A Bacterial Cocaine Esterase Protects Against Cocaine-Induced Epileptogenic Activity and Lethality

Abstract

Study objective Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Methods Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. Results The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (−)-2β-carbomethoxy-3β-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. Conclusion The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted.

A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse

“…wt CocE prevents the short-term toxic effects of cocaine (Cooper et al, 2006;Ko et al, 2007;Jutkiewicz et al, 2009;Wood et al, 2010), but its instability at 37°C and its short duration of action in vivo limit its therapeutic potential. However, CocE-L169K/G173Q seems to be the first attractive CocE candidate for treatment of cocaine abuse (should its half-time in serum be extended) because of its long duration of action and ability to block the reinforcing properties of cocaine.…”

“…found in the Rhizosphere soil surrounding the coca plant, CocE has a high V max toward cocaine (V max ϭ 2300 min Ϫ1 ) (Gao et al, 2009) and produces the same products as BchE (Bresler et al, 2000). CocE has previously been shown to block cocaine-induced cardiac disturbance, neurological changes, and lethality in rodents when administered before or after cocaine (Cooper et al, 2006;Jutkiewicz et al, 2009;Ko et al, 2007;Wood et al, 2010).…”

Repeated Administration of a Mutant Cocaine Esterase: Effects on Plasma Cocaine Levels, Cocaine-Induced Cardiovascular Activity, and Immune Responses in Rhesus Monkeys

“…Although the wild-type (wt) form of CocE dose-dependently protects mice and rats against the cardiovascular, convulsant, and lethal effects of cocaine, it is rapidly inactivated at body temperature with a half-life of ϳ15 min (Cooper et al, 2006;Ko et al, 2007Ko et al, , 2009Jutkiewicz et al, 2009;Wood et al, 2010). Site-directed mutations have improved thermostability and resulted in an equally efficient mutant CocE (T172R/G173Q CocE; RQ CocE; DM CocE) that retains some activity in vitro and in vivo for more than 4 h (Collins et al, 2009;Gao et al, 2009;Narasimhan et al, 2010).…”

Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

“…Although the wild-type (wt) form of CocE is capable of dose dependently protecting mice and rats against the cardiovascular, convulsant, and lethal effects of cocaine, it is rapidly inactivated at body temperature resulting in an in vivo half-life of B15 min (Cooper et al, 2006;Jutkiewicz et al, 2009;Ko et al, 2007Ko et al, , 2009Wood et al, 2010). Sitedirected mutagenesis studies aimed at improving the thermostability of CocE have identified an equally efficient mutant CocE (T172R/G173Q CocE, RQ CocE, DM CocE) with an in vivo half-life of B4.5 h in mice (Gao et al, 2009;Narasimhan et al, 2010), and a high degree of pharmacologic specificity (Brim et al, 2011).…”