The Experts below are selected from a list of 1245 Experts worldwide ranked by ideXlab platform
Marion Ehrich - One of the best experts on this subject based on the ideXlab platform.
-
comparative in vitro study of the inhibition of human and hen esterases by methamidophos enantiomers
Toxicology, 2012Co-Authors: Guilherme Luz Emerick, Georgino H Deoliveira, Regina V Oliveira, Marion EhrichAbstract:Abstract The current Organisation for Economic Co-operation and Development (OECD) guidelines for evaluating organophosphorus-induced Delayed neuropathy (OPIDN) require the observation of dosed animals over several days and the sacrifice of 48 hens. Adhering to these protocols in tests with enantiomers is difficult because large quantities of the compound are needed and many animals must be utilized. Thus, developing an in vitro screening protocol to evaluate chiral organophosphorus pesticides (OPs) that can induce Delayed neuropathy is important. This work aimed to evaluate, in blood and brain samples from hens, human blood, and human cell culture samples, the potential of the enantiomeric forms of methamidophos to induce acetylcholinesterase (AChE) inhibition and/or Delayed Neurotoxicity. Calpain activation was also evaluated in the hen brain and SH-SY5Y human neuroblastoma cells. The ratio between the inhibition of neuropathy target esterase (NTE) and AChE activities by the methamidophos enantiomers was evaluated as a possible indicator of the enantiomers’ abilities to induce OPIDN. The (−)-methamidophos exhibited an IC50 value approximately 6 times greater than that of the (+)-methamidophos for the lymphocyte NTE (LNTE) of hens, and (+)-methamidophos exhibited an IC50 value approximately 7 times larger than that of the (−)-methamidophos for the hen brain AChE. The IC50 values were 7 times higher for the human erythrocyte AChE and 5 times higher for AChE in the SH-SY5Y human neuroblastoma cells. Considering the esterases inhibition and calpain results, (+)-methamidophos would be expected to have a greater ability to induce OPIDN than the (−)-methamidophos in humans and in hens.
-
organophosphorus compound induced Delayed Neurotoxicity in white leghorn hens assessed by fluoro jade
International Journal of Toxicology, 2004Co-Authors: Kent Carlson, Marion EhrichAbstract:Certain organophosphorus (OP) compounds can induce a Delayed neuropathy, termed OPIDN, that involves central and peripheral nervous system axons, terminals, and perikarya. Historically, OPIDN has been characterized by staining neural sections with silver or hematoxylin and eosin (H&E). This study utilized a novel staining method, Fluoro-Jade, for evaluating the distribution and extent of OPIDN in the central nervous system of hens. Results were then compared to synoptically sectioned and stained H&E preparations. White Leghorn hens were injected with phenyl saligenin phosphate (PSP, 2.5 mg/kg, intramuscular [im]), triphenyl phosphite (TPPi, 500 mg/kg, subcutaneous [sc]), or dimethyl sulfoxide vehicle (DMSO, 0.5 ml/kg, im or sc) and evaluated clinically for signs of neurological dysfunction associated with OPIDN. Hens were sacrificed 7, 14, and 21 days post dosing. Brains and spinal cords were removed immediately following sacrifice, fixed in formalin, and embedded in paraffin. Microtomecut sections (7 μm)...
-
altered expression of transcripts for alpha tubulin and an unidentified gene in the spinal cord of phenyl saligenin phosphate treated hens gallus gallus
Journal of Biochemical and Molecular Toxicology, 2003Co-Authors: Jonathan H Fox, Bernard S Jortner, David S Barber, Marion EhrichAbstract:Phenyl saligenin phosphate (PSP) induces a central-peripheral distal axonopathy in domestic fowl that develops 7-21 days after a single exposure. Neurotoxic esterase (NTE) is the initial molecular target for this Neurotoxicity. PSP has to covalently bind to NTE and chemically "age" for induction of axonopathy. It was hypothesized that exposure to PSP results in early changes in spinal cord gene expression that do not occur with phenylmethylsulfonyl fluoride, a non-neuropathic compound that also inhibits NTE, or DMSO controls. Targeted display was used to screen approximately 15,000 gel bands. Three candidate genes were identified, but only the transcript designated P1 showed decreased expression following PSP exposure (2 mg/kg i.m.) in subsequent Northern blot and in situ hybridization experiments in samples taken <48 h after exposure. Additional experiments revealed that a approximately 2.5 kb alpha-tubulin transcript had decreased expression at 12-48 h after PSP exposure, with maximum change at 48 h (33%, p = 0.0479). A approximately 4.5 kb alpha-tubulin transcript had increased expression at 12 h (38%, p = 0.0125) and decreased expression at 48 h (28%, p = 0.0576). In situ hybridization on spinal cord revealed neuronal expression of P1 and alpha-tubulin transcripts. Decreased expression of transcripts for P1 and alpha-tubulin was present at 12 and 48 h, respectively. This decrease occurred in all neurons, not just those whose axons degenerate. Results suggest that (1) in PSP-induced OPIDN (organophosphorus-induced Delayed Neurotoxicity) some gene transcript expression changes are associated with initiation of axonopathy, and (2) PSP modulates spinal cord gene expression in neuronal types that do not undergo axonal degeneration.
-
acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and Delayed Neurotoxicity
Toxicological Sciences, 1997Co-Authors: Marion Ehrich, Linda Correll, Bellina VeronesiAbstract:The differential inhibition of the target esterases acetylcholinesterase (AChE) and neuropathy target esterase (NTE, neurotoxic esterase) by organophosphorus compounds (OPs) is followed by distinct neurological consequences in exposed subjects. The present study demonstrates that neuroblastoma cell lines (human SH-SY5Y and murine NB41A3) can be used to differentiate between neuropathic OPs (i.e., those inhibiting NTE and causing organophosphorus-induced Delayed neuropathy) and acutely neurotoxic OPs (i.e., those highly capable of inhibiting AChE). In these experiments, concentration-response data indicated that the capability to inhibit AChE was over 100x greater than the capability to inhibit NTE for acutely toxic, nonneuropathic OPs (e.g., paraoxon and malaoxon) in both cell lines. Inhibition of AChE was greater than inhibition of NTE, without overlap of the concentration-response curves, for OPs which are more likely to cause acute, rather than Delayed, neurotoxic effects in vivo (e.g., chlorpyrifos-oxon, dichlorvos, and trichlorfon). In contrast, concentrations inhibiting AChE and NTE overlapped for neuropathy-causing OPs. For example, apparent IC50 values for NTE inhibition were less than 9.6-fold the apparent IC50 values for AChE inhibition when cells were exposed to the neuropathy-inducing OPs diisopropyl phosphorofluoridate, cyclic tolyl saligenin phosphate, phenyl saligenin phosphate, mipafox, dibutyl dichlorovinyl phosphate, and di-octyl-dichlorovinyl phosphate. In all cases, esterase inhibition occurred at lower concentrations than those needed for cytoxicity. These results suggest that either mouse or human neuroblastoma cell lines can be considered useful in vitro models to distinguish esterase-inhibiting OP neurotoxicants.
Duke Tanaka - One of the best experts on this subject based on the ideXlab platform.
-
organophosphorus induced Neurotoxicity in the absence of neuropathy target esterase inhibition the effects of triphenyl phosphine in the european ferret
Toxicological Sciences, 1999Co-Authors: S L Davis, Duke Tanaka, R J Aulerich, S J BursianAbstract:Abou-Donia et al. (in Toxicologist, Vol. 30, 1996) have reported that repeated oral administration of the organo-phosphorus compound triphenyl phosphine (TPPn) to the domestic chicken results in neuropathological changes in the spinal cord and peripheral nerves, accompanied by ataxia and paralysis. This study also noted that single doses of TPPn resulted in no inhibition of the enzymes neuropathy target esterase (NTE) and acetylcholinesterase (AChE). We undertook the present study to determine the biochemical, neuropathological, and clinical effects of single doses of TPPn in the European ferret, a mammalian species shown to be susceptible to organophosphorus-induced Neurotoxicity. Eight 12-week-old ferrets were each injected subcutaneously with either 250 mg TPPn/kg bw or 500 mg TPPn/kg bw, or with the peanut oil/ethyl ether vehicle. Twenty-four h after dosing, the brains of 5 animals from each dose group were examined for NTE and AChE activities. The remaining 3 animals in each group were observed for 6 days for the development of clinical signs, after which their brains were processed for the presence of axonal degeneration using the Fink-Heimer silver impregnation method. Single injections of TPPn had no effect on the activities of whole-brain NTE or AChE 24 h after injection. The animals observed for clinical signs showed increasing trunk and hindlimb ataxia beginning 4 days after injection, culminating in fore-and hindlimb paralysis 6 days after injection. All brains exposed to either dose of TPPn showed widespread axonal degeneration extending from the brainstem and cerebellum into midbrain and forebrain areas. The results of this study support the hypothesis that TPPn-induced Neurotoxicity is a separate and distinct form of organophosphorus-induced Neurotoxicity not dependent on NTE inhibition, and therefore not a variant of organophosphorus-induced Delayed Neurotoxicity (OPIDN).
-
potentiation of organophosphorus induced Delayed Neurotoxicity following phenyl saligenin phosphate exposures in 2 5 and 8 week old chickens
Toxicological Sciences, 1997Co-Authors: Paul Harp, Duke Tanaka, C N PopeAbstract:Potentiation of Organophosphorus-lnduced Delayed Neurotoxicity Following Phenyl Saligenin Phosphate Exposures in 2-, 5-, and 8-Week-Old Chickens. Harp, P., Tanaka, Jr., D., and Pope, C. N. (1997). Fundam. Appl. Toxicol. 37, 64-70. Phenylmethylsulfonyl fluoride (PMSF), a nonneuropathic inhibitor of neurotoxic esterase (NTE), is a known potentiator of organophosphorus-induced Delayed Neurotoxicity (OPIDN)- The ability of PMSF posttreatment (90 mg/kg, sc, 4 hr after the last PSP injection) to modify development of Delayed Neurotoxicity was examined in 2-, 5-, and 8-week-old White Leghorn chickens treated either one, two, or three times (doses separated by 24 hr) with the neuropathic OP compound phenyl saligenin phosphate (PSP, 5 mg/kg, sc). NTE activity was measured in the cervical spinal cord 4 hr after the last PSP treatment Development of Delayed Neurotoxicity was measured over a 16-day postexposure period. All PSP-treated groups exhibited >97% NTE inhibition regardless of age or number of OP treatments. Twoweek-old birds did not develop clinical signs of Neurotoxicity in response to either single or repeated OP treatment regimens nor following subsequent treatment with PMSF. Five-week-old birds were resistant to the clinical effects of a single PSP exposure and were minimally affected by repeated doses. PMSF posttreatment, however, significantly amplified the clinical effects of one, two, or three doses of PSP. A single exposure to PSP induced slight to moderate signs of Delayed Neurotoxicity in 8-week-old birds with more extensive Neurotoxicity being noted following repeated dosing. As with 5-week-old birds, PMSF exacerbated the dinkal signs of Neurotoxicity when given after one, two, or three doses of PSP in 8-week-old birds. Axonal degeneration studies supported the clinical findings: PMSF posttreatment did not influence the degree of degeneration in 2-week-old chickens but resulted in more severe degeneration (relative to PSP only exposure) in cervical cords from both 5- and 8-week-old birds. The results indicate that PMSF does not alter the progression of Delayed Neurotoxicity in very young (2 weeks of age) chickens but potentiates PSP-induced Delayed Neurotoxicity in the presence of 0-3% residual NTE activity in older animals. We conclude that posttreatment with neuropathic or nonneuropathic NTE inhibitors, following virtually complete NTE inhibition by either single or repeated doses of a neuropathic agent in sensitive age groups, can modify both the clinical and morphological indices of Delayed Neurotoxicity. This study further supports the hypothesis that potentiation of OPIDN occurs through a mechanism unrelated to NTE. R 1997 sod»>- o Certain organophosphorus compounds are capable of causing a Delayed Neurotoxicity that occurs weeks after the exposure. This syndrome is referred to as organophosphorusinduced Delayed Neurotoxicity (OPIDN) and is characterized by a distal "dying-back" or Wallerian-typ e degeneration of long axons in certain central and peripheral nerve tracts (Johnson, 1982). Clinical signs of the neuropathy in laboratory animals can range from slight incoordination to complete hindlimb paralysis. Initiation of OPIDN is generally agreed to be associated with a two-step process: phosphorylation (inhibition) of the protein neurotoxic esterase (NTE) and "aging" (i.e., loss of
-
organophosphorus induced Delayed Neurotoxicity a comparative study of the effects of tri ortho tolyl phosphate and triphenyl phosphite on the central nervous system of the japanese quail
Neurotoxicology, 1995Co-Authors: R G Varghese, S J Bursian, C Tobias, Duke TanakaAbstract:The neurotoxic effects of single oral doses of tri-ortho-tolylphosphate (TOTP) (500 mg/kg body weight) or single subcutaneous injections of triphenyl phosphite (TPP) (62.5-500 mg/kg body weight) were investigated in the japanese quail (Coturnix coturnix japonica]. Oral doses of TOTP resulted in no detectable clinical signs while injections of TPP resulted in mild ataxia to severe paralysis depending upon the dosage level. At 24hr postdosing, whole-brain activity of neuropathy target esterase (NTE) was inhibited by 90 % in birds exposed to TOTP and by 11-87 % in birds injected with TPP. Oral doses of TOTP resulted in only sparse Fink-Heimer silver-impregnated degeneration in the white matter of the cerebellum with no degeneration noted in any other region of the brain. Injections of TPP resulted in widespread degeneration in large numbers of brainstem nuclei and tracts and in all cerebellar foliae and deep nuclei. These results indicate that the japanese quail responds differentially to exposure to TOTP and TPP. Oral doses of TOTP do not result in clinical signs or in significant amounts of degeneration in the brain even though NTE activity is inhibited by 90 %. In contrast, injections of TPP at higher dosage levels yield severe clinical signs, widespread axonal and terminal degeneration in the CNS, and significant inhibition of NTE activity. This sharp dichotomy in relative sensitivity to TOTP and TPP in the japanese quail suggests that each compound may have its own unique effect on CNS structure and function. In addition, the relationship between levels of NTE inhibition and the onset of clinical signs or neuropathology remains unclear
-
organophosphorus induced Delayed Neurotoxicity a comparative study of the effects of tri ortho tolyl phosphate and triphenyl phosphite on the central nervous system of the japanese quail
Neurotoxicology, 1995Co-Authors: R G Varghese, S J Bursian, C Tobias, Duke TanakaAbstract:The neurotoxic effects of single oral doses of tri-ortho-tolyl phosphate (TOTP) (500 mg/kg body weight) or single subcutaneous injections of triphenyl phosphite (TPP) (62.5-500 mg/kg body weight) were investigated in the Japanese quail (Coturnix coturnix japonica). Oral doses of TOTP resulted in no detectable clinical signs while injections of TPP resulted in mild ataxia to severe paralysis depending upon the dosage level. At 24 hr postdosing, whole-brain activity of neuropathy target esterase (NTE) was inhibited by 90% in birds exposed to TOTP and by 11-87% in birds injected with TPP. Oral doses of TOTP resulted in only sparse Fink-Heimer silver-impregnated degeneration in the white matter of the cerebellum with no degeneration noted in any other region of the brain. Injections of TPP resulted in widespread degeneration in large numbers of brainstem nuclei and tracts and in all cerebellar foliae and deep nuclei. These results indicate that the Japanese quail responds differentially to exposure to TOTP and TPP. Oral doses of TOTP do not result in clinical signs or in significant amounts of degeneration in the brain even though NTE activity is inhibited by 90%. In contrast, injections of TPP at higher dosage levels yield severe clinical signs, widespread axonal and terminal degeneration in the CNS, and significant inhibition of NTE activity. This sharp dichotomy in relative sensitivity to TOTP and TPP in the Japanese quail suggests that each compound may have its own unique effect on CNS structure and function. In addition, the relationship between levels of NTE inhibition and the onset of clinical signs or neuropathology remains unclear.
Albert Lai - One of the best experts on this subject based on the ideXlab platform.
-
mr 016 phase ii pilot study of velcade bortezomib in combination with temozolomide and regional radiation therapy for upfront treatment of patients with newly diagnosed glioblastoma multiforme
Neuro-oncology, 2013Co-Authors: Xiaotang Kong, Stacey Green, Emese Filka, Richard M Green, William H Yong, Phioanh L Nghiemphu, Timothy F Cloughesy, Albert LaiAbstract:PURPOSE: To assess interim safety and tolerability of 12 patients in a phase II pilot study using Bortezomib in combination with concurrent chemoradiation therapy for the treatment of newly-diagnosed glioblastoma. METHODS AND MATERIALS: All patients received standard external beam regional radiation therapy (RT) of 60.0 Gy in 30 fractions started within 3 to 5.5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m2 for 42 days and Bortezomib was given at day 1, 4, 8, 11, 29, 32, 36, and 39 of RT phase at 1.3 mg/m2. After a 2-3 week interval upon completion of RT, the post RT phase commenced with resumption of TMZ at 150-200 mg/m2 for 5 days and Bortezomib at day 1, 4, 8 and 11 in each 4 week cycle. RESULTS: Toxicities were compiled until study discontinuation (median 12.5 months, range 2-22 months) or last follow up before April 20, 2013 for those remaining on-study (median 18 months, range 6-77 months). No serious immediate or Delayed Neurotoxicity. Among the toxicities that could be potentially treatment related include relatively high incidence of fatigue, moderate incidence of injection site reaction, nausea, anorexia, vomiting, constipation, bone marrow suppression, low incidence of rash, pruritus, Delayed allergy, sensory neuropathy, shingles, thrush, hemorrhoids, dental sensitivity, fever, rigors, insomnia, restless legs, elevated LFTs. Four of 12 cases were taken off study because of tumor progression; 1 case off because of allergy; 1 case off voluntarily; 6 still on study with longest as of 77 weeks. All patients are alive. CONCLUSIONS: The observed toxicities were acceptable to continue enrollment toward the overall target group of 50 patients. At this time, our results indicate that Bortezomib combined with Temozolomide/RT in the setting of newly diagnosed glioblastoma is tolerable with no unexpected side effects.
-
phase ii pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up front treatment of patients with newly diagnosed glioblastoma multiforme interim analysis of safety and tolerability
International Journal of Radiation Oncology Biology Physics, 2008Co-Authors: Albert Lai, Emese Filka, William H Yong, Phioanh L Nghiemphu, Bruce Mcgibbon, C Graham, Paul S Mischel, Linda M Liau, Marvin Bergsneider, Whitney B PopeAbstract:Purpose To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma. Methods and Materials All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m 2 for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m 2 for 5 days every 4 weeks and continuation of BV every 2 weeks. Results For these 10 patients, toxicities were compiled until study discontinuation or up to ∼40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or Delayed Neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed. Conclusion The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.
G F Makhaeva - One of the best experts on this subject based on the ideXlab platform.
-
neuropathy target esterase nte pnpla6 and organophosphorus compound induced Delayed Neurotoxicity opidn
Advances in neurotoxicology, 2020Co-Authors: John K. Fink, Robert B Hufnagel, Paul Glynn, G F MakhaevaAbstract:Abstract Systemic inhibition of neuropathy target esterase (NTE) with certain organophosphorus (OP) compounds produces OP compound-induced Delayed Neurotoxicity (OPIDN), a distal degeneration of axons in the central nervous system (CNS) and peripheral nervous system (PNS), thereby providing a powerful model for studying a spectrum of neurodegenerative diseases. Axonopathies are important medical entities in their own right, but in addition, illnesses once considered primary neuronopathies are now thought to begin with axonal degeneration. These disorders include Alzheimer's disease, Parkinson's disease, and motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Moreover, conditional knockout of NTE in the mouse CNS produces vacuolation and other degenerative changes in large neurons in the hippocampus, thalamus, and cerebellum, along with degeneration and swelling of axons in ascending and descending spinal cord tracts. In humans, NTE mutations cause a variety of neurodegenerative conditions resulting in a range of deficits including spastic paraplegia and blindness. Mutations in the Drosophila NTE orthologue SwissCheese (SWS) produce neurodegeneration characterized by vacuolization that can be partially rescued by expression of wild-type human NTE, suggesting a potential therapeutic approach for certain human neurological disorders. This chapter defines NTE and OPIDN, presents an overview of OP compounds, provides a rationale for NTE research, and traces the history of discovery of NTE and its relationship to OPIDN. It then briefly describes subsequent studies of NTE, including practical applications of the assay; aspects of its domain structure, subcellular localization, and tissue expression; abnormalities associated with NTE mutations, knockdown, and conventional or conditional knockout; and hypothetical models to help guide future research on elucidating the role of NTE in OPIDN.
-
esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo
Chemico-Biological Interactions, 2016Co-Authors: G F Makhaeva, E V Rudakova, Alexey Yu Aksinenko, Olga G Serebryakova, Sofya V Lushchekina, S O Bachurin, Rudy J. RichardsonAbstract:We studied 4 serine esterases (EOHs) that are associated with the following consequences from their inhibition by organophosphorus compounds (OPCs): acetylcholinesterase (AChE: acute Neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE; inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: Delayed Neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the "esterase profile" of an OPC, which we hypothesize can serve as a predictor of its overall physiological effects. To test this hypothesis, we selected 3 OPCs known from previous work on reference enzymes to span a wide range of esterase profiles, neuropathic potential, and acute cholinergic toxicity. For each compound, we determined in vitro IC50 and in vivo ED50 values for inhibition of AChE, BChE, CaE, and NTE in mouse brain and blood. The results showed good correlations between in vitro and in vivo measures of potency and selectivity except for brain CaE, a tissue-specific isoform of the enzyme that was less sensitive to the test compounds than expected. Thus, this synthesis of new and previously published results indicates that the concept of the esterase profile of OPCs is useful for the prediction of therapeutic and toxic effects in vivo.
-
organophosphorus compound esterase profiles as predictors of therapeutic and toxic effects
Chemico-Biological Interactions, 2013Co-Authors: G F Makhaeva, Eugene V Radchenko, E V Rudakova, Alexey Yu Aksinenko, V B Sokolov, Vladimir A. Palyulin, Nikolay S. ZefirovAbstract:Abstract Certain organophosphorus compounds (OPCs) inhibit various serine esterases (EOHs) via phosphorylation of their active site serines. We focused on 4 EOHs of particular toxicological interest: acetylcholinesterase (AChE: acute Neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: Delayed Neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the “esterase profile” of an OPC and serves as a major determinant of its net physiological effects. Thus, understanding and controlling the esterase profile of OPC activity and selectivity toward these 4 target enzymes is a significant undertaking. In the present study, we analyzed the inhibitor properties of 52 OPCs against the 4 EOHs, along with pairwise and multitarget selectivities between them, using 2 QSAR approaches: Hansch modeling and Molecular Field Topology Analysis (MFTA). The general formula of the OPCs was (RO)2P(O)X, where R = alkyl, X = – SCH(Hal)COOEt (Hal = Cl, Br), –SCHCl2, –SCH2Br, –OCH(CF3)R1 (R1 = C6H5, CF3, COOEt, COOMe). The Hansch model showed that increasing neuropathic potential correlated with rising R hydrophobicity; moreover, OPC binding to scavenger EOHs (BChE and CaE) had different effects on potential acute and Delayed Neurotoxicity. Predicted protective roles of BChE and CaE against acute toxicity were enhanced with increasing hydrophobicity, but projected protection against OPIDN was decreased. Next, Molecular Field Topology Analysis (MFTA) models were built, considering atomic descriptors, e.g., effective charge, van der Waals radius of environment, and group lipophilicity. Activity/selectivity maps confirmed predictions from Hansch models and revealed other structural factors affecting activity and selectivity. Virtual screening based on multitarget selectivity MFTA models was used to design libraries of OPCs with favorable esterase profiles for potential application as selective inhibitors of CaE without untoward side effects.
-
combined qsar studies of inhibitor properties of o phosphorylated oximes toward serine esterases involved in Neurotoxicity drug metabolism and alzheimer s disease
Sar and Qsar in Environmental Research, 2012Co-Authors: G F Makhaeva, Eugene V Radchenko, Vladimir A. Palyulin, Rudy J. Richardson, I I Baskin, Nikolay S. ZefirovAbstract:Oxime reactivation of serine esterases (EOHs) inhibited by organophosphorus (OP) compounds can produce O-phosphorylated oximes (POXs). Such oxime derivatives are of interest, because some of them can have greater anti-EOH potencies than the OP inhibitors from which they were derived. Accordingly, inhibitor properties of 58 POXs against four EOHs, along with pair-wise selectivities between them, have been analysed using different QSAR approaches. EOHs (with their abbreviations and consequences of inhibition in parentheses) comprised acetylcholinesterase (AChE: acute Neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: Delayed Neurotoxicity). QSAR techniques encompassed linear regression and backpropagation neural networks in conjunction with fragmental de...
-
biosensor detection of neuropathy target esterase in whole blood as a biomarker of exposure to neuropathic organophosphorus compounds
Journal of Toxicology and Environmental Health, 2003Co-Authors: G F Makhaeva, V V Malygin, Larisa V Sigolaeva, L V Zhuravleva, A V Eremenko, I N Kurochkin, Rudy J. RichardsonAbstract:Neuropathy target esterase (NTE) is the target protein for neuropathic organophosphorus (OP) compounds that produce OP compound-induced Delayed Neurotoxicity (OPIDN). Inhibition/aging of brain NTE within hours of exposure predicts the potential for development of OPIDN in susceptible animal models. Lymphocyte NTE has also found limited use as a biomarker of human exposure to neuropathic OP compounds. Recently, a highly sensitive biosensor was developed for NTE activity using a tyrosinase carbon-paste electrode for amperometric detection of phenol produced by hydrolysis of the substrate, phenyl valerate. The I50 (20 min at 37 degrees C) for N,N'-di-2-propylphosphorodiamidofluoridate (mipafox) against hen lymphocyte NTE was 6.94 +/- 0.28 microM amperometrically and 6.02 +/- 0.71 microM colorimetrically. For O,O-di1-propyl O-2,2-dichlorvinyl phosphate (PrDChVP), the I50 against hen brain NTE was 39 +/- 8 nM amperometrically and 42 +/- 2 nM colorimetrically. The biosensor enables NTE to be assayed in whole blood, whereas this cannot be done with the usual colorimetric method. Amperometrically, I50 values for PrDChVP against hen and human blood NTE were 66 +/- 3 and 70 +/- 14 nM, respectively. To study the possibility of using blood NTE inhibition as a biochemical marker of neuropathic OP compound exposure, NTE activities in brain and lymphocytes as well in brain and blood were measured 24 h after dosing hens with PrDChVP. Brain, lymphocyte, and blood NTE were inhibited in a dose-responsive manner, and NTE inhibition was highly correlated between brain and lymphocyte (r = .994) and between brain and blood (r = .997). The results suggest that the biosensor NTE assay for whole blood could serve as a biomarker of exposure to neuropathic OP compounds as well as a predictor of OPIDN and an adjunct to its early diagnosis.
Rudy J. Richardson - One of the best experts on this subject based on the ideXlab platform.
-
esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo
Chemico-Biological Interactions, 2016Co-Authors: G F Makhaeva, E V Rudakova, Alexey Yu Aksinenko, Olga G Serebryakova, Sofya V Lushchekina, S O Bachurin, Rudy J. RichardsonAbstract:We studied 4 serine esterases (EOHs) that are associated with the following consequences from their inhibition by organophosphorus compounds (OPCs): acetylcholinesterase (AChE: acute Neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE; inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: Delayed Neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the "esterase profile" of an OPC, which we hypothesize can serve as a predictor of its overall physiological effects. To test this hypothesis, we selected 3 OPCs known from previous work on reference enzymes to span a wide range of esterase profiles, neuropathic potential, and acute cholinergic toxicity. For each compound, we determined in vitro IC50 and in vivo ED50 values for inhibition of AChE, BChE, CaE, and NTE in mouse brain and blood. The results showed good correlations between in vitro and in vivo measures of potency and selectivity except for brain CaE, a tissue-specific isoform of the enzyme that was less sensitive to the test compounds than expected. Thus, this synthesis of new and previously published results indicates that the concept of the esterase profile of OPCs is useful for the prediction of therapeutic and toxic effects in vivo.
-
combined qsar studies of inhibitor properties of o phosphorylated oximes toward serine esterases involved in Neurotoxicity drug metabolism and alzheimer s disease
Sar and Qsar in Environmental Research, 2012Co-Authors: G F Makhaeva, Eugene V Radchenko, Vladimir A. Palyulin, Rudy J. Richardson, I I Baskin, Nikolay S. ZefirovAbstract:Oxime reactivation of serine esterases (EOHs) inhibited by organophosphorus (OP) compounds can produce O-phosphorylated oximes (POXs). Such oxime derivatives are of interest, because some of them can have greater anti-EOH potencies than the OP inhibitors from which they were derived. Accordingly, inhibitor properties of 58 POXs against four EOHs, along with pair-wise selectivities between them, have been analysed using different QSAR approaches. EOHs (with their abbreviations and consequences of inhibition in parentheses) comprised acetylcholinesterase (AChE: acute Neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: Delayed Neurotoxicity). QSAR techniques encompassed linear regression and backpropagation neural networks in conjunction with fragmental de...
-
Motor neuron disease due to neuropathy target esterase gene mutation: Clinical features of the index families
Muscle & nerve, 2010Co-Authors: Shirley Rainier, Rudy J. Richardson, James W. Albers, Peter J. Dyck, O. Petter Eldevik, Sandra Wilcock, John K. FinkAbstract:Recently, we reported that mutations in the neu- ropathy target esterase (NTE) gene cause autosomal recessive motor neuron disease (NTE-MND). We describe clinical, neuro- physiologic, and neuroimaging features of affected subjects in the index families. NTE-MND subjects exhibited progressive lower extremity spastic weakness that began in childhood and was later associated with atrophy of distal leg and intrinsic hand muscles. NTE-MND resembles Troyer syndrome, except that short stature, cognitive impairment, and dysmorphic fea- tures, which often accompany Troyer syndrome, are not fea- tures of NTE-MND. Early onset, symmetry, and slow progression distinguish NTE-MND from typical amyotrophic lat- eral sclerosis. NTE is implicated in organophosphorus com- pound-induced Delayed Neurotoxicity (OPIDN). NTE-MND patients have upper and lower motor neuron deficits that are similar to OPIDN. Motor neuron degeneration in subjects with NTE mutations supports the role of NTE and its biochemical cascade in the molecular pathogenesis of OPIDN and possibly other degenerative neurologic disorders. Muscle Nerve 43: 19-25, 2011
-
constructs of human neuropathy target esterase catalytic domain containing mutations related to motor neuron disease have altered enzymatic properties
Toxicology Letters, 2010Co-Authors: Nichole D Hein, John K. Fink, Shirley Rainier, Jeanne A Stuckey, Rudy J. RichardsonAbstract:Neuropathy target esterase (NTE) is a phospholipase/lysophospholipase associated with organophosphorus (OP) compound-induced Delayed Neurotoxicity (OPIDN). Distal degeneration of motor axons occurs in both OPIDN and the hereditary spastic paraplegias (HSPs). Recently, mutations within the esterase domain of NTE were identified in patients with a novel type of HSP (SPG39) designated NTE-related motor neuron disease (NTE-MND). Two of these mutations, arginine 890 to histidine (R890H) and methionine 1012 to valine (M1012V), were created in human recombinant NTE catalytic domain (NEST) to measure possible changes in catalytic properties. These mutated enzymes had decreased specific activities for hydrolysis of the artificial substrate, phenyl valerate. In addition, the M1012V mutant exhibited a reduced bimolecular rate constant of inhibition (ki) for all three inhibitors tested: mipafox, diisopropylphosphorofluoridate, and chlorpyrifos oxon. Finally, while both mutated enzymes inhibited by OP compounds exhibited altered time-dependent loss of their ability to be reactivated by nucleophiles (aging), more pronounced effects were seen with the M1012V mutant. Taken together, the results from specific activity, inhibition, and aging experiments suggest that the mutations found in association with NTE-MND have functional correlates in altered enzymological properties of NTE.
-
biosensor detection of neuropathy target esterase in whole blood as a biomarker of exposure to neuropathic organophosphorus compounds
Journal of Toxicology and Environmental Health, 2003Co-Authors: G F Makhaeva, V V Malygin, Larisa V Sigolaeva, L V Zhuravleva, A V Eremenko, I N Kurochkin, Rudy J. RichardsonAbstract:Neuropathy target esterase (NTE) is the target protein for neuropathic organophosphorus (OP) compounds that produce OP compound-induced Delayed Neurotoxicity (OPIDN). Inhibition/aging of brain NTE within hours of exposure predicts the potential for development of OPIDN in susceptible animal models. Lymphocyte NTE has also found limited use as a biomarker of human exposure to neuropathic OP compounds. Recently, a highly sensitive biosensor was developed for NTE activity using a tyrosinase carbon-paste electrode for amperometric detection of phenol produced by hydrolysis of the substrate, phenyl valerate. The I50 (20 min at 37 degrees C) for N,N'-di-2-propylphosphorodiamidofluoridate (mipafox) against hen lymphocyte NTE was 6.94 +/- 0.28 microM amperometrically and 6.02 +/- 0.71 microM colorimetrically. For O,O-di1-propyl O-2,2-dichlorvinyl phosphate (PrDChVP), the I50 against hen brain NTE was 39 +/- 8 nM amperometrically and 42 +/- 2 nM colorimetrically. The biosensor enables NTE to be assayed in whole blood, whereas this cannot be done with the usual colorimetric method. Amperometrically, I50 values for PrDChVP against hen and human blood NTE were 66 +/- 3 and 70 +/- 14 nM, respectively. To study the possibility of using blood NTE inhibition as a biochemical marker of neuropathic OP compound exposure, NTE activities in brain and lymphocytes as well in brain and blood were measured 24 h after dosing hens with PrDChVP. Brain, lymphocyte, and blood NTE were inhibited in a dose-responsive manner, and NTE inhibition was highly correlated between brain and lymphocyte (r = .994) and between brain and blood (r = .997). The results suggest that the biosensor NTE assay for whole blood could serve as a biomarker of exposure to neuropathic OP compounds as well as a predictor of OPIDN and an adjunct to its early diagnosis.