In this study, the effects of pentavalent dimethylarsinic acid ((CH3)(2)AsO(OH); DMA(V)) and trivalent dimethylarsinous acid ((CH3)(2)As(OH); DMA(III)) on synaptic transmission generated by the excitatory Schaffer collateral-CA1 synapse were tested in hippocampal slices of young (14-21 day-old) and adult (2-4 month-old) rats. Both compounds were applied in concentrations of I to 100 mu mol/l.DMA(V) had no effect on the amplitudes of evoked fEPSPs or the induction of LTP recorded from the CA1 dendritic region either in adult or in young rats. However, application of DMA(III) significantly reduced the amplitudes of evoked fEPSPs in a concentration-dependent manner with a total depression following application of 100 mu mol/l DMA(III) in adult and 10 mu mol/l DMA(III). in young rats. Moreover, DMA(III), significantly affected the UP-induction. Application of 10 mu mol/l DMA(III) resulted in a complete failure of the postsynaptic potentiation of the fEPSP amplitudes in slices taken both from adult and young rats. The depressant effect was not reversible after a 30-min washout of the DMA(III). In slices of young rats, the depressant effects of DMA(III) were more pronounced than in those taken from adult ones.Compared to the (absent) effect of DMA(V) on synaptic transmission, the trivalent compound possesses a considerably higher neurotoxic potential. (c) 2007 Elsevier Inc. All rights reserved.

The effects of trivalent arsenite were tested at the Schaffer collateral-CA I synapse of adult (2-4 month) and young (14-21 days) rats. Exposure of 100 mu mol/l arsenite led to a slight and reversible reduction Of the amplitudes Of evoked excitatory postsynaptic field potentials in adult and young rats, while exposure of 0.1 and 1 mu mol/l arsenite had no effects.The long-term potentiation (LTP) was significantly inhibited by arsenite in adult but not ill rats. Exposure of 0.1.1 and 100 mu mol/l arsenite to slices of adult rats before and during the UP Stimulus led to a significant reduction in the potentiated amplitudes amounting to a maximum of 50% of the control values. In young, animals. however, exposure of I mu mol/l arsenite showed no effect on the UP potentiated amplitudes. while exposure of 100 mu mol/l arsenite led initially to a significant reduction in the amplitudes, compared to the control level. which was completely reversible 20 min after washout. Exposure of 100 [mu mol/l arsenite did not affect the paired-pulse facilitation. indicating that arsenite does not exert its effects by influencing presynaptic transmitter release mechanisms. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Pentavalent and trivalent organoarsenic compounds belong to the major metabolites of inorganic arsenicals detected in humans. Recently, the question was raised whether the organic arsenicals represent metabolites of a detoxification process or methylated species with deleterious biological effects. In this study, the effects of trivalent arsenite (AsO3 3−; iAIII), the pentavalent organoarsenic compounds monomethylarsonic acid (CH3AsO(OH)2; MMAV) and dimethylarsinic acid ((CH3)2AsO(OH); DMAV) and the trivalent compounds monomethylarsonous acid (CH3As(OH)2, MMAIII) and dimethylarsinous acid ((CH3)2As(OH); DMAIII) were tested on glutamate receptors and on voltage-operated potassium and sodium channels heterologously expressed in Xenopus oocytes. Membrane currents of ion channels were measured by conventional two-electrode voltage-clamp techniques. The effects of arsenite were tested in concentrations of 1–1,000 μmol/l and the organic arsenical compounds were tested in concentrations of 0.1–100 μmol/l. We found no significant effects on voltage-operated ion channels; however, the arsenicals exert different effects on glutamate receptors. While MMAV and MMAIII significantly enhanced ion currents through N-methyl-d-aspartate (NMDA) receptor ion channels with threshold concentrations <10 μmol/l, DMAV and DMAIII significantly reduced NMDA-receptor mediated responses with threshold concentrations <0.1 μmol/l; iAIII had no effects on glutamate receptors of the NMDA type. MMAIII and DMAV significantly reduced ion currents through α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor ion channels with threshold concentrations <10 μmol/l (MMAIII) and <1 μmol/l (DMAV). MMAV and iAIII had no significant effects on glutamate receptors of the AMPA type. The effects of MMAV, MMAIII, DMAV and DMAIII on glutamate receptors point to a neurotoxic potential of these substances.

A new approach for the synthesis and application of tailor-made derivatizing agents for liquid chromatography is presented. The s-triazine ring serves as the backbone for these substances. Synthesis is performed in three steps based on substitution reactions of cyanuric chloride. A chromophor or fluorophor, a reactive group and a third moiety intended to modify the polarity of the derivatizing agent are coupled to cyanuric chloride. The three groups may be selected freely from molecules which carry functional groups which might be linked to cyanuric chloride. As an example, the synthesis and application of a respective reagent for the determination of aldehydes and ketones using HPLC with fluorescence detection is carried out. Baseline separation of the derivatives and low limits of detection (1.5×10−9mol/l for formaldehyde, 2.0×10−9mol/l for acetaldehyde and 3.0×10−9mol/l for p-tolualdehyde) are obtained with the new versatile reagent.

The actions were examined of 17 frequently used glycol ether compounds on the glutamate receptor-mediated ion currents. The receptors were expressed in Xenopus oocytes by injection of rat brain mRNA. Most of the 17 glycol ethers exerted no effects on the glutamate subreceptors activated by kainate and N-methyl-d-aspartate (NMDA), whereas 2-phenoxyethanol (ethylene glycol monophenyl ether) caused a considerable reduction of NMDA-induced membrane currents in a reversible and concentration-dependent manner. The threshold concentration of the ethylene glycol monophenyl ether effect was <10 μmol/l. The concentration for a 50% inhibition (IC50) was ∼360 μmol/l. The results indicate a neurotoxic potential for 2-phenoxyethanol.

In order to study the mechanisms of acute n-hexane␣intoxication, the effects of n-hexane and its metabolites 2-hexanol, methyl-n-butyl ketone, 2,5-hexanediol and 2,5-hexanedione on the cloned voltage-operated potassium channels Kv1.1, Kv1.4, Kv2.1 and Kv3.4 were investigated with electrophysiological techniques in the expression system of Xenopus oocytes. n-Hexane had no effect at any channel, whereas some of its metabolites led to reductions of the potassium currents. The greatest effects obtained were caused by 2-hexanol at the Kv2.1 channel, resulting in reductions of 13% at 0␣mV with a concentration of 500 mg/l and IC50 of ca. 3500 mg/l. The reduction appeared to be caused by a shift of the current-voltage relation to the right. Methyl-n-butyl ketone showed smaller effects, whereas 2,5-hexanedione and 2,5-hexandiol were nearly ineffective. Concerning the different potassium channels, the sensitivity to the metabolites differed. The metabolites showed greatest sensitivity towards the Kv2.1 channel and lowest sensitivity towards the Kv3.4 channel. Since the n-hexane metabolite concentrations in the brain during acute n-hexane intoxication are unknown, the relevance of the data is still unclear. The size of the effects and the currently available data on tissue concentration, however, make it more likely that the action of n-hexane and its metabolites on voltage-operated potassium channels is not a major mechanism for acute neurotoxicity.

The effects of bivalent lead on ion channels activated by kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) were studied using Xenopus oocytes microinjected with mRNA from rat brain. Lead reduced kainate-induced membrane currents in a reversible and dose-dependent manner, without affecting membrane currents induced by AMPA. Lead decreased the kainate currents with a concentration of 0.1 μmol/l to 0.93 ± 0.01 and with a concentration of 100 μmol/l to 0.41 ± 0.04 of the control values. The blocking effect of lead on kainate responses was voltage dependent. The inhibition was strongest at - 90 mV to - 70 mV and became weaker at more positive membrane potentials. The effect of lead on the kainate-induced membrane currents remained unchanged when the concentration of kainate was increased. Hence lead probably represents a noncompetitive channel-blocking agent for non-N-methyl-d-aspartate (NMDA) receptor channels activated by kainate.

The action of lead (Pb2+) on cloned voltage-operated potassium channels of the rat brain was investigated in oocytes of Xenopus laevis. Pb2+ was found to decrease the potassium currents. This effect was due to a shift of the current-voltage relation in a positive direction (up to 30 mV). The Pb2+ effect appeared at a threshold concentration of about 0.1 mumol/l and was maximal at a concentration of about 30 mumol/l. At a potential of -30 mV, the concentration needed for a 50% reduction of the potassium current was 1.0 mumol/l. The depressant effect of Pb2+ was obtained with all potassium channels tested (Kv1.1, Kv1.2, Kv1.4, Kv2.1, Kv3.4). It was minimal for the Kv2.1 channel and maximal for the Kv1.1 channel at potentials negative to 0 mV. An effect comparable with that of Pb2+ could not be induced by the application of magnesium or calcium. The external application of Pb2+ led to a decrease of potassium currents in outside-out but not in inside-out membrane patches. Overall, Pb2+ had a significant effect on the potassium channels which may contribute to the mechanisms of Pb2+ neurotoxicity.

The influence of nitrogen oxides on the practicability and accuracy of the determination of aldehydes and ketones in air samples using the DNPH-method was examined. Nitrogen dioxide reacts with 2,4-dinitrophenylhydrazine and the reaction products were identified as 2,4-dinitrophenylazide (main product) and 2,4-dinitrochlorobenzene (by-product). They have a similar chromatographic behaviour in high performance liquid chromatography (HPLC) as formaldehyde-2,4-DNP-hydrazone. The chromatographic separation of the reaction products and formaldehyde-2,4-dinitrophenylhydrazone was performed using different gradient systems. Problems which occur in nitrogen dioxide-containing air samples are discussed.