Bioscavenger for Protection From Toxicity of Organophosphorus Compounds

Saxena, Ashima; Sun, Wei; Luo, Chunyuan; Myers, Todd M.; Koplovitz, Irwin; Lenz, David E.; Doctor, Bhupendra P.

doi:10.1385/jmn:30:1:145

Cited by 79 publications

(66 citation statements)

References 3 publications

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“…In humans, immune responses to mutated hBChE are likely to be weaker or absent, because the modified amino acids are confined to the interior of the catalytic gorge (Pancook et al, 2003), poorly available to immune surveillance. It should also be emphasized that extensive research in animals as well as human subjects has revealed no toxicity from hBChE protein (Clark et al, 2005;Saxena et al, 2006). Therefore, the principal concern in hBChE-based gene therapy must be the direct effects of the vector per se along with immune responses to the viral protein or novel DNA.…”

Section: Discussionmentioning

confidence: 99%

Lasting Reduction of Cocaine Action in Neostriatum— A Hydrolase Gene Therapy Approach

Gao¹,

Brimijoin²

2009

J Pharmacol Exp Ther

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We previously found that a quadruple mutant cocaine hydrolase derived from human butyrylcholinesterase [termed cocaine esterase (CocE)] can suppress or reverse cocaine toxicity and abolish drug-primed reinstatement in rats. Here, we examined whether gene transfer of CocE reduces cocaine actions in brain reward centers. Early experiments used a standard, early region 1-deleted adenoviral vector, which, after intravenous delivery of 10 10 plaque-forming units, caused plasma cocaine hydrolase activity to rise 25,000-fold between day 4 and day 7. During this period, under a protocol that typically induces FosB expression in the caudate nucleus, these rats and unprotected controls given only empty vector or saline were subjected to repeated twice-daily injections of cocaine (30 mg/kg i.p.). Immunohistochemistry of the neostriatum on day 7 showed many FosB-reactive nuclei in unprotected rats but few if any in rats pretreated with active vector, which resembled rats never exposed to cocaine. Western blots confirmed this result. In contrast there was a more localized protection against cocaineelicited FosB induction when hydrolase vector was injected directly into the ventral striatum, which generated high transgene expression in many neurons of the target area. Similar results were obtained with systemic and local injection of a more efficient helper-dependent adenoviral vector, which transduced high levels of hydrolase for at least 2 months, with lesser expression continued up to 1 year. Behavioral tests are now warranted to determine whether such effects can reduce drug-seeking behavior and lower the probability of relapse.Efforts guided by computer-based protein engineering have yielded modified versions of human butyrylcholinesterase (hBChE) that hydrolyze cocaine rapidly enough to deserve consideration for therapeutic use (Sun et al., 2001(Sun et al., , 2002aPancook et al., 2003;Pan et al., 2005;Zheng et al., 2008). We found accelerated cocaine metabolism and blunted cardiovascular effects of cocaine in rats given such enzymes directly (Gao and Brimijoin, 2004) or by adenoviral gene transfer . Others observed that bacterial cocaine hydrolase protected rats against the lethal effects of cocaine (Cooper et al., 2006;Ko et al., 2007). Last, we showed that a catalytically efficient hBChE-albumin fusion protein will abort cocaine-induced seizures and selectively suppress cocaine-induced reinstatement of drug-seeking behavior in rats (Brimijoin et al., 2008).Taken together, the above-mentioned results support the idea of a gene therapy for cocaine addiction based on generating sustained levels of a hydrolase that prevents cocaine access to reward centers in the forebrain. As a step toward that goal, we have now evaluated two viral vectors encoding a quadruple mutant hBChE, with a k cat value 200-fold greater than that of wild-type BChE. Each vector was given systemically or by intracerebral injection to test its effects on cocaine accumulation in brain tissue. We also investigated the ability of such treatments ...

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Section: Discussionmentioning

confidence: 99%

Lasting Reduction of Cocaine Action in Neostriatum— A Hydrolase Gene Therapy Approach

Gao¹,

Brimijoin²

2009

J Pharmacol Exp Ther

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“…Large quantities of native BChE are well tolerated by all tested species (Lynch et al, 1997;Carmona et al, 2000;Doctor and Saxena, 2005). Mice with high circulating levels of human BChE showed no clinical signs, postmortem examinations revealed no abnormalities in serum chemistry or hematology (Saxena et al, 2006), and the acoustic startle reflex remained normal (Clark et al, 2005). Finally, daily administration of the partially purified wild-type protein for several weeks to human subjects has evoked no adverse b and c).…”

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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“…Genetic aspects (see above) or intoxication with some compounds such as organophosphate pesticides and/or organophosphonate nerve agents (see below) are sources of false positive findings. BuChE is capable of detoxifying a large number of exogenous substances: procaine 13 , succinylcholine 14 , cocaine 15 , heroin, acetylsalicylic acid 16 , and it can also protect the body from the impact of organophosphorus AChE inhibitors 17 . However the primary reason for the existence of BuChE is still unknown.…”

Section: Butyrylcholinesterasementioning

confidence: 99%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

320

219

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Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology.Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium).Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

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Bioscavenger for Protection From Toxicity of Organophosphorus Compounds

Cited by 79 publications

References 3 publications

Lasting Reduction of Cocaine Action in Neostriatum— A Hydrolase Gene Therapy Approach

Lasting Reduction of Cocaine Action in Neostriatum— A Hydrolase Gene Therapy Approach

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

Cholinesterases, a Target of Pharmacology and Toxicology

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