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At least 217 records · Page 12Linked to original sources
PubMed1982

HI-6: reactivation of central and peripheral acetylcholinesterase following inhibition by soman, sarin and tabun in vivo in the rat.

HI-6, ([[[(4-aminocarbonyl)pyridino]methoxy]methyl]-2-] (hydroxyimino)methyl]-pyridinium dichloride), is an oxime which, when combined with atropine, is an extremely effective therapy against organophosphate poisoning. It was found that, following soman (287 micrograms/kg) poisoning, HI-6 reactivated acetylcholinesterase in the diaphragm and intercostal muscles but not in the brain. At a lower dose of soman (110 micrograms/kg), HI-6 reactivated sarin-inhibited acetylcholinesterase in the brain and in the respiratory musculature but did not reactivate tabun-inhibited acetylcholinesterase. It was also found that soman produced a differential inhibition of diaphragm and intercostal muscle acetylcholinesterase in vivo, whereas the in vitro I50 for soman was the same in both areas. HI-6 was capable of reactivating soman-inhibited acetylcholinesterase when administered up to 30 min post-soman, indicating that the rate of aging of the soman-acetylcholinesterase complex is slower than previously reported. The above results suggest that, in severe soman poisoning, the primary lesion occurs in peripheral acetylcholinesterase in the respiratory musculature (specifically the diaphragm).

Acetylcholinesterase↗
PubMed1986

Dissociation of locomotor depression and ChE activity after DFP, soman and sarin.

The effect of direct intrastriatal injection of three organophosphate cholinesterase inhibitors, DFP (diisopropylphosphorofluoridate), soman (pinacolyl methylphosphonofluoridate) and sarin (isopropyl methylphosphonofluoridate) has been studied on locomotor activity in the rat. The degree of ChE inhibition has been monitored in the striatum, as well as in surrounding brain areas and blood, in order to verify the selectivity of the treatment and rule out effects attributable to actions in these areas and/or the periphery. It has been determined that while enzyme activity is inhibited in the striatum by all three compounds, only DFP significantly reduces locomotor activity at doses that produce no other observable behavioral deficits, or significant leakage into the periphery. Behavioral recovery occurs before enzyme activity returns to control levels. Possible contributions of DFP's action on other neurotransmitters and on ChE in other brain areas to the inhibition of locomotor activity are discussed.

Animals↗
PubMed1986

Relationship between the neurotoxicities of Soman, Sarin and Tabun, and acetylcholinesterase inhibition.

Acetylcholinesterase (AChE)-induced chewing movements, tremors, convulsions and hind limb abduction at doses of 50-85% LD50 in rats were monitored in order to determine whether the severity of these different signs would correlate with brain AChE levels and the time course of such a relationship. 30 min after subcutaneous (s.c.) injection of Soman, the intensities of toxic signs were significantly correlated with the degree of striatal AChE inhibition. In the case of Sarin, the corresponding r-values were not significant except for tremors. For Tabun-induced chewing, tremor and hind-limb abduction, the r-values were significant. The neurotoxicity was most intense between 15 min to 2 h after treatment, but at 2 or 6 h, the r-values were well below 0.5. The inhibition of brain AChE was maximal by 30 min and was still high at 24 h.

Animals↗
PubMed1987

The effects of in vitro exposure to the neurotoxins sarin (GB) and soman (GD) on unscheduled DNA synthesis by rat hepatocytes.

Large amounts of the nerve agents, sarin (GB) and soman (GD), are part of the military chemical arsenal and small amounts are on hand in numerous U.S. research laboratories. Thus, there is a potential for accidental occupational exposure to these compounds. As part of a study of mutagenic, reproductive and subchronic effects of these agents, we measured unscheduled DNA repair synthesis in isolated rat hepatocytes after exposure to GBI (stabilized with tributylamine), GBII (stabilized with diisopropylcarbodiimide) or GD. This was done to determine whether these agents or their metabolites directly damage DNA or their related proteins. Each agent was assayed at least once over concentrations ranging from 3.0 X 10(-4) to 2.4 X 10(-3) M for GBI and GBII and 2.3 X 10(-4) to 1.8 X 10(-3) for GD and at least 3 times at 2.4 X 10(-3) M for GBI and GBII and 1.8 X 10(-3) M for GD, added as 20% of the culture medium. In all assays, no increase in the level of DNA synthesis was observed. On the contrary, significant decreases in repair synthesis were seen in hepatocytes exposed to GBI or GBII. The decreases in DNA synthesis seen in response to GD were less marked and not significant. These observations were not related to cell death, since 8 of 10 assays performed showed no significant decrease in the amount of DNA present in cultures exposed to the nerve agents compared to the negative controls. Our results suggest that the agents GBI, GBII and GD may either inhibit the repair of DNA or protect DNA from damage.

2-Acetylaminofluorene↗
PubMed2005

Gene expression profiles of the rat brain both immediately and 3 months following acute sarin exposure.

We have studied sarin-induced global gene expression patterns at an early time point (15 min; 0.5xLD50) and a later time point (3 months; 1xLD50) using Affymetrix: Rat Neurobiology U34 chips in male, Sprague-Dawley rats and have identified a total of 65 (early) and 38 (late) genes showing statistically significant alterations from control levels at 15 min and 3 months, respectively. At the early time point, those that are classified as ion channel, cytoskeletal and cell adhesion molecules, in addition to neuropeptides and their receptors predominated over all other groups. The other groups included: cholinergic signaling, calcium channel and binding proteins, transporters, chemokines, GABAnergic, glutamatergic, aspartate, catecholaminergic, nitric oxide synthase, purinergic, and serotonergic signaling molecules. At the late time point, genes that are classified as calcium channel and binding proteins, cytoskeletal and cell adhesion molecules and GABAnergic signaling molecules were most prominent. Seven molecules (Ania-9, Arrb-1, CX-3C, Gabab-1d, Nos-2a, Nrxn-1b, PDE2) were identified that showed altered persistent expression in both time points. Selected genes from each of these time points were further validated using semi quantitative RT-PCR approaches. Some of the genes that were identified in the present study have been shown to be involved in organophosphate-induced neurotoxicity by both other groups as well as ours. Principal component analysis (PCA) of the expression data from both time points was used for comparative analysis of the gene expression, which indicated that the changes in gene expression were a function of dose and time of euthanasia after the treatment. Our model also predicts that besides dose and duration of post-treatment period, age and possibly other factors may be playing important roles in the regulation of pathways, leading to the neurotoxicity.

Animals↗
PubMed2005

Comparison of ability of some oximes to reactivate sarin-inhibited brain acetylcholinesterase from different species.

The aim of this work was the comparison of reactivation potency of four oxime acetylcholinesterase (AChE) reactivators (pralidoxime, HI-6, K027 and K033) on three resources of the enzyme (human, pig and rat brain homogenate) inhibited by nerve agent sarin. The results demonstrate remarkable differences in the reactivation of inhibited brain AChE, depending on the oxime and species

Acetylcholinesterase↗
PubMed2004

Association between lower P300 amplitude and smaller anterior cingulate cortex volume in patients with posttraumatic stress disorder: a study of victims of Tokyo subway sarin attack.

Previous investigations of auditory P300 event-related potentials have provided electrophysiological evidence for attentional problems in patients with posttraumatic stress disorder (PTSD). The present study sought to evaluate the relationship between P300 deficits and underlying brain morphological abnormalities in never-treated, comorbidity-free patients with PTSD following the Tokyo subway sarin attack. Out of 47 victims recruited, 8 victims with PTSD and 13 victims without PTSD were identified. Correlational analyses were performed between auditory P300 amplitude at Pz electrode site elicited in an oddball task and anterior cingulate gray matter volume that was shown to be reduced in our previous study using voxel-based morphometry on magnetic resonance imaging. Victims with PTSD showed significantly lower amplitudes of P300 compared with victims without PTSD, and the lower P300 amplitudes at Pz were significantly associated with higher avoidance/numbing scores in the PTSD group. Furthermore, in the PTSD group only, the P300 amplitudes showed a trend toward significant positive correlation with voxel densities of the anterior cingulate cortex gray matter. These results provide the first evidence that electrophysiological deficits of controlled attention observed in patients with PTSD may be linked to underlying brain morphological abnormalities.

Adult↗
PubMed2005

Effects of sarin on the operant behavior of guinea pigs.

The present study evaluated the dose-response effects of subacute exposure to sublethal doses of the organophosphorus (OP) chemical warfare nerve agent (CWNA) sarin (GB) on the operant behavior of guinea pigs. Dietary restricted guinea pigs, trained to respond for food under a progressive ratio (PR) schedule of reinforcement, were injected five times per week (Monday-Friday) for 2 weeks with fractions (0.1, 0.2, and 0.4) of the established LD(50) of GB (42 microg/kg). Changes in body weight, whole blood (WB) acetylcholinesterase (AChE) levels, and operant performances were monitored over the 2 weeks of GB exposure and for an additional 2 weeks following the termination of exposures. There were dose-related changes in body weight and WB AChE levels throughout the exposure and post-exposure periods. Several parameters of PR performance were disrupted during exposure to 0.4 LD50 GB, however, concurrent weight loss indicated the presence of overt toxicity. PR performance recovered following the termination of exposures. Lower doses (0.1 and 0.2 LD50) of GB failed to produce reliable effects on operant performance during the exposure period. Overall responding decreased during exposure to 0.4 LD50 GB, resulting in reduced response rates and break points. The decrease in overall response rates was attributed to an increase in pausing since there was no decrease in running rate. Motor effects of 0.4 LD50 GB were evident as an increase in the proportion of lever press durations > or = 1.0 s. In the present study, doses of GB lower than 0.4 LD50 produced no marked alteration of operant performance in guinea pigs, although WB AChE levels were maximally inhibited to 20% of control.

Animals↗
PubMed2006

Enzyme-kinetic investigation of different sarin analogues reacting with human acetylcholinesterase and butyrylcholinesterase.

The pertinent threat of using organophosphorus compound (OP)-type chemical warfare agents (nerve agents) during military conflicts and by non-state actors requires the continuous search for more effective medical countermeasures. OP inhibit acetylcholinesterase (AChE) and therefore standard treatment of respective poisoning includes AChE reactivators (oximes) in combination with antimuscarinic agents. Hereby, standard oximes, 2-PAM and obidoxime, are considered to be rather insufficient against various nerve agents. Numerous experimental oximes have been investigated in the last decades by in vitro and in vivo models. Recently, we studied the reactivating potency of several oximes with human AChE inhibited by structurally different OP and observed remarkable differences depending on the OP and oxime. In order to investigate structure-activity relationships we determined the various kinetic constants (inhibition, reactivation, aging) for a series of sarin analogues bearing a methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, cyclohexyl or pinacolyl group with human AChE and BChE. The rate constants for the inhibition of human erythrocyte AChE and plasma BChE by these OP (k(i)), for the spontaneous dealkylation (k(a)) and reactivation (k(s)) of OP-inhibited AChE and BChE as well as for the oxime-induced reactivation of OP-inhibited AChE and BChE by the oximes obidoxime, 2-PAM, HI 6, HLö 7 and MMB-4 were determined. With compounds bearing a n-alkyl group the inhibition rate constant increased with chain length. A relation between chain length and spontaneous reactivation velocity was also observed. In contrast, no structure-activity dependence could be observed for the oxime-induced reactivation of AChE and BChE inhibited by the compounds tested. In general, OP-inhibited AChE and BChE were susceptible towards reactivation by oximes. HLö 7 was the most potent reactivator followed by HI 6 and obidoxime while 2-PAM and MMB-4 were rather weak reactivators. These data indicate a potential structure-activity relationship concerning inhibition and spontaneous reactivation but not for oxime-induced reactivation.

Acetylcholinesterase↗
PubMed2003

Partial adenosine A(1) receptor agonists inhibit sarin-induced epileptiform activity in the hippocampal slice.

Organophosphate poisoning can result in seizures and subsequent neuropathology. One possible therapeutic approach would be to employ adenosine A(1) receptor agonists, which have already been shown to have protective effects against organophosphate poisoning. Using an in vitro model of organophosphate-induced seizures, we have investigated the ability of several adenosine A(1) receptor agonists to inhibit epileptiform activity induced by the organophosphate sarin, in the CA1 stratum pyramidale of the guinea pig hippocampal slice. Application of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) or the partial adenosine A(1) receptor agonists 2-deoxy-N(6)-cyclopentyladenosine (2-deoxy-CPA) and 8-butylamino-N(6)-cyclopentyladenosine (8-butylamino-CPA) abolished epileptiform activity in a concentration-related manner. The rank order of potency was CPA (IC(50) 4-5 nM) >2-deoxy-CPA (IC(50) 113-119 nM)=8-butylamino-CPA (IC(50) 90-115 nM). These data suggest that partial adenosine A(1) receptor agonists, which have fewer cardiovascular effects, should be further evaluated in vivo as potential treatments for organophosphate poisoning.

Action Potentials↗
PubMed2002

Packed capillary liquid chromatography-electrospray mass spectrometry of snow contaminated with sarin.

Packed capillary liquid chromatography-electrospray mass spectrometry (LC-ESI-MS) was used for the analysis of a snow sample that was accidentally contaminated with an organophosphorus chemical warfare agent during the destruction of a chemical munition. Sarin, its hydrolysis products and a number of related compounds were identified on the basis of acquired LC-ESI-MS data. Full mass spectra were acquired for 14 compounds, with all exhibiting MH+, [MH+ACN]+ ions and/or protonated dimers that could be used to confirm molecular mass. Sampling cone voltages from 20 to 70 V were utilized with the higher sampling voltages enhancing formation of structurally important product ions in the ESI interface. All data were acquired with a time-of-flight mass spectrometer with a resolution of 5,000 (50% valley definition), a resolution that aided in the assignment of elemental composition of the observed ions. The application of LC-ESI-MS to snow analysis appears to be an attractive alternative to the GC-MS methods, since both chemical warfare agents and their hydrolysis products may be analysed directly, eliminating the need for additional sample handling and derivatization steps.

Chemical Warfare Agents↗
PubMed2002

Selective stationary phase for solid-phase microextraction analysis of sarin (GB).

A number of critical field applications require monitoring air samples for trace levels of chemical warfare agents. Solid-phase microextraction (SPME) is a convenient format to conduct these analyses. Measurements could be significantly improved if a SPME phase selective for nerve agents were substituted for non-selective polymers typically used (e.g., polydimethylsiloxane). This paper evaluates a novel stationary phase, previously developed for methylphosphonate sensor applications, for use with SPME sampling. The phenol-based polymer, BSP3, was found to offer far higher selectivity toward sarin (GB) than polydimethylsiloxane due to a pronounced affinity toward the target analyte and a lower affinity toward hydrocarbons.

Air↗
PubMed2002

Development of an analytical methodology for sarin (GB) and soman (GD) in various military-related wastes.

The Army requires analytical methods that can detect chemical agents down to the low part-per-billion (ppb) levels in their waste streams in order to meet various state regulations regarding the classification of hazardous waste. Analytical methods were developed for the measurement of sarin (GB) and soman (GD) at ppb levels that involved preconcentration of relatively large volumes (40-150 microliters) of a chloroform extract onto a sorbent cartridge, followed by thermal desorption and analysis by GC-flame photometric detection. Certified reporting limits (CRLs) achieved with these methods ranged from 8.3 to 19 ppb for GB and from 1.8 to 5.3 ppb for GD in the three matrices screened. Method detection limits (MDLs) achieved with these methods ranged from 1.7 to 8.2 ppb for GB and from 0.39 to 1.2 ppb for GD. The methods are capable of achieving lower CRLs and MDLs with only minor modification.

Calibration↗
PubMed1997

Gender differences in activities of mouse esterase and sensitivities to DFP and sarin toxicity.

1. Gender differences in the toxicity of diisopropylfluorophosphate (DFP; 4.0 mg/kg) and isopropyl methylphosphonofluoridate (sarin; 0.3 mg/kg) were studied in mice. 2. The animals were killed 3 hr after intraperitoneal (IP) injection of the organophosphates (OPs). 3. Although the activity of plasma butyrylcholinesterase (BChE) was two-fold higher and carboxylesterase (CaE) 1.3-fold higher in females than in males, the elevated BChE and CaE activities did not prevent inhibition of the enzyme by OPs in brain. 4. The differences in plasma BChE and CaE activities do not seem to be critical for the detoxification of OPs used in this study.

Animals↗
PubMed2000

The effects of sarin-like and soman-like organophosphorus agents on MAPK and JNK in rat brains.

One sarin-like and one soman-like organophosphorus agent [bis(isopropyl methyl)phosphonate, BIMP and bis(pinacolyl methyl)phosphonate, BPMP] were injected intravenously (iv) in rats. An increase in the tyrosine phosphorylation of several proteins in the cytosol fraction of the brain was observed. Activation of c-Jun N-terminal kinase (JNK) and slight activation of mitogen-activated protein kinase (MAPK) in the cytosol were also observed. The activation of these enzymes may be related to the high toxicity of these nerve agents.

Animals↗
PubMed2005

Indoor sorption of surrogates for sarin and related nerve agents.

Sorption rate parameters were determined for three organophosphorus (OP) compounds [dimethyl methylphosphonate (DMMP), diethyl ethylphosphonate (DEEP), and triethyl phosphate (TEP)] as surrogates for the G-type nerve agents sarin (GB), soman (GD), and tabun (GA). OP surrogates were injected and vaporized with additional volatile organic compounds into a 50 m3 chamber finished with painted wallboard. Experiments were conducted at two furnishing levels: (i) chamber containing only hard surfaces including a desk, a bookcase, tables, and chairs and (ii) with the addition of plush materials including carpet with cushion, draperies, and upholstered furniture. Each furnishing level was studied with aged and new painted wallboard. Gas-phase concentrations were measured during sealed chamber adsorb and desorb phases and then fit to three mathematical variations of a previously proposed sorption model having a surface sink and allowing for an embedded sink. A four-parameter model allowing unequal transport rates between surface and embedded sinks provided excellent fits for all conditions. To evaluate the potential effect of sorption, this model was incorporated into an indoor air quality simulation model to predict indoor concentrations of a G-type agent and a nonsorbing agent for hypothetical outdoor releases with shelter-in-place (SIP) response. Sorption was simulated using a range of parameters obtained experimentally. Simulations considered outdoor Gaussian plumes of 1- and 5-h duration and infiltration rates of 0.1, 0.3, and 0.9 h(-1). Indoor toxic loads (TL) for a 10-h SIP were calculated as integral C2 dt for a G-type agent. For the 5-h plume, sheltering reduced TLs for the nonsorbing agent to approximately 10-65% of outdoor levels. Analogous TLs for a G-type agent were 2-31% or 0.3-12% of outdoor levels assuming slow or moderate sorption. The relative effect of sorption was more pronounced for the longer plume and higher infiltration rates.

Adsorption↗
PubMed2001

Mobility of the active site bound paraoxon and sarin in zinc-phosphotriesterase by molecular dynamics simulation and quantum chemical calculation.

The kinetic data published on phosphotriesterase (PTE), with various complexed metals, clearly indicates that the P=O and P=S bonds of phosphotriester and thiophosphotriester substrates, respectively, are strongly polarized by one or both of the active site complexed metal ions. However, this observation is not consistent with the three-dimensional X-ray crystal structure of zinc-substituted PTE with active site bound substrate analogue diethyl 4-methylbenzylphosphonate. In this structure, the distance between the phosphoryl oxygen and the nearest zinc is 3.4 A, a distance too large to afford strong polarization. In the present paper, the geometry and mobility of various PTE active site-substrate complexes are examined by performing both molecular dynamics (MD) simulations and quantum mechanical calculations. Two known substrates are considered, paraoxon and sarin, although their turnover rates vary about 100-fold. The results indicate that PTE forms a complex with either substrate in which the phosphoryl oxygen becomes strongly coordinated with the less buried zinc atom. It is shown that the geometry of the active site is changed when the protein is immersed in a water bath and relaxed by MD. The most substantial conformational change is the opening of the gateway in a pocket where the location of the leaving group is expected. The opening is observed for the pure enzyme as well as for the enzyme/substrate complexes and it ranges from 11 to 18 A. It is also shown that the pockets, in which the substrate substituents are localized, exhibit different flexibility and interact with the substrate with coordinated conformational adjustments.

Aryldialkylphosphatase↗
PubMed2006

Phosphonylation mechanisms of sarin and acetylcholinesterase: a model DFT study.

Potential energy surfaces for the phosphonylation of sarin and acetylcholinesterase (AChE) have been theoretically studied at the B3LYP/6-311G(d,p) level of theory. The obtained results show that the phosphonylation process involves a two-step addition-elimination mechanism, with the first step (addition process) being the rate-determining step, while by comparison, the ensuing steps are very rapid. Stable trigonal bipyramidal intermediates are formed in the studied pathways. It is also revealed that the catalytic triad of acetylcholinesterase plays the catalytic role in the reaction by speeding up the phosphonylation process, as it does in the acylation reaction of ACh and AChE. The effect of aqueous solvation was accounted for via the polarizable continuum model. It is concluded that the enzymatic reaction here is influenced strongly by the solvent environment.

Acetylcholinesterase↗