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1.
Biochemistry ; 60(38): 2875-2887, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34494832

RESUMO

The G-type nerve agents, sarin (GB), soman (GD), and cyclosarin (GF), are among the most toxic compounds known. Much progress has been made in evolving the enzyme phosphotriesterase (PTE) from Pseudomonas diminuta for the decontamination of the G-agents; however, the extreme toxicity of the G-agents makes the use of substrate analogues necessary. Typical analogues utilize a chromogenic leaving group to facilitate high-throughput screening, and substitution of an O-methyl for the P-methyl group found in the G-agents, in an effort to reduce toxicity. Till date, there has been no systematic evaluation of the effects of these substitutions on catalytic activity, and the presumed reduction in toxicity has not been tested. A series of 21 G-agent analogues, including all combinations of O-methyl, p-nitrophenyl, and thiophosphate substitutions, have been synthesized and evaluated for their ability to unveil the stereoselectivity and catalytic activity of PTE variants against the authentic G-type nerve agents. The potential toxicity of these analogues was evaluated by measuring the rate of inactivation of acetylcholinesterase (AChE). All of the substitutions reduced inactivation of AChE by more than 100-fold, with the most effective being the thiophosphate analogues, which reduced the rate of inactivation by about 4-5 orders of magnitude. The analogues were found to reliably predict changes in catalytic activity and stereoselectivity of the PTE variants and led to the identification of the BHR-30 variant, which has no apparent stereoselectivity against GD and a kcat/Km of 1.4 × 106, making it the most efficient enzyme for GD decontamination reported till date.


Assuntos
Compostos Organofosforados/toxicidade , Sarina/análogos & derivados , Soman/análogos & derivados , Acetilcolinesterase/química , Catálise , Substâncias para a Guerra Química/química , Hidrólise , Agentes Neurotóxicos , Organofosfatos/química , Compostos Organofosforados/química , Compostos Organotiofosforados/química , Hidrolases de Triester Fosfórico/química , Sarina/química , Sarina/toxicidade , Soman/química , Soman/toxicidade
2.
Anal Chem ; 93(36): 12230-12236, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34469120

RESUMO

Position-specific isotope analysis (PSIA) by NMR spectroscopy is a technique that provides quantitative isotopic values for every site-a so-called isotopic fingerprint-of a compound of interest. The isotopic fingerprint can be used to link samples with a common origin or to attribute a synthetic chemical to its precursor source. Despite PSIA by NMR being a powerful tool in chemical forensics, it has not yet been applied on chemical warfare agents (CWAs). In this study, different batches of the CWA Soman were synthesized from three distinctive pinacolyl alcohols (PinOHs). Prior to NMR analysis, the Soman samples were hydrolyzed to the less toxic pinacolyl methylphosphonate (PMP), which is a common degradation product. The PinOHs and PMPs were applied to PSIA by 2H NMR experiments to measure the isotopic distribution of naturally abundant 2H within the pinacolyl moiety. By normalizing the 2H NMR peak areas, we show that the different PinOHs have unique intramolecular isotopic distributions. This normalization method makes the study independent of references and sample concentration. We also demonstrate, for the first time, that the isotopic fingerprint retrieved from PSIA by NMR remains stable during the production and degradation of the CWA. By comparing the intramolecular isotopic profiles of the precursor PinOH with the degradation product PMP, it is possible to attribute them to each other.


Assuntos
Substâncias para a Guerra Química , Soman , Substâncias para a Guerra Química/análise , Isótopos , Espectroscopia de Ressonância Magnética
3.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361784

RESUMO

The field of gas chromatography-mass spectrometry (GC-MS) in the analysis of chemical warfare agents (CWAs), specifically those involving the organophosphorus-based nerve agents (OPNAs), is a continually evolving and dynamic area of research. The ever-present interest in this field within analytical chemistry is driven by the constant threat posed by these lethal CWAs, highlighted by their use during the Tokyo subway attack in 1995, their deliberate use on civilians in Syria in 2013, and their use in the poisoning of Sergei and Yulia Skripal in Great Britain in 2018 and Alexei Navalny in 2020. These events coupled with their potential for mass destruction only serve to stress the importance of developing methods for their rapid and unambiguous detection. Although the direct detection of OPNAs is possible by GC-MS, in most instances, the analytical chemist must rely on the detection of the products arising from their degradation. To this end, derivatization reactions mainly in the form of silylations and alkylations employing a vast array of reagents have played a pivotal role in the efficient detection of these products that can be used retrospectively to identify the original OPNA.


Assuntos
Agentes Neurotóxicos/análise , Organofosfatos/análise , Compostos Organofosforados/análise , Compostos Organotiofosforados/análise , Sarina/análise , Soman/análise , Alquilação , Fluorbenzenos/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Hidrólise , Metilação , Agentes Neurotóxicos/química , Organofosfatos/química , Compostos Organofosforados/química , Compostos Organotiofosforados/química , Sarina/química , Soman/química
4.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201878

RESUMO

Composites of metal-organic frameworks and carbon materials have been suggested to be effective materials for the decomposition of chemical warfare agents. In this study, we synthesized UiO-66-NH2/zeolite-templated carbon (ZTC) composites for the adsorption and decomposition of the nerve agents sarin and soman. UiO-66-NH2/ZTC composites with good dispersion were prepared via a solvothermal method. Characterization studies showed that the composites had higher specific surface areas than pristine UiO-66-NH2, with broad pore size distributions centered at 1-2 nm. Owing to their porous nature, the UiO-66-NH2/ZTC composites could adsorb more water at 80% relative humidity. Among the UiO-66-NH2/ZTC composites, U0.8Z0.2 showed the best degradation performance. Characterization and gas adsorption studies revealed that beta-ZTC in U0.8Z0.2 provided additional adsorption and degradation sites for nerve agents. Among the investigated materials, including the pristine materials, U0.8Z0.2 also exhibited the best protection performance against the nerve agents. These results demonstrate that U0.8Z0.2 has the optimal composition for exploiting the degradation performance of pristine UiO-66-NH2 and the adsorption performance of pristine beta-ZTC.


Assuntos
Carbono/química , Estruturas Metalorgânicas/química , Agentes Neurotóxicos/química , Compostos Organometálicos/química , Ácidos Ftálicos/química , Zeolitas/química , Adsorção , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/ultraestrutura , Microscopia Eletrônica de Varredura , Porosidade , Sarina/química , Soman/química , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química , Difração de Raios X
5.
Chem Biol Interact ; 344: 109499, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961835

RESUMO

Exogenously administered human serum butyrylcholinesterase (Hu BChE) affords protection by binding to organophosphorus (OP) nerve agents and pesticides in circulation. The resulting Hu BChE-OP conjugate undergoes 'aging' and the conjugate circulates until cleared from the body. Thus, we evaluated the effects of Hu BChE-OP conjugates on the general health and operant behavior of macaques. Rhesus macaques trained to perform a six-item serial probe recognition (SPR) task were administered 30 mg/kg of Hu BChE-soman conjugate (n = 4) or Hu BChE-VX conjugate (n = 4) by intramuscular injection. Performance on the SPR task was evaluated at 60-90 min after conjugate administration and daily thereafter for the next 4 weeks. Diazepam (3.2 mg/kg), a positive control, was administered 5 weeks after conjugate administration and performance on the SPR task was evaluated as before. Blood collected throughout the study was analyzed for acetylcholinesterase (AChE) and BChE activities. Residual BChE activity of conjugates displayed a similar pharmacokinetic profile as free Hu BChE. Neither of the Hu BChE-OP conjugates produced clear or pronounced degradations in performance on the SPR task. In contrast, diazepam clearly impaired performance on the SPR task on the day of administration in 7 of 8 macaques (and sometimes longer). Taken together, these results suggest that Hu BChE-OP conjugates are safe and provide further support for the development of Hu BChE as a bioscavenger for use in humans.


Assuntos
Butirilcolinesterase/toxicidade , Agentes Neurotóxicos/toxicidade , Compostos Organotiofosforados/toxicidade , Soman/toxicidade , Animais , Butirilcolinesterase/química , Butirilcolinesterase/farmacocinética , Diazepam/farmacologia , Feminino , Humanos , Macaca mulatta , Masculino , Memória/efeitos dos fármacos , Agentes Neurotóxicos/química , Agentes Neurotóxicos/farmacocinética , Compostos Organotiofosforados/química , Compostos Organotiofosforados/farmacocinética , Soman/química , Soman/farmacocinética
6.
Toxicol Appl Pharmacol ; 419: 115515, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33798593

RESUMO

Exposure to organophosphorus nerve agents (NAs) like sarin (GB) and soman (GD) can lead to sustained seizure activity, or status epilepticus (SE). Previous research has shown that activation of A1 adenosine receptors (A1ARs) can inhibit neuronal excitability, which could aid in SE termination. Two A1AR agonists, 2-Chloro-N6-cyclopentyladenosine (CCPA) and N-Bicyclo(2.2.1)hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA), were effective in terminating GD-induced SE in rats when administered via intraperitoneal (IP) injection. However, IP injection is not a clinically relevant route of administration. This study evaluated the efficacy of these agonists in terminating NA-induced SE when administered via intramuscular (IM) route. Adult male rats were exposed subcutaneously (SC) to either GB (150 µg/kg) or GD (90 µg/kg) and were treated with ENBA or CCPA at 15, 30, or 60 min after seizure onset or left untreated. Up to 7 days after exposure, deeply anesthetized rats were euthanized and perfused brains were removed for histologic assessment of neuropathology (i.e., neuronal damage) in six brain regions (amygdala, cerebral cortex, piriform cortex, thalamus, dorsal hippocampus, and ventral hippocampus). A total neuropathy score (0-24) was determined for each rat by adding the scores from each of the six regions. The higher the total score the more severe the neuropathology. With the GB model and 60 min treatment delay, ENBA-treated rats experienced 78.6% seizure termination (N = 14) and reduced neuropathology (11.6 ± 2.6, N = 5), CCPA-treated rats experienced 85.7% seizure termination (N = 14) and slightly reduced neuropathology (20.7 ± 1.8, N = 6), and untreated rats experienced no seizure termination (N = 13) and severe neuropathology (22.3 ± 1.0, N = 4). With the GD model and 60 min treatment delay, ENBA-treated rats experienced 92.9% seizure termination (N = 14) and reduced neuropathology (13.96 ± 1.8, N = 9), CCPA-treated rats experienced 78.6% seizure termination (N = 14) and slightly reduced neuropathology (22.0 ± 0.9, N = 10); and untreated rats experienced 16.7% seizure termination (N = 12) and severe neuropathology (22.0 ± 1.8, N = 5). While ENBA and CCPA both demonstrate a clear ability to terminate SE when administered up to 60 min after seizure onset, ENBA offers more neuroprotection, making it a promising candidate for NA-induced SE.


Assuntos
Agonistas do Receptor A1 de Adenosina/administração & dosagem , Adenosina/análogos & derivados , Anticonvulsivantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Desoxiadenosinas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Norbornanos/administração & dosagem , Sarina , Soman , Estado Epiléptico/prevenção & controle , Adenosina/administração & dosagem , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Esquema de Medicação , Injeções Intramusculares , Masculino , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Fatores de Tempo
7.
Chem Biol Interact ; 342: 109463, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831382

RESUMO

Memantine is the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, used in the treatment of Alzheimer's disease. It is also known that memantine pretreatment assured protection of skeletal muscles from poisoning with nerve agents and an interaction between memantine and AChE was proposed. In the study presented we examined interactions of memantine and its main metabolite (1-amino-3-hydroxymethyl-5-methyl adamantine, Mrz 2/373) with AChE in vitro as well as their effect on kinetics of the soman-induced AChE inhibition and aging. The results have shown that memantine and Mrz 2/373 exerted concentration-dependent inhibition of AChE, with Mrz 2/373 being a more potent inhibitor than the parent compound. Addition of soman 7.5 nmol/l induced gradual AChE inhibition that became almost complete after 20 min. Memantine (0.1, 0.5 and 1 mmol/l) and Mrz 2/373 (0.1, 0.5 and 1 mmol/l) concentration-dependently slowed down the AChE inhibition. After 30 min of incubation of AChE with soman, 5 min of aging and 20 min of reactivation by asoxime (HI-6 dichloride), AChE activity was 8.1% in control medium, 30.7% and 41.9% after addition of 1 and 10 mmol/l memantine, and 16.1% after addition of 1 mmol/l Mrz 2/373. It was concluded that it is possible that memantine and Mrz 2/373 can prevent AChE from inhibition by soman, which could, along with known memantine's neuroprotective activity, explain its potent antidotal effect in soman poisoning. The potential effect on aging of the soman-AChE complex warrants further studies.


Assuntos
Inibidores da Colinesterase/farmacologia , Memantina/farmacologia , Soman/farmacologia , Animais , Bovinos , Inibidores da Colinesterase/química , Dopaminérgicos/farmacologia , Redução da Medicação , Memantina/química , Memantina/metabolismo , Estrutura Molecular , Fatores de Tempo
8.
Neurosci Bull ; 37(7): 905-920, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33761112

RESUMO

Nerve agents are used in civil wars and terrorist attacks, posing a threat to public safety. Acute exposure to nerve agents such as soman (GD) causes serious brain damage, leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and neuroinflammation. However, data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are limited. Here, we evaluated the potential effects of transient receptor vanilloid 4 (TRPV4) in the treatment of soman-induced status epilepticus (SE) and secondary brain injury. We demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced seizures. Administration of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE intensity. TRPV4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman exposure. Further in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate excitotoxicity. The protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1ß and IL-18 increased in soman-exposed rat hippocampus. However, TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome pathway. In conclusion, our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated neuroinflammation. To our knowledge, this is the first study regarding the "dual-switch" function of TRPV4 in the treatment of soman intoxication.


Assuntos
Lesões Encefálicas , Soman , Estado Epiléptico , Animais , Encéfalo , Inflamassomos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Receptores de N-Metil-D-Aspartato , Soman/toxicidade , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Canais de Cátion TRPV
9.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672922

RESUMO

The identification of improved medical countermeasures against exposure to chemical warfare nerve agents (CWNAs), a class of organophosphorus compounds, is dependent on the choice of animal model used in preclinical studies. CWNAs bind to acetylcholinesterase and prevent the catalysis of acetylcholine, causing a plethora of peripheral and central physiologic manifestations, including seizure. Rodents are widely used to elucidate the effects of CWNA-induced seizure, albeit with a caveat: they express carboxylesterase activity in plasma. Carboxylesterase, an enzyme involved in the detoxification of some organophosphorus compounds, plays a scavenging role and decreases CWNA availability, thus exerting a protective effect. Furthermore, species-specific amino acid differences in acetylcholinesterase confound studies that use oximes or other compounds to restore its function after inhibition by CWNA. The creation of a human acetylcholinesterase knock-in/serum carboxylesterase knockout (C57BL/6-Ces1ctm1.1LocAChEtm1.1Loc/J; a.k.a KIKO) mouse may facilitate better modeling of CWNA toxicity in a small rodent species. The current studies characterize the effects of exposure to soman, a highly toxic CWNA, and evaluate the efficacy of anti-seizure drugs in this newly developed KIKO mouse model. Data demonstrate that a combination of midazolam and ketamine reduces seizure duration and severity, eliminates the development of spontaneous recurrent seizures, and protects certain brain regions from neuronal damage in a genetically modified model with human relevance to organophosphorus compound toxicity. This new animal model and the results of this study and future studies using it will enhance medical countermeasures development for both defense and homeland security purposes.


Assuntos
Acetilcolinesterase/metabolismo , Carboxilesterase/metabolismo , Modelos Animais de Doenças , Contramedidas Médicas , Soman/toxicidade , Acetilcolinesterase/genética , Anestésicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Carboxilesterase/genética , Substâncias para a Guerra Química/toxicidade , Humanos , Ketamina/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Midazolam/farmacologia , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Convulsões/prevenção & controle
10.
Toxicol Appl Pharmacol ; 416: 115466, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631229

RESUMO

Soman, an organophosphorus (OP) compound, disrupts nervous system function through inactivation of acetylcholinesterase (AChE), the enzyme that breaks down acetylcholine at synapses. Left untreated, a state of prolonged seizure activity (status epilepticus, SE) is induced, causing widespread neuronal damage and associated cognitive and behavioral impairments. Previous research demonstrated that therapeutic stimulation of A1 adenosine receptors (A1ARs) can prevent or terminate soman-induced seizure. This study examined the ability of three potent A1AR agonists to provide neuroprotection and, ultimately, prevent observable cognitive and behavioral deficits following exposure to soman. Sprague Dawley rats were challenged with a seizure-inducing dose of soman (1.2 x LD50) and treated 1 min later with one of the following A1AR agonists: (6)-Cyclopentyladenosine (CPA), 2-Chloro-N6-cyclopentyladenosine (CCPA) or N-bicyclo(2.2.1)hept-2-yl-5'-chloro-5'-deoxyadenosine (cdENBA). An active avoidance shuttle box task was used to evaluate locomotor responses to aversive stimuli at 3, 7 and 14 days post-exposure. Animals treated with CPA, CCPA or cdENBA demonstrated a higher number of avoidance responses and a faster reaction to the aversive stimulus than the soman/saline control group across all three sessions. Findings suggest that A1AR agonism is a promising neuroprotective countermeasure, capable of preventing the long-term deficits in learning and memory that are characteristic of soman intoxication.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Intoxicação por Organofosfatos/prevenção & controle , Receptor A1 de Adenosina/efeitos dos fármacos , Convulsões/prevenção & controle , Soman , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Desoxiadenosinas/farmacologia , Modelos Animais de Doenças , Masculino , Intoxicação por Organofosfatos/etiologia , Intoxicação por Organofosfatos/metabolismo , Intoxicação por Organofosfatos/fisiopatologia , Ratos Sprague-Dawley , Receptor A1 de Adenosina/metabolismo , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia
11.
Toxicol Lett ; 336: 50-56, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33147512

RESUMO

Nerve agent exposure can cause debilitating neurological damage even with treatment. Currently accepted treatments involve attenuating the cholinergic crisis and seizure onset but do not focus directly on neuroprotection. Hence, there is a need for improved treatments to reduce neurological deficits. It is important to understand the pathophysiology of nerve agent mediated injury in order to identify effective treatment targets. Nerve agent-induced seizures are believed to be the main contributor to the neuropathology. Recently seizures have been shown to cause vascular changes that may actually attenuate neurological damage. This study evaluated the effect of soman-induced convulsive seizures on the relationship between CNS oxygen consumption and supply. To simultaneously assess changes in oxygenation and perfusion, rats were implanted with permanently fixed fiber-optic tissue oxygen sensing probes in the motor cortex and imaged with continuous arterial spin labelling MRI to measure cerebral blood flow. Baseline tissue oxygen tension (ptO2) and cerebral blood flow (CBF) were measured in isoflurane anaesthetized rats at least one day prior to soman or saline exposure. Rats were pretreated with HI-6 dimethansulfonate and atropine methyl nitrate (125 mg/kg and 20 mg/kg; intraperitoneal) followed by a convulsive dose of soman (90 µg/kg; subcutaneous) or equal volume of saline. Three additional treatments of HI-6/AMN were administered to improve survival. At 1.5 -hs after exposure, ptO2 and cerebral blood flow measurements were conducted. There was a significant decrease in CBF 1.5 -hs following soman exposure but no change in ptO2 was found. When we correlated ptO2 and CBF, for a given ptO2, there was lower CBF following soman exposure. This may indicate metabolism is inhibited, possibly because of mitochondrial impairment, therefore reducing oxygen demand. These data show hypoperfusion in brain following soman exposure which would be expected to contribute to soman-related neuropathology.


Assuntos
Circulação Cerebrovascular , Substâncias para a Guerra Química , Metabolismo Energético , Córtex Motor/irrigação sanguínea , Consumo de Oxigênio , Oxigênio/sangue , Convulsões/induzido quimicamente , Soman , Animais , Modelos Animais de Doenças , Masculino , Ratos Sprague-Dawley , Convulsões/sangue , Convulsões/fisiopatologia , Fatores de Tempo
12.
J Chromatogr A ; 1636: 461784, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33360649

RESUMO

Commercial gas chromatograph-mass spectrometers, one of which being Inficon's HAPSITE® ER, have demonstrated chemical detection and identification of nerve agents (G-series) and blistering agents (mustard gas) in the field; however most analyses relies on self-contained or external calibration that inherently drifts over time. We describe an analytical approach that uses target-based thermal desorption standards, called focusing agents, to accurately calculate concentrations of chemical warfare agents that are analyzed by gas chromatograph-mass spectrometry. Here, we provide relative response factors of focusing agents (2-chloroethyl ethyl sulfide, diisopropyl fluorophosphate, diethyl methylphosphonate, diethyl malonate, methyl salicylate, and dichlorvos) that are used to quantify concentrations of tabun, sarin, soman, cyclosarin and sulfur mustard loaded on thermal desorption tubes (Tenax® TA). Aging effects of focusing agents are evaluated by monitoring deviations in quantification as thermal desorption tubes age in storage at room temperature and relative humidity. The addition of focusing agents improves the quantification of tabun, sarin, soman, cyclosarin and sulfur mustard that is analyzed within the same day as well as a 14-day period. Among the six focusing agents studied here, diisopropyl fluorophosphate has the best performance for nerve agents (G-series) and blistering agents (mustard gas) compared to other focusing agents in this work and is recommended for field use for quantification. The use of focusing agent in the field leads to more accurate and reliable quantification of Tabun (GA), Sarin (GB), Soman (GD), Cyclosarin (GF) and Sulfur Mustard (HD) than the traditional internal standard. Future improvements on the detection of chemical, biological, radiological, nuclear, and explosive materials (CBRNE) can be safely demonstrated with standards calibrated for harmful agents.


Assuntos
Substâncias para a Guerra Química/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Gás de Mostarda/análise , Organofosfatos/análise , Compostos Organofosforados/análise , Sarina/análise , Soman/análise , Substâncias para a Guerra Química/normas , Cromatografia Gasosa-Espectrometria de Massas/instrumentação , Cromatografia Gasosa-Espectrometria de Massas/normas , Padrões de Referência
13.
Toxicol Mech Methods ; 30(9): 703-710, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32878547

RESUMO

Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD50 values of nerve agents over 24 h following poisoning without or with a single administration of antidotal treatment. In this study, LD50 values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated poisoning were evaluated in mice for two experimental end points - 6 h and 24 h. While the efficacy of atropine or oxime-based antidotal treatment was the same regardless of the experimental end point, the therapeutic efficacy of all three newly developed bispyridinium non-oxime compounds (MB408, MB442, and MB444) was mostly slightly higher at the 6 h end point compared to the 24 h end point, although the therapeutic efficacy of MB compounds was not superior to oxime-based antidotal treatment. These results contrast with a study in guinea-pigs using a structurally-related compound, MB327, which showed a striking increase in protection at 6 h compared to 24 h. It is suggested that the disparity may be due to pharmacokinetic differences between the two animal species.


Assuntos
Antídotos/farmacologia , Substâncias para a Guerra Química/toxicidade , Reativadores da Colinesterase/farmacologia , Antagonistas Nicotínicos/farmacologia , Intoxicação por Organofosfatos/tratamento farmacológico , Animais , Dose Letal Mediana , Masculino , Camundongos , Intoxicação por Organofosfatos/etiologia , Organofosfatos/toxicidade , Compostos Organofosforados/toxicidade , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Sarina/toxicidade , Soman/toxicidade , Fatores de Tempo
14.
Sci Rep ; 10(1): 13007, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747689

RESUMO

Organophosphorus compounds, such as chemical warfare nerve agents and pesticides, are known to cause neurological damage. This study measured nerve agent-related neuropathology and determined whether quantitative T2 MRI could be used as a biomarker of neurodegeneration. Quantitative T2 MRI was performed using a 9.4 T MRI on rats prior to and following soman exposure. T2 images were taken at least 24 h prior, 1 h and 18-24 h after soman exposure. Rats were pre- and post-treated with HI-6 dimethanesulfonate and atropine methyl nitrate. A multicomponent T2 acquisition and analysis was performed. Brains were stained with Fluoro-Jade C to assess neurodegeneration. Rats exposed to soman developed behavioral expression of electrographic seizures. At 18-24 h after soman exposure, significant increases in T2, a possible marker of edema, were found in multiple regions. The largest changes were in the piriform cortex (before: 47.7 ± 1.4 ms; 18-24 h: 82.3 ± 13.4 ms). Fluoro-Jade C staining showed significant neurodegeneration 18-24 h post exposure. The piriform cortex had the strongest correlation between the change in relaxation rate and percent neurodegeneration (r = 0.96, p < 0.001). These findings indicate there is regionally specific neurodegeneration 24 h after exposure to soman. The high correlation between T2 relaxivity and histopathology supports the use of T2 as a marker of injury.


Assuntos
Substâncias para a Guerra Química/toxicidade , Imageamento por Ressonância Magnética/métodos , Soman/toxicidade , Animais , Masculino , Modelos Animais , Córtex Piriforme/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente
15.
J Pharmacol Exp Ther ; 375(1): 115-126, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32759369

RESUMO

Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible acetylcholinesterase (AChE) inhibitors can serve as adjunct pretreatments against poisoning by organophosphorus compounds, including the nerve agent soman. The present study was designed to determine whether pretreatment with a clinically relevant oral dose of galantamine HBr mitigates the acute toxicity of 4.0×LD50 soman (15.08 µg/kg) in Macaca fascicularis posttreated intramuscularly with the conventional antidotes atropine (0.4 mg/kg), 2-pyridine aldoxime methyl chloride (30 mg/kg), and midazolam (0.32 mg/kg). The pharmacokinetic profile and maximal degree of blood AChE inhibition (∼25%-40%) revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr in these nonhuman primates (NHPs) translate to human-equivalent doses that are within the range used for AD treatment. Subsequent experiments demonstrated that 100% of NHPs pretreated with either dose of galantamine, challenged with soman, and posttreated with conventional antidotes survived 24 hours. By contrast, given the same posttreatments, 0% and 40% of the NHPs pretreated, respectively, with vehicle and pyridostigmine bromide (1.2 mg/kg, oral), a peripherally acting reversible AChE inhibitor approved as pretreatment for military personnel at risk of exposure to soman, survived 24 hours after the challenge. In addition, soman caused extensive neurodegeneration in the hippocampi of saline- or pyridostigmine-pretreated NHPs, but not in the hippocampi of galantamine-pretreated animals. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supralethal doses of soman in NHPs. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a clinically relevant oral dose of galantamine effectively prevents lethality and neuropathology induced by a supralethal dose of the nerve agent soman in Cynomolgus monkeys posttreated with conventional antidotes. These findings are of major significance for the continued development of galantamine as an adjunct pretreatment against nerve agent poisoning.


Assuntos
Antídotos/uso terapêutico , Substâncias para a Guerra Química/toxicidade , Galantamina/uso terapêutico , Hipocampo/efeitos dos fármacos , Intoxicação por Organofosfatos/prevenção & controle , Soman/toxicidade , Acetilcolinesterase/sangue , Administração Oral , Animais , Antídotos/administração & dosagem , Área Sob a Curva , Galantamina/administração & dosagem , Galantamina/sangue , Hipocampo/patologia , Dose Letal Mediana , Macaca fascicularis , Masculino , Intoxicação por Organofosfatos/enzimologia
16.
Inorg Chem ; 59(16): 11595-11605, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32799468

RESUMO

Due to the unpredictable nature of a battlefield environment, in the simultaneous degradation of sulfur mustard and nerve agents it is preferable to use just one decontaminant. Herein, the new composite HPVMo@MOF-808 (HPVMo = H5PV2Mo10O40) was deliberately synthesized via a simple impregnation method and thoroughly characterized. The results showed that the decontamination rate of the composites (30-40 mg) with optimal HPVMo loadings for HD (4 µL) and GD (4 µL) under ambient conditions was 97.2% (within 120 min) and 90.8% (within 30 min), respectively. Due to the combinational/synergistic effect of MOF-808 and encapsulated homogeneously dispersed HPVMo, the composite can very efficiently oxidize HD to nontoxic products in a single system, while retaining the inherent excellence of MOF-808 in hydrolytically degrading GD. The decontamination process was found to follow first-order reaction kinetics, and the rate constant and half-life of the composite for HD and GD were 0.0231 min-1, 30.13 min and 0.0795 min-1, 8.72 min, respectively. In addition, experimental results in guinea pigs and Kunming mice used as animal models showed that the composite provided effective skin protection against HD and GD, showing great potential for application in skin decontamination and protection.


Assuntos
Substâncias para a Guerra Química/química , Estruturas Metalorgânicas/química , Gás de Mostarda/química , Soman/química , Compostos de Tungstênio/química , Animais , Substâncias para a Guerra Química/envenenamento , Cobaias , Camundongos , Envenenamento/prevenção & controle
17.
ACS Chem Neurosci ; 11(17): 2638-2648, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32702963

RESUMO

The widespread use of organophosphorous (OP) compounds and recent misuse of nerve agents on civilians requires an urgent need to decode their complex biological response to develop effective drugs. Proteomic profiling of biological target tissues helps in identification of molecular toxicity mechanisms. Quantitative proteomics profiling of the rat hippocampus was studied in this study. Liquid chromatography mass spectrometry (LC-MS) analysis of tandem mass tag (TMT)-labeled lysates identified 6356 proteins. A total of 69, 61, and 77 proteins were upregulated, and 66, 35, and 70 proteins were downregulated at 30 min, 1 day, and 7 days after soman exposure. This is the first report on the soman-induced proteomic changes to the best of our knowledge. Bioinformatics analysis revealed soman-induced broad-range proteomic changes in key pathways related to glutamate, acetylcholine, GABA, 5-hydroxytryptamine, and adrenergic receptors, G-protein signaling, chemokine and cytokine-mediated inflammation, cytoskeleton, neurodegeneration (Parkinson's and Alzheimer's), Wnt signaling, synaptic vesicle trafficking, MAP kinases, proteosome degradation, metabolism, and cell death. Selected protein changes were verified by immunoblotting, and neuropathological findings indicated significant brain damage. Results demonstrate that persistent proteomic changes in the brain can cause multiple neurological effects through cholinergic and non-cholinergic pathways, and these mechanistic insights are useful in the development of novel drugs.


Assuntos
Agentes Neurotóxicos , Soman , Animais , Cromatografia Líquida , Hipocampo , Proteômica , Ratos
18.
Ann N Y Acad Sci ; 1480(1): 116-135, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32671850

RESUMO

Nerve agents (NAs) produce acute and long-term brain injury and dysfunction, as evident from the Japan and Syria incidents. Magnetic resonance imaging (MRI) is a versatile technique to examine such chronic anatomical, functional, and neuronal damage in the brain. The objective of this study was to investigate long-term structural and neuronal lesion abnormalities in rats exposed to acute soman intoxication. T2-weighted MRI images of 10 control and 17 soman-exposed rats were acquired using a Siemens MRI system at 90 days after soman exposure. Quantification of brain tissue volumes and T2 signal intensity was conducted using the Inveon Research Workplace software and the extent of damage was correlated with histopathology and cognitive function. Soman-exposed rats showed drastic hippocampal atrophy with neuronal loss and reduced hippocampal volume (HV), indicating severe damage, but had similar T2 relaxation times to the control group, suggesting limited scarring and fluid density changes despite the volume decrease. Conversely, soman-exposed rats displayed significant increases in lateral ventricle volumes and T2 times, signifying strong cerebrospinal fluid expansion in compensation for tissue atrophy. The total brain volume, thalamic volume, and thalamic T2 time were similar in both groups, however, suggesting that some brain regions remained more intact long-term after soman intoxication. The MRI neuronal lesions were positively correlated with the histological markers of neurodegeneration and neuroinflammation 90 days after soman exposure. The predominant MRI hippocampal atrophy (25%) was highly consistent with massive reduction (35%) of neuronal nuclear antigen-positive (NeuN+ ) principal neurons and parvalbumin-positive (PV+ ) inhibitory interneurons within this brain region. The HV was significantly correlated with both inflammatory markers of GFAP+ astrogliosis and IBA1+ microgliosis. The reduced HV was also directly correlated with significant memory deficits in the soman-exposed cohort, confirming a possible neurobiological basis for neurological dysfunction. Together, these findings provide powerful insight on long-term region-specific neurodegenerative patterns after soman exposure and demonstrate the feasibility of in vivo neuroimaging to monitor neuropathology, predict the risk of neurological deficits, and evaluate response to medical countermeasures for NAs.


Assuntos
Hipocampo , Interneurônios , Imageamento por Ressonância Magnética , Transtornos da Memória , Agentes Neurotóxicos/envenenamento , Doenças Neurodegenerativas , Neuroimagem , Soman/envenenamento , Animais , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
19.
Anal Chem ; 92(15): 10578-10587, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32496758

RESUMO

Nerve agents (NAs) are notorious chemical warfare agents that pose a serious threat to national security and public health. The total number of theoretical chemicals of NAs and their degradation products (DPs) exceeds 410 000, according to 1.A.01-1.A.03 in the Schedules of Chemicals of the Chemical Weapons Convention, which poses great challenges for identification and verification. A three-step integrated untargeted screening strategy was developed based on high-resolution mass spectrometry. First, an extensible homemade library for targeted screening of common classical agents was established. Second, a set of in-source collision-induced dissociation mass spectrometry (MS)-alerting ions was extracted and concluded based on fragmentation behavior studies, which included 40 specific alerting ions and 10 types of characteristic structural fragments from total NAs and their DPs. A novel "alerting ion" searching method was developed to rapidly and sensitively screen whether or not nerve agent-related compounds were present and of which type they were. Third, we built a theoretical exact mass database including 202 accurate masses or molecular formulas, which could cover all structural possibilities of the NAs and their DPs. Comprehensively, the elemental composition of pseudomolecular ions, fragment ions, MS/MS spectra, and isotope pattern information were obtained from the full scan MS/data dependent-MS2 experiments and elucidated for identification of the candidates selected in the screening step. This strategy was successfully applied to the identification of unknown chemicals in real samples with good stability and a low limit of detection of 1-10 ng/mL. These procedures are applicable for trace forensic investigations in cases of the alleged use of nerve agents.


Assuntos
Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Compostos Organotiofosforados/química , Sarina/química , Soman/química , Substâncias para a Guerra Química/química , Bases de Dados de Compostos Químicos , Sensibilidade e Especificidade , Bibliotecas de Moléculas Pequenas
20.
Epilepsy Behav ; 111: 107229, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32575012

RESUMO

Delayed treatment of cholinergic seizure results in benzodiazepine-refractory status epilepticus (SE) that is thought, at least in part, to result from maladaptive trafficking of N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid type A (GABAA) receptors, the effects of which may be ameliorated by combination therapy with the NMDA receptor antagonist ketamine. Our objective was to establish whether ketamine and midazolam dual therapy would improve outcome over midazolam monotherapy following soman (GD) exposure when evaluated in a mouse model that, similar to humans, lacks plasma carboxylesterase, greatly reducing endogenous scavenging of GD. In the current study, continuous cortical electroencephalographic activity was evaluated in male and female plasma carboxylesterase knockout mice exposed to a seizure-inducing dose of GD and treated with midazolam or with midazolam and ketamine combination at 40 min after seizure onset. Ketamine and midazolam combination reduced GD-induced lethality, seizure severity, and the number of mice that developed spontaneous recurrent seizure (SRS) compared with midazolam monotherapy. In addition, ketamine-midazolam combination treatment reduced GD-induced neuronal degeneration and microgliosis. These results support that combination of antiepileptic drug therapies aimed at correcting the maladaptive GABAA and NMDA receptor trafficking reduces the detrimental effects of GD exposure. Ketamine may be a beneficial adjunct to midazolam in reducing the epileptogenesis and neuroanatomical damage that follows nerve agent exposure and pharmacoresistant SE.


Assuntos
Encéfalo/patologia , Carboxilesterase/sangue , Ketamina/administração & dosagem , Midazolam/administração & dosagem , Soman/toxicidade , Estado Epiléptico/sangue , Animais , Anticonvulsivantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Carboxilesterase/deficiência , Quimioterapia Combinada , Eletroencefalografia/métodos , Feminino , Masculino , Camundongos , Camundongos Knockout , Convulsões/sangue , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico
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