Reactivation of Paraoxon-inactivated Cholinesterase in the Rat Cerebral Cortex by Pralidoxime Chloride

Мilošević, Мiloš; Andjelkovic, Darinka

doi:10.1038/210206a0

Cited by 22 publications

(4 citation statements)

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“…28 But one of the in vivo study indicated that certain amount of unmetabolized carbonyl derivatives of 2-PAM entered some anatomical areas of the brain as in Paraoxon (diethyl 4-nitrophenyl phosphate)-poisoned rats, 2-PAM showed significant reactivation inside the cerebral cortex. 29,30 Since HNK-102 showed protection inside the brain (in case of sarin poisoning); therefore, HNK-102 might have entered in the brain region. This observation can be supported by the structural difference between the HNK analogs and simple oximes (2-PAM).…”

Section: Discussionmentioning

confidence: 99%

“…31 Also measuring only the levels of serum AChE, the severity of OP poisoning can never be validated. 29,32 In light of the discussed points, it is not justified to predict the better reactivation efficacy of the oximes only on the grounds of serum cholinesterase enzyme activity. Moreover, dissimilar rate of AChE reactivation in various species including primates and guinea pigs having none or low levels of blood carboxylesterases, while rat and mice, having highest carboxylesterases level, showed that OP compounds differently inhibit the cholinesterase enzyme in different species.…”

Section: Discussionmentioning

confidence: 99%

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In vivo protection studies of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl) acetamide derivatives against sarin poisoning in mice

et al. 2016

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In vivo antidotal efficacy of new bis- quaternary 2-(hydroxyimino)- N-(pyridin-3yl) acetamide derivatives (HNK series), to counter multiples of lethal doses of nerve agent sarin (GB) and reactivation of acetylcholinesterase (AChE), was evaluated in Swiss albino mice. [Protection index PI; median lethal dose (LD50) of sarin with treatment/LD50 of sarin] was estimated, using 0.05, 0.10, and 0.20 LD50 as treatment doses of all the oximes with atropine against sarin poisoning. Dose-dependent time course study was conducted at 0.2, 0.4 and 0.8 LD50 dose of sarin for estimating maximum AChE inhibition. At optimized time (15 min), in vivo enzyme half inhibition concentration (IC50) was calculated. AChE reactivation efficacy of HNK series and pralidoxime (2-PAM) were determined by plotting shift of log IC50 doses. HNK-102 with atropine showed three fold higher PI compared to 2-PAM. In vivo IC50 of sarin for brain and serum AChE was found to be 0.87 LD50 (139.2 µg/kg) and 0.48 LD50 (77.23 µg/kg), respectively. Treatment with HNK-102 and HNK-111 (equal to their 0.20LD50) significantly reactivated sarin-intoxicated AChE ( p < 0.05) at 2× IC50 dose of sarin, compared to 2-PAM. The study revealed that HNK-102 oxime was three times more potent as antidote, for acute sarin poisoning compared to 2-PAM in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In vivo protection studies of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl) acetamide derivatives against sarin poisoning in mice

et al. 2016

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“…Also, following inhibition, the phosphylated serine may undergo a spontaneous O- dealkylation event termed “aging”. The result is a phosphylated serine oxyanion toward which oxime therapeutics are completely ineffective. − Moreover, many of the most effective oxime reactivators are positively charged, resulting in poor blood–brain barrier permeability, and rendering these charged oximes less suitable for reactivation of OP-inhibited AChE in the CNS. − …”

Section: Introductionmentioning

confidence: 99%

4-Amidophenol Quinone Methide Precursors: Effective and Broad-Scope Nonoxime Reactivators of Organophosphorus-Inhibited Cholinesterases and Resurrectors of Organophosphorus-Aged Acetylcholinesterase

Lovins,

Miller,

Buck

et al. 2024

ACS Chem. Neurosci.

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Acetylcholinesterase (AChE) inhibition by organophosphorus (OP) compounds poses a serious health risk to humans. While many therapeutics have been tested for treatment after OP exposure, there is still a need for efficient reactivation against all kinds of OP compounds, and current oxime therapeutics have poor blood−brain barrier penetration into the central nervous system, while offering no recovery in activity from the OP-aged forms of AChE. Herein, we report a novel library of 4-amidophenol quinone methide precursors (QMP) that provide effective reactivation against multiple OP-inhibited forms of AChE in addition to resurrecting the aged form of AChE after exposure to a pesticide or some phosphoramidates. Furthermore, these QMP compounds also reactivate OP-inhibited butyrylcholinesterase (BChE) which is an in vivo, endogenous scavenger of OP compounds. The in vitro efficacies of these QMP compounds were tested for reactivation and resurrection of soluble forms of human AChE and BChE and for reactivation of cholinesterases within human blood as well as blood and brain samples from a humanized mouse model. We identify compound 10c as a lead candidate due to its broad-scope efficacy against multiple OP compounds as well as both cholinesterases. With methylphosphonates, compound 10c (250 μM, 1 h) shows >60% recovered activity from OEt-inhibited AChE in human blood as well as mouse blood and brain, thus highlighting its potential for future in vivo analysis. For 10c, the effective concentration (EC 50 ) is less than 25 μM for reactivation of three different methylphosphonate-inhibited forms of AChE, with a maximum reactivation yield above 80%. Similarly, for OP-inhibited BChE, 10c has EC 50 values that are less than 150 μM for two different methylphosphonate compounds. Furthermore, an in vitro kinetic analysis show that 10c has a 2.2-and 92.1-fold superior reactivation efficiency against OEt-inhibited and O i Bu-inhibited AChE, respectively, when compared to an oxime control. In addition to 10c being a potent reactivator of AChE and BChE, we also show that 10c is capable of resurrecting (ethyl paraoxon)-aged AChE, which is another current limitation of oximes.

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“…Non-anaesthetized rats of both sexes weighing 200 to 250 g were used in all experiments. They were inReceived: May 3, 1966. jected with oximes at doses of tO to 20 mg/kg, which were found previously to be effective in reactivating phosphorylated cholinesterase in the rat brain cortex (Milosevic and Andjelkovic, 1966). Paraoxon (pure sample) was made as 1% stock solution in ethanol and 0.9% NaCl was used for subsequent dilu tions.…”

Section: Methodsmentioning

confidence: 99%

The Effect of Oximes on the Hypertensive Action of Paraoxon and Physostigmine in Non-Anaesthetized Rats

Мilošević¹

1967

Pharmacology

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Reactivation of Paraoxon-inactivated Cholinesterase in the Rat Cerebral Cortex by Pralidoxime Chloride

Cited by 22 publications

References 1 publication

In vivo protection studies of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl) acetamide derivatives against sarin poisoning in mice

In vivo protection studies of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl) acetamide derivatives against sarin poisoning in mice

4-Amidophenol Quinone Methide Precursors: Effective and Broad-Scope Nonoxime Reactivators of Organophosphorus-Inhibited Cholinesterases and Resurrectors of Organophosphorus-Aged Acetylcholinesterase

The Effect of Oximes on the Hypertensive Action of Paraoxon and Physostigmine in Non-Anaesthetized Rats

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