An investigation on the central effects of harmine, harmaline and related β-carbolines

Fuentes, José A.; Longo, Vincenzo

doi:10.1016/0028-3908(71)90004-9

Cited by 96 publications

(37 citation statements)

References 9 publications

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“…It is, however, also a strong MAOA inhibitor and a hallucinogenic central nervous system stimulant 38,39 . INDY showed comparable inhibitory potency and similar substrate selectivity with harmine, but had the unique advantage that it did not inhibit MAOA.…”

Section: Discussionmentioning

confidence: 99%

Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

et al. 2010

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Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A) is a serine/ threonine kinase essential for brain development and function, and its excessive activity is considered a pathogenic factor in Down syndrome. The development of potent, selective inhibitors of Dyrk1A would help to elucidate the molecular mechanisms of normal and diseased brains, and may provide a new lead compound for molecular-targeted drug discovery. Here, we report a novel Dyrk1A inhibitor, InDY, a benzothiazole derivative showing a potent ATPcompetitive inhibitory effect with IC 50 and K i values of 0.24 and 0.18 µm, respectively. X-ray crystallography of the Dyrk1A/InDY complex revealed the binding of InDY in the ATP pocket of the enzyme. InDY effectively reversed the aberrant tau-phosphorylation and rescued the repressed nFAT (nuclear factor of activated T cell) signalling induced by Dyrk1A overexpression. Importantly, proInDY, a prodrug of InDY, effectively recovered Xenopus embryos from head malformation induced by Dyrk1A overexpression, resulting in normally developed embryos and demonstrating the utility of proInDY in vivo.

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Section: Discussionmentioning

confidence: 99%

Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

et al. 2010

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“…The β-carboline alkaloid tremor shares many features with ET. These include several of the principal clinical features (e.g., tremor frequency and electromyographic characteristics of the tremor) and drugresponse characteristics (pharmacological responsiveness to benzodiazepines, alcohol, and barbiturates) (Cross et al, 1993;Fuentes and Longo, 1971;Milner et al, 1995;Rappaport et al, 1984;Sinton et al, 1989;Trouvin et al, 1987). Also, underlying brain changes are similar.…”

Section: Discussionmentioning

confidence: 99%

“…Laboratory animals injected with high doses acutely exhibit action tremor that resembles ET (Fuentes and Longo, 1971;Zetler et al, 1972). Human volunteers exposed to high doses display a coarse, reversible action tremor (Lewin, 1928).…”

Section: Introductionmentioning

confidence: 99%

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Louis

2008

NeuroToxicology

127

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Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3 ± 15.5 vs. 65.5 ± 14.2 years, p = 0.94). Mean log blood harmane concentration was ∼50% higher in cases than controls (0.50 ± 0.54 g -10 /ml vs. 0.35 ± 0.62 g -10 /ml, p = 0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (OR adjusted 1.56, 95% CI 1.01 -2.42, p = 0.04), and odds of ET was 1.90 (95% CI 1.07 -3.39, p = 0.029) in the highest vs. lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53 ± 0.57 g -10 /ml), intermediate in cases with sporadic ET (0.43 ± 0.45 g -10 /ml) and lowest in controls (0.35 ± 0.62 g -10 /ml) (test for trend, p = 0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors.

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“…11 Human volunteers acutely exposed to large doses of BCAs display a coarse tremor. 12,13 BCA-induced tremor shares many features with ET including its principal clinical features, drug-response characteristics, [14][15][16][17][18][19] and underlying brain changes (cerebellar changes have been noted in physiologic and imaging studies of patients with ET; similarly, BCAs damage olivary-cerebellar pathways). 10,14,18,[20][21][22][23] The etiology of ET is poorly understood 24 and a better understanding of disease etiology and mechanisms has the potential to modify or prevent a disorder that affects as much as 4% of the adult population.…”

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confidence: 99%

Blood harmane concentrations and dietary protein consumption in essential tremor

Louis¹,

Zheng²,

Applegate³

et al. 2005

Neurology

144

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Background-β-Carboline alkaloids (e.g., harmane) are highly tremorogenic chemicals. Animal protein (meat) is the major dietary source of these alkaloids. The authors previously demonstrated that blood harmane concentrations were elevated in patients with essential tremor (ET) vs controls. Whether this difference is due to greater animal protein consumption by patients or their failure to metabolize harmane is unknown.

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An investigation on the central effects of harmine, harmaline and related β-carbolines

Cited by 96 publications

References 9 publications

Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Blood harmane concentrations and dietary protein consumption in essential tremor

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