Evaluation of the Neuroprotective Efficacy of Newly Developed Oximes (K206, K269) and Currently Available Oximes (Obidoxime, HI‐6) in Cyclosarin‐Poisoned Rats

Kassa, Jiřı́; Karasová, Jana Žďárová; Bajgar, Jiří; Tesarova, Sandra; Kuča, Kamil; Musílek, Kamil

doi:10.1111/j.1742-7843.2008.00352.x

Cited by 4 publications

(1 citation statement)

References 28 publications

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“…The question of their penetration through the blood brain barrier (BBB) as well as the possibility of their achievement of effective brain concentration is under discussion (Bajgar et al 2007a There is direct and indirect evidence for the ability of oximes to penetrate the BBB. The indirect evidence is based on AChE reactivation in the brain following OP intoxication (Bajgar et al 1972, Kassa et al 2007, Žďárová Karasová et al 2008. The direct evidence for presence of oximes in the brain has been demonstrated by Sakurada et al (2003) using microdialysis detection of pralidoxime.…”

Section: Introductionmentioning

confidence: 99%

In vitro screening of blood-brain barrier penetration of clinically used acetylcholinesterase reactivators

Karasová¹,

Stodůlka²,

Kuča³

2010

JAB

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In this in vitro study, using the HPLC method, we determined the ability of acetylcholinesterase (AChE) reactivators, used clinically, to penetrate the blood-brain barrier (BBB). We evaluated pralidoxime, HI-6, obidoxime, trimedoxime and methoxime-reactivators varying in the position of the oxime group on the pyridinium ring and linker connecting the pyridinium rings. Our results indicated that pralidoxime, a monoquaternary AChE reactivator, was the oxime with the most penetration. Molecular weight seems to be the most important factor for passive transport through the BBB. From the structural perspective, the connecting linker also plays a key role in the ability of the reactivators to penetrate the CNS. In this case, the simple and short linker is favorable for permeation of these compounds. The location of the oxime group on the pyridine ring may also influence passive transport into the brain; the best position of the oxime group seems to be position four.

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Section: Introductionmentioning

confidence: 99%

In vitro screening of blood-brain barrier penetration of clinically used acetylcholinesterase reactivators

Karasová¹,

Stodůlka²,

Kuča³

2010

JAB

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Effects of K074 and pralidoxime on antioxidant and acetylcholinesterase response in malathion-poisoned mice

Santos

Ribeiro

et al. 2011

NeuroToxicology

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The organophosphorus (OP) pesticide malathion is a highly neurotoxic compound and its toxicity is primarily caused by the inhibition of acetylcholinesterase (AChE), leading to cholinergic syndrome. Although oximes have been used as potential antidotal treatments in malathion poisoning because of their potential capability to reactivate the inhibited enzyme, the clinical experience with the clinically available oximes (e.g. pralidoxime) is disappointing and their routine use has been questioned. In the present study, we investigated the potency of pralidoxime and K074 in reactivating AChE after acute exposure to malathion, as well as in preventing malathion-induced changes in oxidative-stress related parameters in mice. Malathion (1.25 g/kg, s.c.) induced a significant decrease in cortico-cerebral, hippocampal and blood AChE activities at 24h after exposure. Oxime treatments (1/4 of LD(50), i.m., 6h after malathion poisoning) showed that pralidoxime significantly reversed malathion-induced blood AChE inhibition, although no significant effects were observed after K074 treatment. Interestingly, both oximes tested were unable to reactivate the cortico-cerebral and hippocampal enzymes after intramuscular or intracerebroventricular injection (1/4 of LD(50), 6h after malathion poisoning). Biochemical parameters related to oxidative stress (cerebro-cortical and hippocampal glutathione peroxidase, glutathione reductase and catalase activities, as well as lipid peroxidation) were not affected in animals treated with malathion, oximes or atropine alone. However, pralidoxime and K074, administered intramuscularly 6h after malathion poisoning, were able to increase the endogenous activities of these antioxidant enzymes in the prefrontal cortex and hippocampus. Taken together, the results presented herein showed that pralidoxime (the most common clinically used oxime) and the recently developed oxime K074, administered 6h after malathion poisoning, were unable to reactivate the inhibited AChE in mouse prefrontal cortex and hippocampus. However, only pralidoxime significantly reversed the blood AChE inhibition induced by malathion poisoning. This indicates that peripheral and central AChE activities are not necessarily correlated after the treatment of OP compounds and/or oximes, which should be taken into account in the diagnosis and management of OP-exposed humans. In addition, considering that the available treatments to malathion poisoning appear to be ineffective, the present study reinforce the need to search for potential new AChE reactivators able to efficiently reactivate the brain and blood AChEs after malathion poisoning.

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In vitro effects of acetylcholinesterase reactivators on monoamine oxidase activity

et al. 2011

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Evaluation of the Neuroprotective Efficacy of Newly Developed Oximes (K206, K269) and Currently Available Oximes (Obidoxime, HI‐6) in Cyclosarin‐Poisoned Rats

Cited by 4 publications

References 28 publications

In vitro screening of blood-brain barrier penetration of clinically used acetylcholinesterase reactivators

In vitro screening of blood-brain barrier penetration of clinically used acetylcholinesterase reactivators

Effects of K074 and pralidoxime on antioxidant and acetylcholinesterase response in malathion-poisoned mice

In vitro effects of acetylcholinesterase reactivators on monoamine oxidase activity

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