-HT-related behaviors (head shaking and 5-HT syndrome) in rats treated with 5-hydroxytryptophan (5-HTP). Administration of the non-selective MAO inhibitor, pargyline, and the selective MAO-A inhibitor, clorgyline, resulted in 5-HT syndrome in 5-HTP-treated rats, and subchronic co-administration of fluvoxamine intensified the syndrome. However, administration of the selective MAO-B inhibitor, selegiline, did not induce 5-HT syndrome with or without subchronic fluvoxamine co-administration. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with SSRI. Further, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor, selegiline.     

An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders

Importance of the field: The increase in life expectancy in developed countries has given rise to several emerging social problems. Of particular note is the dramatic rise in the incidence of neurodegenerative diseases. Given this new social scenario, there is a need to identify therapeutic strategies to delay the advance of these pathologies, for which no effective treatment is currently available.

Areas covered in this review: The present review discusses some of the drugs that are now under development with antiapoptotic activity or currently on the market that may have a potential application for the treatment of neurodegenerative diseases. Moreover, we also comment on potential compounds such as resveratrol and melatonin. Despite the lack of information from clinical trials on these two compounds, they are attracting considerable attention because of their natural origin and antioxidant and antiapoptotic action. Furthermore, they do not show toxicity in humans. In addition, we discuss the potential application of several compounds, such as NMDA antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of neurodegenerative disorders.

What the reader will gain: This article will review recent developments in the field of apoptosis inhibitors, which might provide future tools for the treatment of the neurodegenerative diseases.

Take home message: The treatment of neurodegenerative diseases is a major challenge in medicine. This is partly because the incidence of these disorders is expected to rise in the coming years. New developments in the field of apoptosis inhibitors may provide future tools for the treatment of the aforementioned neurodegenerative diseases.     

Using Drosophila models of neurodegenerative diseases for drug discovery

Introduction: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are increasing in prevalence as our aging population increases in size. Despite this, currently there are no disease-modifying drugs available for the treatment of these conditions. Drosophila melanogaster is a highly tractable model organism that has been successfully used to emulate various aspects of these diseases in vivo. These Drosophila models have not been fully exploited in drug discovery and design strategies.

Areas covered: This review explores how Drosophila models can be used to facilitate drug discovery. Specifically, we review their uses as a physiologically-relevant medium to high-throughput screening tool for the identification of therapeutic compounds and discuss how they can aid drug discovery by highlighting disease mechanisms that may serve as druggable targets in the future. The reader will appreciate how the various attributes of Drosophila make it an unsurpassed model organism and how Drosophila models of neurodegeneration can contribute to drug discovery in a variety of ways.

Expert opinion: Drosophila models of human neurodegenerative diseases can make a significant contribution to the unmet need of disease-modifying therapeutic intervention for the treatment of these increasingly common neurodegenerative conditions.     

Pyrazolopyridines as inhibitors of the kinase LRRK2: a patent evaluation (WO2011141756)

Scientific evaluation of a patent aiming for the development of pyrazolopyridine derivatives as LRRK2 kinase inhibitors, a potential therapeutic target for combating Parkinson's disease.     

Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer

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