An Unsuccessful Attempt to Confirm the Occurrence of 4′-O-β- d-Glucosyl-9-O-(6″-deoxysaccharosyl)olivil in Valerian Root

The lignan 4′-O-β- d-glucosyl-9-O-(6″-deoxysaccharosyl)olivil had previously been discovered in a methanolic extract of valerian root (Valeriana officinalis agg.) and characterized as a potent partial agonist at the A1 adenosine receptors. Today, countless scientific sources, webpages, and press articles mention this compound and discuss it as an active constituent for the sedative effect of this herbal drug. As no second report confirmed the occurrence of this lignan in valerian root during the 20 years since its first description in 1998, we intended to re-prove its presence by means of LCMS using other genuine or added lignans as a quantitative benchmark. Whilst those lignans were clearly detectable in methanolic valerian extracts of all six investigated batches of valerian root, no positive proof of 4′-O-β- d-glucosyl-9-O-(6″-deoxysaccharosyl)olivil was achieved. Our result suggests that this compound does not occur regularly in valerian root in the amounts expected from the single report on the occurrence of this compound.

HIF-1 - Alternative signals pathways of activation and formation of tolerance to hypoxia/ischemia

Альтернативные сигнальные механизмы активации транскрипционного фактора HIF-1 принципиально можно подразделить на 3 типа: связанные с ингибированием пролилгидроксилаз и ограничением деградации HIF-1α; связанные с индукцией HIF-1α; связанные с активацией HIF-1α. Особый практический интерес представляет активация фактора HIF-1 во время гиперкапнии, которая часто сопутствует гипоксии. Пермиссивная гиперкапния вызывает повышение концентрации HIF-1α в ткани головного мозга и потенцирует активацию HIF-1α, что выражается в повышении содержания HIF-1α в гиппокампальных нейронах СА1 региона после гиперкапнически-гипоксического воздействия. При изолированном применении гипоксии аналогичный эффект отсутствует. Перспективным для разработки методов повышения толерантности органов и тканей к гипоксии/ишемии является комбинирование средств, повышающих активность HIF-1, с респираторными гиперкапнически-гипоксическими тренировками и препаратами, влияющими на другие адаптогенные механизмы. Along with the classical oxygen-dependent mechanism of activation of the transcription factor HIF-1, there are alternative signaling mechanisms of this process. These mechanisms can be fundamentally divided into the following types: associated with the inhibition of prolyl hydroxylases and limiting the degradation of HIF-1α (iron chelators, NO, succinate, inhibitors of lysosomal degradation); associated with the induction of HIF-1α (TNFα, IL-1, angiotensin); associated with the activation of HIF-1α (MAPK, PI3K). Of particular practical interest is the activation of HIF-1 factor when exposed to CO2 during hypercapnia, which is often associated with hypoxia. Permissive hypercapnia causes an increase in the concentration of HIF-1α in brain tissue at an equivalent level of hypoxia, and also potentiates the effectiveness of hypoxia in relation to HIF-1α activation, which is expressed in an increase in the content of HIF-1α in hippocampal neurons of the CA1 region after hypercapnic-hypoxic exposure, on the absence of a similar effect with the isolated use of hypoxia. Promising for the development of methods to increase the tolerance of organs and tissues to hypoxia / ischemia is a combination of agents that increase the activity of HIF-1, with respiratory hypercapnic-hypoxic training and drugs that affect other adaptogenic mechanisms (A1-adenosine receptors, mitoK+ATP-channels, opioid receptors).

From Bench to Bedside and Back Again

Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. Anesthesiology 1988; 125:590–4. Abstract reprinted with permission. The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the α2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (d-enantiomer) or levomedetomidine (l-enantiomer) 10, 30, and 100 μg/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the d-, but not the l-, stereoisomer. At the highest dose of dexmedetomidine (100 μg/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether α2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg intraperitoneally, a highly selective α2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and α-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine-depleted rats. These data indicate that the reduction of MAC caused by dexmedetomidine is mediated through α2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic α2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic α2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.