Protection of rhesus monkeys against soman and prevention of performance decrement by pretreatment with acetylcholinesterase

Maxwell, Donald M.; Castro, Carl A.; Hoz, D.M. De La; Gentry, Mary K.; Gold, Mark B.; Solana, Richard P.; Wolfe, Alan D.; Doctor, Bhupendra P.

doi:10.1016/0041-008x(92)90365-y

Cited by 72 publications

(16 citation statements)

References 19 publications

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“…Antibodies arise after heterologous administration of BChE, but not after homologous administration, within a given species (Maxwell et al, 1992). Large quantities of native BChE are well tolerated by all tested species (Lynch et al, 1997;Carmona et al, 2000;Doctor and Saxena, 2005).…”

Section: Use Of Human Bchementioning

confidence: 99%

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

Brimijoin

Gao

Anker

et al. 2008

Neuropsychopharmacol

125

167

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Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.

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Section: Use Of Human Bchementioning

confidence: 99%

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

Brimijoin

Gao

Anker

et al. 2008

Neuropsychopharmacol

125

167

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“…Current treatments for OP poisoning are effective in preventing lethality from OP exposure, but do not prevent the toxic effects and incapacitation observed in animals and likely to occur in humans [2]. Consequently, current research efforts are focused on the development of a bioscavenger [3] to remove OP compounds from circulation before they can reach their physiological target [4].…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, current research efforts are focused on the development of a bioscavenger [3] to remove OP compounds from circulation before they can reach their physiological target [4]. Anti-OP bioscavengers should be specific and efficient, function under physiological conditions, and not produce any deleterious pharmacological side effects in the absence of OP exposure [2,[5][6][7]. Human paraoxonase 1 (HuPON1) is a serum protein that is associated with high-density lipoprotein (HDL) in vivo [8,9].…”

Section: Introductionmentioning

confidence: 99%

Structure/function analyses of human serum paraoxonase (HuPON1) mutants designed from a DFPase-like homology model

Yeung¹,

Josse

Nicholson³

et al. 2004

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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and Cerasoli, Douglas M., "Structure/function analyses of human serum paraoxonase (HuPON1) mutants designed from a DFPaselike homology model" (2004 AbstractHuman serum paraoxonase (HuPON1) is a calcium-dependent enzyme that hydrolyzes esters, including organophosphates and lactones, and exhibits anti-atherogenic properties. A few amino acids have been shown to be essential for the enzyme's arylesterase and organophosphatase activities. Until very recently, a three-dimensional model was not available for HuPON1, so functional roles have not been assigned to those residues. Based on sequence-structure alignment studies, we have folded the amino acid sequence of HuPON1 onto the sixfold h-propeller structure of squid diisopropylfluorophosphatase (DFPase). We tested the validity of this homology model by circular dichroism (CD) spectroscopy and site-directed mutagenesis. Consistent with predictions from the homology model, CD data indicated that the structural composition of purified HuPON1 consists mainly of h-sheets. Mutants of HuPON1 were assayed for enzymatic activity against phenyl acetate and paraoxon. Substitution of residues predicted to be important for substrate binding (L69, H134, F222, and C284), calcium ion coordination (D54, N168, N224, and D269), and catalytic mechanism of HuPON1 (H285) led to enzyme inactivation. Mutants F222Y and H115W exhibited substrate-binding selectivity towards phenyl acetate and paraoxon, respectively. The homology model presented here is very similar to the recently obtained PON1 crystal structure, and has allowed identification of several residues within the enzyme active site. D

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“…Among all the tested enzymes that were promising candidates as scavengers of highly toxic nerve agents, significant advances were achieved using cholinesterases 56 . Exogenous administration of plasma-derived cholinesterases of both rodent and non-human primate models have been successfully used as a safe and efficacious prophylactic treatment to prevent poisoning by OP compounds 57 . A theoretical model for the protection against organophosporus poisoning has been developed and verified on seven OPs 58 .…”

Section: Bioscavengersmentioning

confidence: 99%

Prophylaxis Against Nerve Agent Intoxications

Patočka¹,

Jun²,

Bajgar³

et al. 2006

DSJ

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The acute toxicity of organophosphates is usually attributed to their irreversible inhibition of an enzyme acetylcholinesterase that hydrolyses the neurotransmitter acetylcholine. The resultant increase in concentration of acetylcholine at the cholinergic synapses of the peripheral and central nervous system, and neuromuscular junction is manifested by over-stimulation of the cholinergic neurotransmission. Current antidotal regimens for organophosphate poisoning consisting of a post-exposure therapy with anticholinergics such as atropine, acetylcholinesterase reactivators (oximes), benzodiazepines have some limitations. Therefore, effective prophylaxis before intoxication is of a special interest. Four fundamental prophylactic methods are: (i) protection of acetylcholinesterase against irreversible inhibition by organophosphates using different reversible inhibitors, (ii) protection against neurotoxic effect of organophosphates using benzodiazepines, memantine, NMDA receptor blockers, (iii) administration of cholinesterase preparations of different sources (sometimes commercially available at present) acting as bioscavengers, and (iv) gene therapy being a new treatment modality under intensive research using enzymes hydrolysing/splitting organophosphates with the aim to eliminate toxic agent before it is transported to the target organs.

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Protection of rhesus monkeys against soman and prevention of performance decrement by pretreatment with acetylcholinesterase

Cited by 72 publications

References 19 publications

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

Structure/function analyses of human serum paraoxonase (HuPON1) mutants designed from a DFPase-like homology model

Prophylaxis Against Nerve Agent Intoxications

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