Adenosine A1Receptor AgonistN6-Cyclopentyladenosine Affects the Inactivation of Acetylcholinesterase in Blood and Brain by Sarin

Bueters, Tjerk; Joosen, Marloes J.A.; Helden, H.P.M. van; IJzerman, Adriaan P.; Danhof, Meindert

doi:10.1124/jpet.102.044644

Cited by 25 publications

(15 citation statements)

References 32 publications

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“…The inhibition levels in these two animals were *90 and 95%, in striate body and brain, respectively, compared to 75 and 90%, in animals that did not have seizures on their EEG. These high levels of central AChE inhibition, expected to be a requirement for seizure development, are in line with previous studies [21][22][23]. Other workers have shown in guinea pigs, using a different route of administration, that of all nerve agents tested, VX was least likely to produce seizure activity in all animals [24,25].…”

Section: Discussionsupporting

confidence: 84%

Percutaneous Exposure to VX: Clinical Signs, Effects on Brain Acetylcholine Levels and EEG

Joosen¹,

Schans²,

Helden³

2007

Neurochem Res

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The nerve agent VX has a variable and delayed absorption through the skin, which may have implications for treatment regimens. In the present study, central and peripheral effects of percutaneous VX intoxication were investigated in hairless guinea pigs. Although onset times of clinical signs varied considerably, the relative onset times of signs of poisoning were shown to have a predictive value for survival time. All animals showed elevation of brain choline (Ch) levels. Only two of six animals demonstrated seizure activity on EEG, which was accompanied by acetylcholine (ACh) accumulation. The non-seizing animals displayed only marginal increases of ACh levels, but significant changes in all EEG bands. Acetylcholinesterase activity was highly inhibited in brain and diaphragm. The increases in Ch levels and EEG effects observed in non-seizing animals probably reflected those of ischemia induced by peripheral effects leading to cardiorespiratory compromise. In conclusion, clinical signs will mainly serve as indicators for the onset and maintenance of treatment in subsequent studies.

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Section: Discussionsupporting

confidence: 84%

Percutaneous Exposure to VX: Clinical Signs, Effects on Brain Acetylcholine Levels and EEG

Joosen¹,

Schans²,

Helden³

2007

Neurochem Res

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“…It was shown previously that AChE activity in blood is a bad predictor for cholinergic clinical signs due to acute OP poisoning (Bueters et al 2003). Logistic regression analysis of the present results, using lower doses of OP compared to that study, revealed the inhibition of AChE in blood to be a good predictor for the probability of chewing, shivering, seizures, convulsions and tremor, but not for respiratory distress and death (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The decline of therapeutic efficacy at higher doses of obidoxime might be ascribed to the inhibitory actions that phosphonylated obidoxime exerts on AChE (Harvey et al 1986; van Helden et al 1994). The slight delay of complete inhibition of AChE in the blood and probably also in the brain by obidoxime might explain its therapeutic efficacy, as only little amounts of active AChE in the brain are sufficient to improve the aforementioned parameters (Bueters et al 2003). In addition, suspected direct pharmacological actions of obidoxime might facilitate adaptive processes (van Helden et al 1994, 1996).…”

Section: Discussionmentioning

confidence: 99%

Treatment efficacy in a soman-poisoned guinea pig model: added value of physostigmine?

Joosen¹,

Smit²,

Helden³

2010

Arch Toxicol

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Current treatment of organophosphate poisoning is insufficient, and survivors may suffer from long-lasting adverse effects, such as cognitive deficits and sleep-wake disturbances. In the present study, we aimed at developing a guinea pig model to investigate the benefits of immediate and delayed stand-alone therapy on the development of clinical signs, EEG, heart rate, respiration and AChE activity in blood and brain after soman poisoning. The model allowed the determination of the therapeutic effects at the short-term of obidoxime, atropine and physostigmine. Obidoxime exerted the highest therapeutic efficacy at administration of the lowest dose (3.1 mg/kg i.m.), whereas two higher doses (9 and 18 mg/kg) were less effective on most parameters. Addition of atropine at 0.03 and 3 mg/kg (i.m.) to the treatment did not improve the therapeutic effects of obidoxime alone. Physostigmine (0.8 mg/kg im) at 1 min after poisoning increased mortality. Two lower doses (0.1 and 0.3 mg/kg i.m.) showed improvements on all parameters but respiration. The middle dose was most effective in preventing seizure development and therefore assessed as the most efficacious dose. Combined treatment of obidoxime and physostigmine shortened the duration of seizures, if present, from up to 80 min to ~10–15 min. In practice, treatment will be employed when toxic signs appear, with the presence of high levels of AChE inhibition in both blood and brain. Administration of physostigmine at that moment showed to be redundant or even harmful. Therefore, treatment of OP poisoning with a carbamate, such as physostigmine, should be carefully re-evaluated.

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“…These samples were stored at Ϫ70°C until analysis. Thawed samples were appropriately diluted and were assayed in quadruplicate for AChE activity using a 96-well microplate modification of the Ellman method (Bueters et al, 2003). Ethopropazine (10 M) was used as a specific inhibitor of butyrylcholinesterase.…”

Section: Methodsmentioning

confidence: 99%

Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase

Smulders

Bueters²,

Kleef

et al. 2003

Toxicology and Applied Pharmacology

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Effects of commonly used carbamate pesticides on rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. The potencies of these effects have been compared to the potencies of the carbamates to inhibit rat brain acetylcholinesterase. The potency order of six carbamates to inhibit ␣4␤4 nicotinic receptors is fenoxycarb Ͼ EPTC Ͼ carbaryl, bendiocarb Ͼ propoxur Ͼ aldicarb with IC50 values ranging from 3 M for fenoxycarb to 165 M for propoxur and Ͼ1 mM for aldicarb. Conversely, the potency order of these carbamates to inhibit rat brain acetylcholinesterase is bendiocarb Ͼ propoxur, aldicarb Ͼ carbaryl Ͼ Ͼ EPTC, fenoxycarb with IC50 values ranging from 1 M for bendiocarb to 17 M for carbaryl and Ͼ Ͼ1 mM for EPTC and fenoxycarb. The ␣4␤2, ␣3␤4, and ␣3␤2 nicotinic acetylcholine receptors are inhibited by fenoxycarb, EPTC, and carbaryl with potency orders similar to that for ␣4␤4 receptors. Comparing the potencies of inhibition of the distinct subtypes of nicotinic acetylcholine receptors shows that the ␣3␤2 receptor is less sensitive to inhibition by fenoxycarb and EPTC. The potency of inhibition depends on the carbamate as well as on a combination of ␣ and ␤ subunit properties. It is concluded that carbamate pesticides affect different subtypes of neuronal nicotinic receptors independently of acetylcholinesterase inhibition. This implicates that neuronal nicotinic receptors are additional targets for some carbamate pesticides and that these receptors may contribute to carbamate pesticide toxicology, especially after long-term exposure.

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Adenosine A₁Receptor AgonistN⁶-Cyclopentyladenosine Affects the Inactivation of Acetylcholinesterase in Blood and Brain by Sarin

Cited by 25 publications

References 32 publications

Percutaneous Exposure to VX: Clinical Signs, Effects on Brain Acetylcholine Levels and EEG

Percutaneous Exposure to VX: Clinical Signs, Effects on Brain Acetylcholine Levels and EEG

Treatment efficacy in a soman-poisoned guinea pig model: added value of physostigmine?

Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase

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