Inhibitory Effects of Tutin on Glycine Receptors in Spinal Neurons. Eur J Pharmacol 559: 61

Department of Physiology, University of Concepcion, Chile.
European Journal of Pharmacology (Impact Factor: 2.53). 04/2007; 559(1):61-4. DOI: 10.1016/j.ejphar.2006.12.018
Source: PubMed


We studied the effects of tutin, a sesquiterpenoid obtained from Coriaria ruscifolia subspecie ruscifolia, a native poisonous Chilean plant, on spinal glycine receptors using patch clamp recordings. In addition, cytosolic Ca(2+) transients and activation of cAMP response element-binding protein (CREB) were measured in the presence of tutin. Application of tutin (1-1000 microM) inhibited the glycinergic evoked current in a concentration-dependent manner. Moreover, the frequency of spontaneous Ca(2+) spikes and spontaneous synaptic activity (AMPAergic events) was augmented and correlated with an increase in phosphorylated CREB levels, suggesting an enhancement in neuronal excitability. These results may explain the toxic effects of the plant characterized by seizures and convulsions with subsequent coma and death seen in humans and mice.

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    • "Since that publication , no other compounds related to tutin and hyenanchin, or other chemically unrelated potential toxins in tutu honeydew honey have been reported. Tutin has also been found in Coriaria species that grow in other parts of the world, for example the Asian Coriaria nepalensis (Wei et al., 1998) and Coriaria japonica (Kinoshita et al., 2005), and the South American Coriaria ruscifolia (Fuentealba et al., 2007). Chemically tutin is a sesquiterpene lactone related to picrotoxin (a 1:1 mixture of picrotoxinin and picrotin), a central nervous system convulsant widely used in neuropharmacology studies (Olsen, 2006; Fig. 1). "
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    ABSTRACT: Over the last 150 years a number of people in New Zealand have been incapacitated, hospitalised, or died from eating honey contaminated with tutin, a plant-derived neurotoxin. A feature of the most recent poisoning incident in 2008 was the large variability in the onset time of clinical signs and symptoms of toxicity (0.5 to 17 h). To investigate the basis of this variability a pharmacokinetic study was undertaken in which 6 healthy males received a single oral dose of tutin-containing honey giving a tutin dose of 1.8μg/kg body weight. The serum concentration-time curve for all volunteers exhibited two discrete peaks with the second and higher level occurring at approximately 15 hours post-dose. Two subjects reported mild, transient headache at a time post-dose corresponding to maximum tutin concentrations. There were no other signs or symptoms typical of tutin intoxication such as nausea, vomiting, dizziness or seizures. Pharmacokinetic analysis using a two-site absorption model resulted in a good fit to the observed concentration data. A novel analytical method subsequently revealed the presence of glycoside conjugates of tutin in addition to unconjugated tutin in honey. These pharmacokinetic data will be important to better define a safe maximum tutin concentration in honey.
    Full-text · Article · Jul 2014 · Food and Chemical Toxicology
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    • "Tutin was isolated from dried leaves of Coriaria ruscifolia locally collected (Concepción, Chile) and the purification has been previously described (Fuentealba et al., 2007). In brief, the final purification was made from chloroformic and ethyl acetate portions and the purity (>99%) was assayed with "
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    ABSTRACT: In the present study we characterized the effects of the South American neurotoxin tutin on recombinant glycine receptors (GlyR) expressed in HEK 293 cells using whole-cell patch-clamp techniques. Tutin induced a concentration-dependent inhibition of α(1) and α(2) homomeric GlyRs, with IC(50)s of 35 ± 1 and 15 ± 3 μM, respectively. The co-expression of αβ subunits reduced the potency of tutin, thus increasing the IC(50) to 51 ± 4 and 41 ± 8 μM for α(1)β and α(2)β GlyRs, respectively. The inhibitory effect of tutin was competitive, independent of membrane potential and reversible suggesting a pore independent site. On the other hand, low tutin concentrations enhanced the current, which was not synergic with Zn(2+) or ethanol. A mutation in Lys385 altered ethanol but not tutin sensitivity, suggesting different sites for modulation of α1-containing GlyRs. Our results suggest that tutin affects the GlyR by a mechanism distinct to that of picrotoxin and ethanol, and that the pharmacological profile of tutin exhibits a "Zn-like" behaviour. In conclusion, these results provide information on molecular mechanisms important for understanding the toxic effects of a recently discovered South American neurotoxin.
    Full-text · Article · Oct 2010 · Neuropharmacology

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