Relationship between blood harmane and harmine concentrations in familial essential tremor, sporadic essential tremor and controls

Abstract

Introduction-Harmane, a potent tremor-producing β-carboline alkaloid, may play a role in the etiology of essential tremor (ET). Blood harmane concentrations are elevated in ET cases compared with controls yet the basis for this elevation remains unknown. Decreased metabolic conversion (harmane to harmine) is one possible explanation. Using a sample of >500 individuals, we hypothesized that defective metabolic conversion of harmane to harmine might underlie the observed elevated harmane concentration in ET, and therefore expected to find a higher harmane to harmine ratio in familial ET than in sporadic ET or controls.Methods-Blood harmane and harmine concentrations were quantified by high performance liquid chromatography.Results-There were 78 familial ET cases, 187 sporadic ET cases, and 276 controls. Blood harmane and harmine concentrations were correlated with one another (Spearman's r = 0.24, p < 0.001). The mean (±SD) harmane/harmine ratio = 23.4 ± 90.9 (range = 0.1 -987.5). The harmane/harmine ratio was highest in familial ET (46.7 ± 140.4 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Financial disclosure: The National Institutes of Health played no role in the study design, the collection of data, the analysis and interpretation of data, the writing of the report or in the decision to submit the paper for publication. Statistical Analyses:The statistical analyses were conducted by Dr. Louis. Conflict of Interest StatementThe authors declare that there are no conflicts of interest. NIH Public Access Author ManuscriptNeurotoxicology. Author manuscript; available in PMC 2011 December 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript controls (13.5 ± 50.3)(p = 0.03). In familial ET cases, there was no association between this ratio and tremor severity (Spearman's r = 0.08, p=0.48) or tremor duration (Spearman's r = 0.14, p = 0.24).Conclusion-The basis for the elevated blood harmane concentration, particularly in familial ET, is not known, although the current findings (highest harmane/harmine ratio in familial ET cases) lends support to the possibility that it could be the result of a genetically-driven reduction in harmane metabolism.

An inherited episodic head tremor syndrome in Doberman pinscher dogs

“…Clinical and genetic heterogeneity as well as lack of suitable animal models hinder the elucidation of the pathophysiology behind these disorders. Neurotoxicity of harmane derivatives, cerebellar and brainstem neurodegeneration, and an association with a mutation in the LINGO1 gene provide important clues for further investigation 18–20. Clinical subtypes of essential tremor and a familial form that is observed in young adults are similar to what is seen in DPs with HT.…”

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

“…For example, early onset ET cases might differ in their rates of progression and their tremor-related brain oscillatory circuits when compared to late onset ET cases [13,14]. The presence of family history in ET might indicate an underlying genetic etiology [15,16] as well as possible differences in the ability to metabolize naturally-occurring tremorgenic compounds [17]. In addition, ET cases with head tremor might have different degrees of cerebellar involvement than ET cases without head tremor, based on neuroimaging findings [18].…”

Potent inhibition of human organic cation transporter 2 (hOCT2) by β-carboline alkaloids

“…Many β-carbolines are readily absorbed and distributed in body tissues and brain (Louis et al, 2010; Matsubara et al, 1993, 1995). β-carbolines (e.g.…”

“…In humans, there are many potential sources of β-carboline exposure including foods, beverages, and cigarette smoking (Herraiz, 2000a,b, 2004; Totsuka et al, 1999). They have been detected in human body fluids (blood, urine, cerebrospinal fluid) and tissues including brain, liver and kidney (Airaksinen & Kari, 1981; Louis et al, 2010; Matsubara et al, 1993, 1995). Beta-carbolines have a broad spectrum of biological, pharmacological and toxicological activities, including antitumor, antimicrobial, anti-inflammatory, cardiovascular, neuroactive, psychoactive or neurotoxic actions (Du et al, 1997; Glennon et al, 2000; Gockler et al, 2009; Herraiz et al, 2010).…”