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Christopher J. Gordon - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological analysis of Diisopropyl Fluorophosphate: effects on core temperature, heart rate, and motor activity in the unrestrained rat.
Pharmacology biochemistry and behavior, 1996Co-Authors: Christopher J. GordonAbstract:Abstract Humans acutely exposed to anticholinesterase (anti-ChE) pesticides often become febrile, whereas rats and other rodents become markedly hypothermic. The rat may nonetheless be a useful model for anti-ChE toxicity because recent work using radiotelemetry demonstrated an elevation in core temperature of unrestrained rats for several days following acute exposure to the anti-ChE, Diisopropyl Fluorophosphate (DFP). To discern the mechanisms of DFP-induced hypothermia and hyperthermia, various pharmacological agents were administered acutely or chronically to rats injected with 1.5 mg/kg DFP (SC). Core temperature, heart rate, and motor activity were monitored continuously via radiotelemetry. Methylscopolamine, a peripheral muscarinic antagonist, attenuated the DFP-induced hypothermia by 1.0 °C and reversed the DFP-induced bradycardia. Chronic scopolamine, a central and peripheral muscarinic antagonist, delivered via a subcutaneously implanted minipump (9.5 mg/kg/day) blocked DFP-induced hypothermia and hyperthermia. Propranolol (10 mg/kg; SC), a general beta blocker, augmented the bradycardic effects of DFP but had no effect on body temperature. Sodium salicylate (200 and 300 mg/kg; IP), an antipyretic that inhibits prostaglandin synthesis, administered during the period of DFP-induced hyperthermia produced a transient recovery in body temperature. Overall, DFP-induced hypothermia and hyperthermia in the rat appear to be mediated via cholinergic activation in the CNS because both are blocked by scopolamine. The decrease in core temperature following sodium salicylate suggests that prostaglandin release is involved in the manifestation of DFP-induced hyperthermia. The elevation in core temperature after DFP appears to involve neurochemical pathways similar to that of fever.
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Factors influencing Diisopropyl Fluorophosphate-induced hypothermia and hyperthermia in the rat
Neurotoxicology and teratology, 1995Co-Authors: Christopher J. GordonAbstract:Abstract Exposing rats to the anticholinesterase (anti-ChE) Diisopropyl Fluorophosphate (DFP) causes a transient period of hypothermia followed by a period of hyperthermia lasting approximately 48 h. Because a fever is a predominant thermoregulatory response in humans exposed to anti-ChE pesticides, the hyperthermic response in the rat may be important to understanding the central neural mechanisms of anti-ChEs. The purpose of the present study was to assess the dependence of DFP-induced thermoregulatory changes on basal behavioral and autonomic activity in the rat. Core temperature (Tc), heart rate (HR), and motor activity (MA) were monitored via radiotelemetry in unrestrained rats 24 h prior to and 72 h after administration of the peanut oil vehicle or 1.5 mg/kg DFP. Mean Tc decreased by ∼4°C by 4 h after DFP, returned to baseline by 27 h, and then remained ∼ 0.8 °C above control daytime levels during the second day after DFP injection. Correlations of DFP-induced hypothermia and hyperthermia with baseline Tc, HR, and MA were performed. The baseline Tc was inversely correlated with the magnitude of DFP-induced hyperthermia (r2 = 0.6). DFP-induced hyperthermia was also inversely correlated with baseline HR and MA. The minimum core temperature during DFP-induced hypothermia was directly correlated with the baseline Tc. The inverse pattern between baseline Tc and DFP-induced hyperthermia is similar to that of rats administered endotoxin and other pyrogenic agents. Sixty percent of the variation in DFP-induced hyperthermia, a toxic response seen > 48 h after exposure, can be explained by individual differences in baseline Tc. This relationship may be important in understanding the thermoregulatory and metabolic effects of anti-ChE agents.
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Autonomic and behavioral responses of selectively bred hypercholinergic rats to oxotremorine and Diisopropyl Fluorophosphate
Pharmacology biochemistry and behavior, 1994Co-Authors: Amir H. Rezvani, David H. Overstreet, Archana Ejantkar, Christopher J. GordonAbstract:The hypercholinergic Flinders Sensitive Line (FSL) rat was significantly more sensitive than the Flinders Resistant Line (FRL) rat to the biotelemetrically recorded hypothermic effects of oxotremorine, a direct-acting muscarinic agonist, and Diisopropyl Fluorophosphate (DFP), an anticholinesterase agent. The effects of these agents on heart rate and motor activity, also recorded biotelemetrically, indicate either small differences (DFP) or no significant effect (oxotremorine) between the lines. These findings confirm the dramatic differences in temperature responses to cholinergic compounds between FSL and FRL rats, for which they were selectively bred, but suggest that a general increase in the sensitivity of the FSL rats to all muscarinic-mediated responses may not occur.
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24-hour control of body temperature in the rat: II. Diisopropyl Fluorophosphate-induced hypothermia and hyperthermia.
Pharmacology biochemistry and behavior, 1994Co-Authors: Christopher J. GordonAbstract:Abstract Diisopropyl Fluorophosphate (DFP) and other anticholinesterase (antiChE) agents have been found to induce marked hypothermic responses in laboratory rodents. To characterize the effects of DFP on autonomic and behavioral thermoregulation, rats of the Long-Evans strain were injected with DFP while housed in a temperature gradient. The gradient allowed for the measurement of selected ambient temperature ( T a ) and motor activity (MA) over a 6- to 7-day period. Core temperature ( T c ) and heart rate (HR) were also monitored simultaneously using radiotelemetry. Injection of the peanut oil vehicle led to transient elevations in T c , HR, and MA, but no change in selected T a . The next day animals were injected with 0.25, 1.0, or 1.5 mg/kg DFP. DFP (1.0 AND 1.5 mg/kg) led to a marked reduction in T c . The decrease in T c was accompanied by reductions in HR, MA, and selected T a . During the first night after DFP, selected T a remained elevated as T c recovered to its preinjection level. The second 24-h period after 1.0 and 1.5 mg/kg DFP was associated with a significant elevation in the daytime T c . In conclusion, with the option of using behavioral thermoregulatory responses, the hypothermic effects of acute DFP treatment are mediated by a selection for cooler T a s . An elevation in T c during recovery from acute DFP corroborates the many incidents of fever in humans exposed to anti-ChE agents.
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Acute and delayed effects of Diisopropyl Fluorophosphate on body temperature, heart rate, and motor activity in the awake, unrestrained rat
Journal of toxicology and environmental health, 1993Co-Authors: Christopher J. GordonAbstract:Acute exposure to Diisopropyl Fluorophosphate (DFP) causes irreversible inhibition of acetylcholinesterase activity, leading to various behavioral and autonomic sequelae including hypothermia, reduced motor activity, and other neurological dysfunctions. To characterize the acute response and recovery of autonomic and behavioral processes to DFP exposure, rats of the Long‐Evans strain were implanted with radiotrans‐mitters that allowed the monitoring of core temperature, heart rate, and motor activity in unrestrained animals 24 h/d. These parameters were monitored for 96 h following subcutaneous injection of DFP at a dose of 0, 0.1, or 1.0 mg/kg. Rats given 0 and 0.1 mg/kg DFP displayed an increase in core temperature and motor activity during the first 24 h postinjection. The 1.0 mg/kg group showed a typical hypothermic response for the first 24 h following DFP administration. Core temperature decreased a maximum of 1.9°C by 5 h after DFP and then started to recover, reaching control levels by 17 h after ...
Anna Karlsson - One of the best experts on this subject based on the ideXlab platform.
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Ionomycin-induced neutrophil NADPH oxidase activity is selectively inhibited by the serine protease inhibitor Diisopropyl Fluorophosphate.
Antioxidants & redox signaling, 2002Co-Authors: Claes Dahlgren, Anna KarlssonAbstract:The calcium-specific ionophore ionomycin triggers neutrophils to activate their NADPH oxidase and generate reactive oxygen species. This activation is restricted to intracellular sites and involves the neutrophil granules. Cells that have experienced an ionomycin-induced rise in intracellular calcium will also mobilize their intracellular granules and are primed to subsequent challenge with the chemoattractant formylmethionyl-leucyl-phenylalanine (fMLF), but have lost their ability to become desensitized to the same agonist. We have investigated the involvement of serine proteases in the calcium-induced effector functions using the inhibitor Diisopropyl Fluorophosphate (DFP). The ionomycin-induced NADPH oxidase activity was abrogated by the protease inhibitor, whereas the activity induced by fMLF was unaffected. The DFP-dependent inhibition was restricted to the NADPH oxidase activity, as all other ionomycin-induced cellular activities were largely unaffected. We thus suggest that a serine protease is of importance for the calcium ionophore-induced signal(s) to reach and activate the dormant NADPH oxidase in the neutrophil granules.
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Ionomycin-induced neutrophil NADPH oxidase activity is selectively inhibited by the serine protease inhibitor Diisopropyl Fluorophosphate.
Antioxidants & redox signaling, 2002Co-Authors: Claes Dahlgren, Anna KarlssonAbstract:The calcium-specific ionophore ionomycin triggers neutrophils to activate their NADPH oxidase and generate reactive oxygen species. This activation is restricted to intracellular sites and involves the neutrophil granules. Cells that have experienced an ionomycin-induced rise in intracellular calcium will also mobilize their intracellular granules and are primed to subsequent challenge with the chemoattractant formylmethionyl-leucyl-phenylalanine (fMLF), but have lost their ability to become desensitized to the same agonist. We have investigated the involvement of serine proteases in the calcium-induced effector functions using the inhibitor Diisopropyl Fluorophosphate (DFP). The ionomycin-induced NADPH oxidase activity was abrogated by the protease inhibitor, whereas the activity induced by fMLF was unaffected. The DFP-dependent inhibition was restricted to the NADPH oxidase activity, as all other ionomycin-induced cellular activities were largely unaffected. We thus suggest that a serine protease is of ...
Pierre E. Bougis - One of the best experts on this subject based on the ideXlab platform.
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Binding of 125I-fasciculin to Rat Brain Acetylcholinesterase. The Complex Still Binds Diisopropyl Fluorophosphate
The Journal of biological chemistry, 1993Co-Authors: Pascale Marchot, A. Khelif, Pascal Mansuelle, Pierre E. BougisAbstract:Iodination of fasciculin 3 (FAS3) from Dendroaspis viridis venom provided us with a fully active specific probe of fasciculin binding sites on rat brain acetylcholinesterase (AChE). Binding and inhibition are concomitant, as association and inhibition rate constants k1 and ki are identical. The 125I-FAS3.AChE complex dissociates very slowly (t 1/2 = 48 h) and is characterized by a dissociation constant, Kd, of 0.4 pM. All the specific binding of 125I-FAS3 to AChE is prevented by FAS3 as from D. angusticeps venom (Kd = 0.4, 14, and 25 pM, respectively). It is also prevented by propidium iodide, BW284C51, and d-tubocurarine, which bind to peripheral anionic sites of AChE, by Ca2+ and Mg2+, known to enhance AChE activity through an allosteric phenomenon and by acetylthiocholine concentrations which lead to excess substrate inhibition of the enzyme. Diisopropyl fluorphosphate and paroxon, which inhibit AChE by phosphorylating the catalytic serine, have no effect on either the binding rate or the number of binding sites of 125I-FAS3. O-Ethyl-S2-Diisopropylaminoethyl methylphosphonothionate, however, which binds irreversibly to the AChE catalytic site but reversibly to a peripheral site, induces a 130% increase in the binding rate of 125I-FAS3, without changing the total number of 125I-FAS3 binding sites. Our results demonstrate that fasciculins bind on a peripheral site of AChE, distinct from the catalytic site and, at least partly, common with the sites on which some cationic inhibitors and the substrate in excess bind. Since phosphorylation of the catalytic serine (esteratic subsite) by [1,3-3H]Diisopropyl Fluorophosphate can still occur on the FAS3.AChE complex, the structural modification induced by fasciculins may affect the anionic subsite of AChE catalytic site.
G. Maurin - One of the best experts on this subject based on the ideXlab platform.
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Computational evaluation of the chemical warfare agents capture performances of robust MOFs
Microporous and Mesoporous Materials, 2019Co-Authors: C. Vieira Soares, A.a. Leitão, G. MaurinAbstract:A series of stable MOFs containing zirconium or titanium ions as metal centers was screened to assess their capture performances for nerve agents including sarin and soman as well as their standard simulants, i.e. the dimethyl-methyl-phosphonate and Diisopropyl Fluorophosphate. These Monte Carlo simulations revealed that some of these MOFs show very high uptakes that significantly outperform those of other families of porous materials and interestingly they exhibit a very high affinity for these toxic molecules at low loading. These combined features make them potentially attractive to act as nerve agent filters. This set of adsorption data was further rationalized to establish structure-adsorption performances relationship and Monte Carlo simulations were combined with Density Functional Theory calculations to gain more insight into the adsorption mechanism in play. Finally, the choice of reliable simulants to accurately mimic the adsorption behavior of real toxic molecules in MOFs has been further discussed and in particular it has been established that soman is better described considering the pinacolyl methylphosphonate rather than the standard dimethyl-methyl-phosphonate and Diisopropyl Fluorophosphate simulants.
Yarlagadda S. Babu - One of the best experts on this subject based on the ideXlab platform.
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Structure of Diisopropyl Fluorophosphate-inhibited factor D.
Acta Crystallographica Section D Biological Crystallography, 1997Co-Authors: L B Cole, J M Kilpatrick, John E. Volanakis, Sthanam V. L. Narayana, N Chu, Yarlagadda S. BabuAbstract:Factor D (D) is a serine protease, crucial for the activation of the alternative complement pathway. Only a limited number of general serine protease inhibitors are known to inhibit D, most of which covalently bind to the serine hydroxyl of the catalytic triad. The structure of the first enzyme:inhibitor covalent adduct of D with Diisopropyl Fluorophosphate (DIP:D) to a resolution of 2.4 A is described. The inhibited enzyme is similar in overall structure to the native enzyme and to trypsin, yet exhibits notable differences in the active site. One region of the active site is conserved between D and trypsin with respect to amino-acid sequence and to conformation. Another reflects the amino-acid substitutions and conformational flexibility between these enzymes. The active-site histidine residue is observed in the gauche+ conformation, not the normal gauche- orientation seen in the classic catalytic triad arrangement required for enzymatic activity in serine proteases. Comparisons of the active sites between native D, the DIP:D adduct, and DIP-inhibited trypsin have provided fundamental insights currently being employed in the design of novel small-molecule pharmaceutical agents capable of modulating the alternative complement pathway.