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Neurobiology of Disease Jan 2020Organophosphate (OP) chemicals include pesticides such as parathion, and nerve gases such as sarin and soman and are considered major chemical threat agents. Acute OP... (Review)
Review
Organophosphate (OP) chemicals include pesticides such as parathion, and nerve gases such as sarin and soman and are considered major chemical threat agents. Acute OP exposure is associated with a cholinergic crisis and status epilepticus (SE). It is also known that the survivors of OP toxicity exhibit neurobehavioral deficits such as mood changes, depression, and memory impairment, and acquired epilepsy. Our research has focused on addressing the need to develop effective therapeutic agents that could be administered even after prolonged seizures and would prevent or lessen the chronic morbidity associated with OP-SE survival. We have developed rat survival models of OP pesticide metabolite paraoxon (POX) and nerve agent sarin surrogate diisopropyl fluorophosphate (DFP) induced SE that are being used to screen for medical countermeasures against an OP attack. Our research has focused on studying neuronal calcium (Ca) homeostatic mechanisms for identifying mechanisms and therapeutics for the expression of neurological morbidities associated with OP-SE survival. We have observed development of a "Ca plateau" characterized by sustained elevations in neuronal Ca levels in OP-SE surviving rats that coincided with the appearance of OP-SE chronic morbidities. These Ca elevations had their origin in Ca release from the intracellular stores such that blockade with antagonists like dantrolene, carisbamate, and levetiracetam lowered OP-SE mediated Ca plateau and afforded significant neuroprotection. Since the Ca plateau lasts for a prolonged period, our studies suggest that blocking it after the control of SE may represent a unique target for development of novel countermeasures to prevent long term Ca mediated OP-SE neuropsychiatric comorbidities such as depression, anxiety, and acquired epilepsy (AE).
Topics: Animals; Brain; Calcium; Depression; Epilepsy; Homeostasis; Memory Disorders; Neurons; Organophosphate Poisoning; Rats; Status Epilepticus
PubMed: 30872159
DOI: 10.1016/j.nbd.2019.03.006 -
PloS One 20154R-cembranoid (4R) is a natural cyclic diterpenoid found in tobacco leaves that displays neuroprotective activity. 4R protects against NMDA, paraoxon (POX), and...
4R-cembranoid (4R) is a natural cyclic diterpenoid found in tobacco leaves that displays neuroprotective activity. 4R protects against NMDA, paraoxon (POX), and diisopropylfluorophosphate (DFP) damage in rat hippocampal slices and against DFP in rats in vivo. The purpose of this study was to examine the metabolism and pharmacokinetics of 4R as part of its preclinical development as a neuroprotective drug. 10 µM 4R was found to be very stable in plasma for up to 1 hr incubation. 4R metabolism in human microsomes was faster than in the rat. Ten metabolites of 4R were detected in the microsomal samples; 6 dihydroxy and 4 monohydroxy forms of 4R. Male rats received a single dose of 4R at 6 mg/kg i.v., i.m., or s.c. The i.v. group had the highest plasma concentration of 1017 ng/mL. The t1/2 was 36 min and reached the brain within 10 min. The brain peak concentration was 6516 ng/g. The peak plasma concentration in the i.m. group was 163 ng/mL compared to 138 ng/mL in the s.c. group. The t1/2 of 4R after i.m. and s.c. administration was approximately 1.5 hr. The brain peak concentration was 329 ng/g in the i.m. group and 323 ng/g for the s.c. group. The brain to plasma ratio in the i.v. group was 6.4, reached 10 min after dose, whereas in the i.m. and s.c. groups was 2.49 and 2.48, respectively, at 90 min after dose. Our data show that 4R crosses the BBB and concentrates in the brain where it exerts its neuroprotective effect.
Topics: Animals; Diterpenes; Female; Humans; Male; Metabolome; Microsomes, Liver; Rats, Sprague-Dawley
PubMed: 25811857
DOI: 10.1371/journal.pone.0121540 -
International Journal of Molecular... Sep 2023Organophosphorus insecticides (OPs), acting as serine phosphorylating agents in acetylcholinesterase (AChE), are highly effective neurotoxic insecticides. In our...
Organophosphorus insecticides (OPs), acting as serine phosphorylating agents in acetylcholinesterase (AChE), are highly effective neurotoxic insecticides. In our previous research, we found that six herbivorous pests and four ladybirds howed significantly higher AChE LC50 values than seven parasitoids and a predator (), and that there was a significant correlation with the corresponding bimolecular rate constant (Ki) value. The Ki value of pests was much smaller than that of natural enemies and had a higher LC50 value.Then, we speculated that the low sensitivity of the pest AChE to OPs may be associated with its higher recovery and lower aging ability. In this work, the I50 and I90 were calculated, to determine the sensibility of AChE in ten representative species, including , , , and , to paraoxon and malaoxon. The enzyme activities were measured at various time points, and kinetic calculations were used to obtain their spontaneous reactivation (Ks) and aging (Ka) constants, which were comprehensively compared. We conclude that the Ka and Ks of the AChE inhibited by OPs showed primarily species-specific correlations, and little correlation with the sensitivity to OPs. The differences in the AChE sensitivity to paraoxon among the ten species were much greater than in the sensitivity to malaoxon. Compared to paraoxon, malaoxon was more selective for . Coleoptera insects showed a stronger dephosphorylation ability than other insect groups. The recovery ability of phospho-AChE was stronger in mammals than in insects, which could be related to the low sensitivity of the AChE site of action to OPs. The Ka of the AChE inhibited by malaoxon was larger than that inhibited by paraoxon with the corresponding biomaterials, indicating that the OP type had a substantial relationship with the Ka of the AChE. We further discovered that, when insects were inhibited by OP, the tendency of AChE to undergo aging was greater than that of dephosphorylation. Overall, the study provides valuable information on the action mechanism of various OPs on AChE in several species, which could be used to further research into AChE and the potential dangers that organophosphates pose to animals.
PubMed: 37762515
DOI: 10.3390/ijms241814213 -
Annals of the New York Academy of... Aug 2016Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its... (Review)
Review
Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase. We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH-cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the Food and Drug Administration for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity.
Topics: Animals; Cholinesterase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Delivery Systems; Humans; Insecticides; Organophosphate Poisoning; Parathion; Vitamin K 3
PubMed: 27441453
DOI: 10.1111/nyas.13156 -
Ecotoxicology and Environmental Safety Jul 2022Exogenous pollution of Chinese medicinal materials by pesticide residues and heavy metal ions has attracted great attention. Relying on the rapid development of...
Exogenous pollution of Chinese medicinal materials by pesticide residues and heavy metal ions has attracted great attention. Relying on the rapid development of nanotechnology and multidisciplinary fields, fluorescent techniques have been widely applied in contaminant detection and pollution monitoring due to their advantages of simple preparation, low cost, high throughput and others. Most importantly, synchronous detection of multi-targets has always been pursued as one of the major goals in the design of fluorescent probes. Herein, we firstly develop a simultaneous sensing method for methyl-paraoxon (MP) and Nickel ion (Ni, Ⅱ) by using carbon based fluorescent nanocomposite with ratiometric signal readout and nanozyme. Notably, the designed system showed excellent effectiveness even when the two pollutants co-exist. Under the optimum conditions, this method provides low limits of detection of 1.25 µM for methyl-paraoxon and 0.01 µM for Ni (Ⅱ). To further verify the reliability, recovery studies of these two analytes were performed on ginseng radix et rhizoma, nelumbinis semen, and water samples. In addition, smartphone-based visual analysis has been introduced to expand its applicability in point of care detection. This work not only expands the application of the dual-mode approach to pollutant detection, but also provides insights into the analysis of multiple pollutants in a single assay.
Topics: Environmental Pollutants; Fluorescent Dyes; Limit of Detection; Paraoxon; Pesticide Residues; Reproducibility of Results
PubMed: 35623151
DOI: 10.1016/j.ecoenv.2022.113668 -
The Journal of Pharmacology and... Jan 2024Synthesis of the acetylcholinesterase inhibitor paraoxon (POX) as a carbon-11 positron emission tomography tracer ([C]POX) and profiling in live rats is reported. Naïve...
Synthesis of the acetylcholinesterase inhibitor paraoxon (POX) as a carbon-11 positron emission tomography tracer ([C]POX) and profiling in live rats is reported. Naïve rats intravenously injected with [C]POX showed a rapid decrease in parent tracer to ∼1%, with an increase in radiolabeled serum proteins to 87% and red blood cells (RBCs) to 9%. Protein and RBC leveled over 60 minutes, reflecting covalent modification of proteins by [C]POX. Ex vivo biodistribution and imaging profiles in naïve rats had the highest radioactivity levels in lung followed by heart and kidney, and brain and liver the lowest. Brain radioactivity levels were low but observed immediately after injection and persisted over the 60-minute experiment. This showed for the first time that even low POX exposures (∼200 ng tracer) can rapidly enter brain. Rats given an LD dose of nonradioactive paraoxon at the LD 20 or 60 minutes prior to [C]POX tracer revealed that protein pools were blocked. Blood radioactivity at 20 minutes was markedly lower than naïve levels due to rapid protein modification by nonradioactive POX; however, by 60 minutes the blood radioactivity returned to near naïve levels. Live rat tissue imaging-derived radioactivity values were 10%-37% of naïve levels in nonradioactive POX pretreated rats at 20 minutes, but by 60 minutes the area under the curve (AUC) values had recovered to 25%-80% of naïve. The live rat imaging supported blockade by nonradioactive POX pretreatment at 20 minutes and recovery of proteins by 60 minutes. SIGNIFICANCE STATEMENT: Paraoxon (POX) is an organophosphorus (OP) compound and a powerful prototype and substitute for OP chemical warfare agents (CWAs) such as sarin, VX, etc. To study the distribution and penetration of POX into the central nervous system (CNS) and other tissues, a positron emission tomography (PET) tracer analog, carbon-11-labeled paraoxon ([C]POX), was prepared. Blood and tissue radioactivity levels in live rats demonstrated immediate penetration into the CNS and persistent radioactivity levels in tissues indicative of covalent target modification.
Topics: Rats; Animals; Paraoxon; Tissue Distribution; Acetylcholinesterase; Positron-Emission Tomography; Organophosphorus Compounds; Carbon Radioisotopes
PubMed: 37770203
DOI: 10.1124/jpet.123.001832 -
Journal of Healthcare Engineering 2022This paper aims to investigate the correlation between high mobility group protein-1 (HMG-b1), antioxidant enzyme-1 (paraoxon-1, PON-1), monocyte chemoattractant...
BACKGROUND
This paper aims to investigate the correlation between high mobility group protein-1 (HMG-b1), antioxidant enzyme-1 (paraoxon-1, PON-1), monocyte chemoattractant protein-1 (monocyte chemoattractant protein-1, MCP-1), , and MSAF.
MATERIALS AND METHODS
The total sample size comprised of 73 cases in both groups. These patients were further subdivided into 2 groups: the MSAF group and the control group. 38 women were in the MSAF group and 35 women with term amniotic fluid serum were in the control group. The MSAF group was selected as a full-term singleton amniotic fluid fecal infection group. Clinical data were collected, and specimens were collected. Fecal staining of amniotic fluid and full-term amniotic fluid removes the placenta and umbilical cord blood. The expression of HMGB1 in the placenta was observed by immune-histochemical staining of MSAF and control groups. The content of PON-1 in cord blood was determined by ELISA.
RESULTS
Correlation between maternal and neonatal clinical data and MSAF was done; MSAF group mean gestational age was 41.38 ± 1.40 weeks; control group mean gestational age was 39.20 ± 1.24 weeks. This study found no correlation between the birth weight, maternal age, sex, first/transmaternal, hyperthyroidism, hypothyroidism, and anemia between the MSAF and control group with nonsignificant value ( > 0.05). However, the fatal age, gestational diabetes, gestational hypertension, umbilical cord abnormalities, placental abnormalities, and neonatal asphyxia factors were statistically different with a significant value of <0.05 between both groups. HMGB1 and Periodontal are mostly expressed in placental trophoblast, vascular endothelial cells, and amniotic epithelial and interstitial cells. After HE staining of 72 placentas by HE in MSAF and control, 6 had acute chorioamnionitis (5.1 control), 32 had chronic (23.9), 35 had abnormal placentas, and three in MSAF had chorionic columnar metaplasia. In immune-histochemistry experiments, the HMGB1 expression intensity of placental tissue was higher in the MSAF group ( < 0.05); however, the level of PON-1 was lower in the MSAF group as compared to the controls ( < 0.05).
CONCLUSIONS
Gestational age and placental abnormalities are clinical high-risk factors for MSAF. HMGB1, PON-1, MCP-1, and Periodontal may be involved in the development of MSAF, suggesting an oxidative/antioxidant imbalance with inflammation, and may be one of the mechanisms for MSAF development.
Topics: Amniotic Fluid; Antioxidants; Aryldialkylphosphatase; Bacteroidaceae Infections; Chemokine CCL2; Endothelial Cells; Female; HMGB1 Protein; Humans; Infant; Infant, Newborn; Male; Meconium; Periodontium; Placenta; Porphyromonas gingivalis; Pregnancy
PubMed: 35242296
DOI: 10.1155/2022/3143102 -
International Journal of Molecular... Nov 2022Seven pyridoxal dioxime quaternary salts (-) were synthesized with the aim of studying their interactions with human acetylcholinesterase (AChE) and...
Seven pyridoxal dioxime quaternary salts (-) were synthesized with the aim of studying their interactions with human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The synthesis was achieved by the quaternization of pyridoxal monooxime with substituted 2-bromoacetophenone oximes (phenacyl bromide oximes). All compounds, prepared in good yields (43-76%) and characterized by 1D and 2D NMR spectroscopy, were evaluated as reversible inhibitors of cholinesterase and/or reactivators of enzymes inhibited by toxic organophosphorus compounds. Their potency was compared with that of their monooxime analogues and medically approved oxime HI-6. The obtained pyridoxal dioximes were relatively weak inhibitors for both enzymes ( = 100-400 µM). The second oxime group in the structure did not improve the binding compared to the monooxime analogues. The same was observed for reactivation of VX-, tabun-, and paraoxon-inhibited AChE and BChE, where no significant efficiency burst was noted. In silico analysis and molecular docking studies connected the kinetic data to the structural features of the tested compound, showing that the low binding affinity and reactivation efficacy may be a consequence of a bulk structure hindering important reactive groups. The tested dioximes were non-toxic to human neuroblastoma cells (SH-SY5Y) and human embryonal kidney cells (HEK293).
Topics: Humans; Butyrylcholinesterase; Acetylcholinesterase; Cholinesterase Reactivators; Molecular Docking Simulation; Cholinesterase Inhibitors; HEK293 Cells; Neuroblastoma; Oximes; Pyridoxal; Ligands
PubMed: 36362178
DOI: 10.3390/ijms232113388 -
Nanomaterials (Basel, Switzerland) Apr 2022Selective and sensitive identification of paraoxon residue in agricultural products is greatly significant for food safety but remains a challenging task. Herein, a...
Selective and sensitive identification of paraoxon residue in agricultural products is greatly significant for food safety but remains a challenging task. Herein, a detection platform was developed by integrating Cu nanoclusters (Cu NCs) with MnO nanosheets, where the fluorescence of Cu NCs was effectively quenched. Upon introducing butyrylcholinesterase and butyrylcholine into the system, their hydrolysate, thiocholine, leads to the decomposition of the platform through a reaction between the MnO nanosheets and thiol groups on thiocholine. The electron-rich groups on thiocholine can further promote the fluorescence intensity of Cu NCs through host-guest interactions. Adding paraoxon results in the failure of fluorescence recovery and further promotion, which could be utilized for the quantitative detection of paraoxon, and a limit of detection as low as 0.22 ng/mL can be achieved. The detection platform shows strong tolerance to common interference species, which endows its applications for the detection of paraoxon in vegetables and fruit. These presented results not only open a new door for the functionalization of metal nanoclusters but also offer an inspiring strategy for analytic techniques in nanomedicine and environmental science.
PubMed: 35564138
DOI: 10.3390/nano12091429 -
Annals of the New York Academy of... Jun 2016Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP-based chemical attacks against civilians. Current antidotes are... (Review)
Review
Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP-based chemical attacks against civilians. Current antidotes are essential in limiting immediate mortality associated with OP exposure. However, further research is needed to identify the molecular mechanisms underlying long-term neurological deficits following survival of OP toxicity in order to develop effective therapeutics. We have developed rat survival models of OP-induced status epilepticus (SE) that mimic chronic mortality and morbidity following OP intoxication. We have observed significant elevations in hippocampal calcium levels after OP SE that persisted for weeks following initial survival. Drugs inhibiting intracellular calcium-induced calcium release, such as dantrolene, levetiracetam, and carisbamate, lowered OP SE-mediated protracted calcium elevations. Given the critical role of calcium signaling in modulating behavior and cell death mechanisms, drugs targeted at preventing the development of the calcium plateau could enhance neuroprotection, help reduce morbidity, and improve outcomes following survival of OP SE.
Topics: Animals; Behavior, Animal; Calcium; Disease Models, Animal; Humans; Neurons; Organophosphorus Compounds; Risk Factors; Status Epilepticus
PubMed: 27327161
DOI: 10.1111/nyas.13122