RT Journal Article
SR Electronic
T1 Cocaine Esterase: Interactions with Cocaine and Immune Responses in Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 926
OP 933
DO 10.1124/jpet.106.114223
VO 320
IS 2
A1 Mei-Chuan Ko
A1 Luvina D. Bowen
A1 Diwahar Narasimhan
A1 Aaron A. Berlin
A1 Nicholas W. Lukacs
A1 Roger K. Sunahara
A1 Ziva D. Cooper
A1 James H. Woods
YR 2007
UL http://jpet.aspetjournals.org/content/320/2/926.abstract
AB Cocaine esterase (CocE) is the most efficient protein catalyst for the hydrolysis of cocaine characterized to date. The aim of this study was to investigate the in vivo potency of CocE in blocking cocaine-induced toxicity in the mouse and to assess CocE's potential immunogenicity. Cocaine toxicity was quantified by measuring the occurrence of convulsions and lethality. Intravenous administration of CocE (0.1–1 mg) 1 min before cocaine administration produced dose-dependent rightward shifts of the dose-response curve for cocaine toxicity. More important, i.v. CocE (0.1–1 mg), given 1 min after the occurrence of cocaine-induced convulsions, shortened the recovery time after the convulsions and saved the mice from subsequent death. Effects of repeated exposures to CocE were evaluated by measuring anti-CocE antibody titers and the protective effects of i.v. CocE (0.32 mg) against toxicity elicited by i.p. cocaine (320 mg/kg) (i.e., 0–17% occurrence of convulsions and lethality). CocE retained its potency against cocaine toxicity in mice after a single prior CocE exposure (0.1–1 mg), and these mice did not show an immune response. CocE retained similar effectiveness in mice after three prior CocE exposures (0.1–1 mg/week for 3 weeks), although these mice displayed 10-fold higher antibody titers. CocE partially lost effectiveness (i.e., 33–50% occurrence of convulsions and lethality) in mice with four prior exposures to CocE (0.1–1 mg/2 week for four times), and these mice displayed ∼100-fold higher antibody titers. These results suggest that CocE produces robust protection and reversal of cocaine toxicity, indicating CocE's therapeutic potential for acute cocaine toxicity. Repeated CocE exposures may increase its immunogenicity and partially reduce its protective ability. The American Society for Pharmacology and Experimental Therapeutics