Beside the key inhibition of acetylcholinesterase (AChE), involvement of oxidative stress in organophosphate (OP)-induced toxicity has been supported by experimental and human studies. On the other hand, according to our best knowledge, possible antioxidant properties of oximes, the only causal antidotes to OP-inhibited AChE, have been examined only by a few studies. Thus, we have determined the effect of four conventional (obidoxime, trimedoxime, pralidoxime, asoxime) and two promising experimental oximes (K027, K203) on dichlorvos (DDVP)-induced oxidative changes in vivo. Wistar rats (5/group) were treated with oxime (5% LD50 i.m) immediately after DDVP challenge (75% LD50 s.c). Oxidative stress biomarkers were determined in plasma and brain 60 min after the treatment: prooxidative-superoxide anion (O2·-) and total oxidative status (TOS); antioxidative-superoxide dismutase (SOD), total thiol (SH) groups, total antioxidant status (TAS) and paraoxonase (PON1); tissue oxidative stress burden-prooxidative-antioxidative balance (PAB) and oxidative stress index (OSI); oxidative tissue damage-malondialdehyde (MDA) and advanced oxidation protein products (AOPP). All oximes were able to attenuate DDVP-induced oxidative stress in rat plasma and brain. Changes of determined parameters in brain were not as prominent as it was seen in plasma. Based on OSI, better abilities of oxime K027, K203 and obidoxime to maintain DDVP-induced oxidative stress in rat brain were shown as compared to trimedoxime, pralidoxime and asoxime. Oximes can influence the complex in vivo redox processes that might contribute to their overall therapeutic efficacy. Further research is needed to understand the underlying molecular mechanisms involved in this phenomenon.
- MeSH
- aryldialkylfosfatasa krev MeSH
- biologické markery krev MeSH
- cholinesterasové inhibitory farmakologie MeSH
- dichlorvos toxicita MeSH
- krysa rodu rattus MeSH
- malondialdehyd krev MeSH
- mozek účinky léků MeSH
- obidoxim chlorid farmakologie MeSH
- otrava organofosfáty farmakoterapie MeSH
- oxidační stres účinky léků MeSH
- oximy farmakologie MeSH
- pralidoximové sloučeniny MeSH
- pyridinové sloučeniny farmakologie MeSH
- superoxiddismutasa krev MeSH
- trimedoxim farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Inhibition of acethylcholinesterase (AChE) as a key molecular event induced by organophosphate (OP) pesticides and nerve agents presents a human health concern. In efficacy testing of experimental oximes, potential antidotes in OP poisoning, reactivation of OP-inhibited AChE is used as specific endpoint. However, according to our best knowledge, so far oximes have not been quantitatively evaluated by comprehensive benchmark dose (BMD) approach, that would improve both identification and quantification of the effect and allow more rigorous comparison of efficacies. Thus, we have examined in vivo dose-response relationship for two promising experimental oximes, K203 and K027, concerning reactivation of erythrocyte AChE inhibited by dichlorvos (DDVP). Groups of Wistar rats were treated with six different doses of oximes (i.m) immediately after DDVP challenge (s.c) and AChE was measured 60 min later. Dose-response modeling was done by PROAST software 65.5 (RIVM, The Nederlands). BMD-covariate method resulted in four-parameter model from both exponential and Hill model families as the best estimate of relationship between AChE activity and oxime dose, with potency parameter being oxime-dependent. Oxime K027 was shown to be 1.929-fold more potent considering that 58% increase in AChE activity was achived with the dose BMD58-K027 = 52 μmol/kg in contrast to BMD58-K203 = 100 μmol/kg.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory metabolismus MeSH
- dichlorvos chemie farmakologie MeSH
- erytrocyty enzymologie MeSH
- krysa rodu rattus MeSH
- molekulární struktura MeSH
- oximy chemie farmakologie MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny chemie farmakologie MeSH
- reaktivátory cholinesterasy farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
As oxime-based structures are the only causal antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE), the majority of studies on these have been directed towards their synthesis and testing. In this study, experimental bispyridinium oximes K027 and K203, which have shown promising results in the last decade of research, were examined in vivo for their therapeutic and reactivating ability in acute poisoning by the direct AChE-inhibitor dichlorvos (DDVP), used as a dimethyl OP structural model. Additionally, the efficacy of oximes K027 and K203 was compared with the efficacy of four oximes (pralidoxime, trimedoxime, obidoxime and HI-6), already used in efficacy experiments and human medicine. To evaluate therapeutic efficacy, groups of Wistar rats were treated with equitoxic doses of oximes (5% LD50, i.m.) and/or atropine (10mg/kg, i.m.) immediately after s.c. DDVP challenge (4-6 doses). Using the same antidotal protocol, AChE activity was measured in erythrocytes, diaphragm and brain 60min after s.c. DDVP exposure (75% LD50). The oxime K027 was the most efficacious in reducing the DDVP induced lethal effect in rats, while the oxime K203 was more efficacious than trimedoxime, pralidoxime and HI-6. Significant reactivation of DDVP inhibited AChE was achieved only with oxime K027 or its combination with atropine in erythocytes and the diaphragm. Moreover, the acute i.m. toxicity of oxime K027 in rats was lower than all other tested oximes. The results of this study support previous studies considering the oxime K027 as a promising experimental oxime structure for further testing against structurally-different OP compounds.
- MeSH
- cholinesterasové inhibitory toxicita MeSH
- dichlorvos toxicita MeSH
- krysa rodu rattus MeSH
- LD50 MeSH
- lékové interakce MeSH
- oximy farmakologie MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny farmakologie MeSH
- reaktivátory cholinesterasy farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The cholinesterase biosensors are analytical devices suitable for assay of cholinesterase inhibitors in the course of suppression of the biorecognition element activity. Both acetylcholinesterase and butyrylcholinesterase are used for their assay. The biosensors can be used for assay of organophosphorus and carbamate pesticides, nerve agents, drugs in Alzheimer´s disease and myasthenia treatment. The review summarizes the knowledge of cholinesterases, their immobilization and inhibitors as well as shows examples of their activities.
- MeSH
- acetylcholinesterasa MeSH
- Alzheimerova nemoc MeSH
- biosenzitivní techniky * metody využití MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory * MeSH
- dichlorvos * analýza normy MeSH
- karbamáty * farmakologie MeSH
- lidé MeSH
- organofluorofosfonáty * farmakologie MeSH
- reaktivátory cholinesterasy analýza MeSH
- sarin farmakologie MeSH
- Check Tag
- lidé MeSH
The present study was carried out to search whether organophosphate pesticides affect the mechanical properties of the thoracic aorta. Wistar female rats (aged 6-8 weeks) were assigned randomly to a control group and groups treated with either dichlorvos or chlorpyriphos for 90 days at a dose of 5 mg/kg/day. After that period, animals were killed and thoracic aorta strips in longitudinal direction were isolated. The stress, strain and elastic modulus were obtained from the strips. Our results showed that chronic administration of chlorpyriphos and dichlorvos caused downward shift of the stress-strain relations compared to the control curve. The elastic modulus-stress curve revealed distinct characteristics in the low and high stress regions. A power function was used to simulate the low stress region while a line was fit to the high stress region. Curve fitting procedure illustrated that both pesticides influenced mainly the high stress region, but they had diverse effects at the low stress region. The results also imply that chlorpyriphos and dichlorvos decrease the strength of the aorta and therefore might influence the response of the aorta to mechanical loading induced by blood pressure.
- MeSH
- aorta thoracica účinky léků MeSH
- dichlorvos farmakologie MeSH
- dursban farmakologie MeSH
- financování organizované MeSH
- insekticidy farmakologie MeSH
- krevní tlak účinky léků MeSH
- krysa rodu rattus MeSH
- mechanický stres MeSH
- pevnost v tahu MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Klíčová slova
- korovník obilní, Rhizopertha dominica, potemník hnědý, rus domácí,
- MeSH
- anthelmintika MeSH
- cholinesterasové inhibitory MeSH
- dezinsekce * statistika a číselné údaje MeSH
- dichlorvos * MeSH
- Ectobiidae účinky léků MeSH
- insekticidy * MeSH
- mortalita MeSH
- Tribolium účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- benaktyzin aplikace a dávkování terapeutické užití MeSH
- cholinesterasové inhibitory MeSH
- deriváty atropinu aplikace a dávkování terapeutické užití MeSH
- dichlorvos terapie toxicita MeSH
- krysa rodu rattus MeSH
- obidoxim chlorid aplikace a dávkování terapeutické užití MeSH
- reaktivátory cholinesterasy aplikace a dávkování terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- MeSH
- analýza krevních plynů MeSH
- biochemická analýza krve MeSH
- dichlorvos toxicita MeSH
- insekticidy MeSH
- krev MeSH
- krysa rodu rattus MeSH
- organofosforové sloučeniny MeSH
- otrava MeSH
- respirační insuficience chemicky indukované MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
