harmine and Parkinson-Disease

Harman and norharman, two neuroactive β-carbolines, are present in several plants and in thermally processed foods. They exhibited a wide spectrum of biological and pharmacological effects, including antioxidant, neuroprotective, and anti-inflammatory effects. In this article, we review the progress of recent research on the presence of these compounds in food, as well as their various biological and neuroactive properties. Our findings strongly suggest that some foods, especially coffee, can act as a rich source of β-carbolines, which may possibly be associated with a reduced risk for serious neurodegenerative diseases, such as Parkinson's and Alzheimer's.

Topics: Animals; Brain; Brain Chemistry; Carbolines; Essential Tremor; Food; Food Handling; Harmine; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Plant Extracts

The drug treatment of Parkinson's disease since the original description of the malady in 1817 is described. Consideration is given to the historic use of alkaloids of the belladonna, harmala, and aporphine families, and of amphetamine. The introduction of the L-dopa treatment is described. The modes of action of the various drugs employed in the past as well as those in current use are described in the context of knowledge of the functioning of the nigrostriatal tract.

Topics: Apomorphine; Aporphines; Harmine; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parasympatholytics; Parkinson Disease

It is of historical interest that 63 years ago Louis Lewin reported the use of a hallucinogenic compound prepared from the South American vine, Banisteria Caapi, to treat Parkinson's disease (PD). This psychoactive compound, named banisterine, proved to be identical to harmine, but 30 years were to pass before it was shown to be a reversible monoamine oxidase (MAO) inhibitor. The first reports of the use of banisterine to treat postencephalitic parkinsonism in 1929 created a stir in the popular press and banisterine was hailed as a "magic drug." Despite continued studies of the harmala alkaloids by other researchers, interest in the therapeutic value of these compounds vanished during the 1930's. The story of banisterine is reviewed because it was the first MAO inhibitor to be used in parkinsonism, and illustrates the historical role of psychoactive drugs in the development of effective therapies, and in elucidating the pathophysiology of PD.

Topics: Harmine; Humans; Parkinson Disease

Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [(11)C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A V(T), an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex (P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa-levodopa administration (P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels.

Topics: Carbidopa; Carbon Radioisotopes; Corpus Striatum; Dopamine; Dopamine Agonists; Drug Combinations; Harmine; Humans; Levodopa; Monoamine Oxidase; Parkinson Disease; Positron-Emission Tomography; Prefrontal Cortex; Protein Binding; Serotonin; Substrate Specificity; Time Factors; Tryptophan

Monoamine oxidase (MAO) plays an important role in psychiatric and neurological disorders, such as depression and Parkinson's disease. As a result, MAO represents a key target for developing drugs to treat these conditions. The present study aimed to synthesise and discover compounds that inhibit the MAO enzymes and which may be relevant to the treatment of neurological disorders. A series of nine 2H-1,4-benzothiazin-3(4H)-ones were synthesised and evaluated as potential in vitro inhibitors of human MAO-A and MAO-B. The benzothiazinones bear structural similarity to a series of 3,4-dihydro-2(1H)-quinolinones that have been shown to be highly potent MAO-B inhibitors. The results show that the benzothiazinones inhibit both MAO isoforms but are more potent MAO-B inhibitors. The most potent inhibitors exhibit IC

Topics: Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Structure-Activity Relationship

Parkinson's disease (PD) is a progressive neurodegenerative disease manifested by core symptoms of loss of motor control and postural instability. Loss of dopaminergic neurons is the cause of PD, thus enhancing dopamine level by pharmacological treatment is one of the key treatment strategies for PD. However, the limitations of current treatment strategies open the possibility of novel drug candidates for the treatment of PD.. To investigate the anti-PD potential of Harmine and Harmaline. We aim to evaluate the therapeutic potential of Harmine and Harmaline by in-silico approaches; molecular docking, pharmacokinetic and Prediction of Activity Spectra for Substances (PASS) analysis were used for evaluating the therapeutic potential of Harmine and Harmaline and standard drug levodopa (L-DOPA).. Auto dock vina was used for molecular docking of all three compounds against D2- and D3- dopamine receptors. The pharmacokinetics (PKs) and toxicity profile were predicted by pkCSM, and the pharmacological activity was predicted by PASS analysis.. Molecular docking showed a higher binding affinity of Harmine and Harmaline as compared to L-DOPA, and these results were supported by in-silico pharmacokinetic and toxicity profiling. Moreover, PASS analysis showed anti-PD activity of Harmine and Harmaline.. Harmine and Harmaline exhibit higher binding affinity towards D2- and D3- dopamine receptors compared to L-DOPA, and PKs and toxicity profile support their potential as drug candidates for PD therapy.

Topics: Alkaloids; Carbolines; Harmaline; Harmine; Humans; Molecular Docking Simulation; Neurodegenerative Diseases; Parkinson Disease

Parkinson's disease (PD) is a late-life neurodegenerative disease. Genetic and environmental factors play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin that shows structural resemblance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).. In 2002 and 2007, we demonstrated elevated blood harmane concentrations [HA] in essential tremor (ET) cases. We now assessed whether blood [HA] were elevated in Parkinson's disease (PD) as well.. Blood [HA] were quantified by high performance liquid chromatography. Subjects comprised 113 PD cases and 101 controls.. Mean log blood [HA] in PD cases was double that of controls (0.59±0.63 g(-10)/ml vs. 0.27±0.63 g(-10)/ml, p<0.001). A non-parametric test on non-transformed data (median blood [HA]=3.31 g(-10)/ml in cases and 1.44 g(-10)/ml in controls) also showed this difference (p<0.001). In unadjusted and then adjusted logistic regression analyses, log blood [HA] was associated with PD (odds ratio [OR]unadjusted 2.31, 95% confidence interval [CI] 1.46-3.67, p<0.001; OR(adjusted) 2.54, 95% CI 1.55-4.16, p<0.001). In PD, log blood [HA] co-varied with family history, being lowest in PD cases with no family history (0.54±0.60 g(-10)/ml) and highest in PD cases with a family history of both ET and PD (0.84±0.68 g(-10)/ml) (p=0.06).. Blood harmane appears to be elevated in PD. The finding needs to be reproduced in additional cohorts to assess its generalizability. The higher concentration in familial PD suggests that the mechanism may involve genetic factors.

Topics: Aged; Female; Harmine; Humans; Male; Neurotoxins; Parkinson Disease; Risk Factors

Banisteriopsis caapi, a woody vine from the Amazonian basin, is popularly known as an ingredient of a sacred drink ayahuasca, widely used throughout the Amazon as a medicinal tea for healing and spiritual exploration. The usefulness of Banisteriopsis caapi has been established for alleviating symptoms of neurological disorders including Parkinson's disease.. Primary objective of this study was to develop the process for preparing standardized extracts of Banisteriopsis caapi to achieve high potency for inhibition of human monoamine oxidases (MAO) and antioxidant properties. The aqueous extracts prepared from different parts of the plant collected from different geographical locations and seasons were analyzed by HPLC for principal bioactive markers. The extracts were simultaneously tested in vitro for inhibition of human MAOs and antioxidant activity for analysis of correlation between phytochemical composition of the extracts and bioactivities.. Reversed-phase HPLC with photodiode array detection was employed to profile the alkaloidal and non-alkaloidal components of the aqueous extract of Banisteriopsis caapi. The Banisteriopsis caapi extracts and standardized compositions were tested in vitro for inhibition of recombinant preparations of human MAO-A and MAO-B. In vitro cell-based assays were employed for evaluation of antioxidant property and mammalian cell cytotoxicity of these preparations.. Among the different aerial parts, leaves, stems/large branches and stem bark of Banisteriopsis caapi, HPLC analysis revealed that most of the dominant chemical and bioactive markers (1, 2, 5, 7-9) were present in high concentrations in dried bark of large branch. A library of HPLC chromatograms has also been generated as a tool for fingerprinting and authentication of the studied Banisteriopsis caapi species. The correlation between potency of MAO inhibition and antioxidant activity with the content of the main active constituents of the aqueous Banisteriopsis caapi extracts and standardized compositions was established. Phytochemical analysis of regular/commercial Banisteriopsis caapi dried stems, obtained from different sources, showed a similar qualitative HPLC profile, but relatively low content of dominant markers 1, 2, 7, and 9, which led to decreased MAO inhibitory and antioxidant potency compared to Banisteriopsis caapi Da Vine.. The ethnopharmacological use of bark of matured stem/large branch of Banisteriopsis caapi as well as whole matured stem is supported by the results obtained in this investigation. Among various constituents of Banisteriopsis caapi, harmine (7), harmaline (6) and tetrahydroharmine (5) are responsible for MAO-A inhibition, while two major proanthocyanidines, epicatechin (8) and procyanidine B2 (9) produce antioxidant effects. The compounds 1-9 can serve as reliable markers for identification and standardization of Banisteriopsis caapi aerial parts, collected in different seasons and/or from different geographical regions.

Topics: Alkaloids; Animals; Banisteriopsis; Beverages; Biflavonoids; Catechin; Ethnopharmacology; Harmaline; Harmine; Humans; Monoamine Oxidase; Neurodegenerative Diseases; Parkinson Disease; Plant Leaves; Plant Stems; Plants; Proanthocyanidins; Reference Standards; Superoxide Dismutase

The activity of beta-carboline-2-N-methyltransferase results in the formation of neurotoxic N-methylated beta-carbolinium compounds. We have hypothesized that these N-methylated beta-carbolinium cations may contribute to the development of idiopathic Parkinson's disease. This report describes experiments undertaken to optimize assay conditions for bovine brain beta-carboline-2-N-methyltransferase activity. The activity of beta-carboline-2-N-methyltransferase is primarily localized in the cytosol, has a pH optimum of 8.5-9, and obeys Michaelis-Menten kinetics with respect to its substrates, 9-methylnorharman (9-MeNH) and S-adenosyl-L-methionine (SAM). Kinetic constants, KM and Vmax, with respect to 9-MeNH, are 75 microM and 48 pmol/h/mg protein, respectively. The KM for SAM is 81 microM and the Vmax is 53 pmol/h/mg protein. In addition, enzyme activity is inhibited by S-adenosyl-L-homocysteine (SAH) or zinc, and is increased 2-fold in the presence of iron or manganese. Enzyme characterization is a prerequisite to the purification of this N-methyltransferase from bovine brain as well as comparison of its activity in human brain from control and Parkinson's disease individuals.

Topics: Animals; Brain; Carbolines; Cattle; Cytosol; Enzyme Inhibitors; Harmine; Humans; Hydrogen-Ion Concentration; Kinetics; Methylation; Methyltransferases; Parkinson Disease; S-Adenosylhomocysteine; S-Adenosylmethionine; Zinc

Death of dopaminergic neurons in Parkinson's disease (PD) may partially be caused by synthesis and accumulation of endogenous and exogenous toxins. Because of structural similarity to MPTP, beta-carbolines, like norharman and harman, have been proposed as putative neurotoxins. In vivo they may easily be formed by cyclization of indoleamines with e.g. aldehydes. For further elucidation of the role of beta-carbolines in neurodegenerative disorders harman and norharman levels in cerebrospinal fluid (CSF) were measured in 14 patients with PD and compared to an age- and sex-matched control group (n = 14). CSF levels of norharman and harman in PD were significantly higher compared to controls. These results may suggest a possible role of harman and norharman or its N-methylated carbolinium ions in the pathophysiological processes initiating PD. However the origin of increased levels of these beta-carbolines remains unclear. On the one hand one may speculate, that unknown metabolic processes induce the increased synthesis of harman and norharman in PD. On the other hand a possible impact of exogenous sources may also be possible.

Topics: Adult; Aged; Carbolines; Case-Control Studies; Female; Harmine; Humans; Male; Middle Aged; Neurotoxins; Parkinson Disease

Several lines of evidence suggest that endogenous and exogenous toxins may play a major role in the pathogenesis of Parkinson's disease (PD). In the brain aromatic beta-carbolines, like harman or norharman, may be formed by cyclization of indoleamines. Because of the structural similarity to MPTP, beta-carbolines have been proposed as endogenous toxins. For further elucidation of the role of beta-carbolines in neurodegenerative disorders, harman and norharman plasma levels were measured in 36 patients with PD and compared to an age- and sex-matched control group. Plasma levels of norharman in PD were significantly higher compared to the control group. Harman in the plasma of Parkinsonian patients was also elevated compared to the controls, but this difference was not significant. On the one hand these results may suggest a possible role of beta-carbolines in the pathophysiological processes initiating PD. But on the other hand one may speculate that elevated levels of norharman and harman are due to an endogenous upregulation, caused by unknown metabolic processes to reduce oxidative stress by inhibiting e.g. monoaminooxidases in neurons.

Topics: Aged; Aged, 80 and over; Carbolines; Case-Control Studies; Female; Harmine; Humans; Male; Middle Aged; Neurotoxins; Parkinson Disease