Inhibition of cyclooxygenase-2 protects against cocaine hepatotoxicity in CF-1 mice |
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Authors: | Thomas Visalli Rita Turkall |
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Institution: | 1. Department of Pharmacology and Physiology, New Jersey Medical School , University of Medicine and Dentistry of New Jersey , Newark, NJ, USA;2. Department of Pharmacology and Physiology, New Jersey Medical School , University of Medicine and Dentistry of New Jersey , Newark, NJ, USA;3. Department of Clinical Laboratory Sciences, School of Health Related Professions , University of Medicine and Dentistry of New Jersey , Newark, NJ, USA |
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Abstract: | Gender differences in oral cocaine hepatotoxicity have been observed and lipopolysaccharide (LPS) was shown to potentiate cocaine hepatotoxicity in male CF-1 mice. Since cocaine and LPS inflict hepatocellular damage through the production of harmful reactive species, the role of cyclooxygenase-2 (COX-2) in gender-dependent cocaine hepatotoxicity was investigated. COX-2 increases nitric oxide (NO) synthesis and pro-inflammatory mediator production in response to hepatocellular insult. Male and female CF-1 mice were orally administered 20 mg kg?1 cocaine hydrochloride once daily for 7 days. Four hours after the last cocaine administration, the mice received 12 × 106 EU LPS intraperitoneally (cocaine + LPS). Mice receiving meloxicam (7.5 mg kg?1, p.o.), a selective COX-2 inhibitor, were pretreated 1 h before each cocaine administration. Meloxicam prevented liver damage in males produced by cocaine and cocaine + LPS as evidenced by microscopic appearance and biochemical indices equivalent to saline treatment. Acetaminophen (APAP) was administered orally as a positive control which shows no gender dependency and elicited a hepatotoxic response in both males and females. Altered biochemical indices suggest that COX-2 is activated, possibly to a greater extent in females versus males in APAP-induced hepatotoxicity. Meloxicam prevented all oxidative stress changes induced in males following APAP. The results suggest that the induction of COX-2 is responsible, in part, for cocaine hepatotoxicity with and without LPS exposure in male mice. |
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Keywords: | acetaminophen cyclooxygenase-2 hepatotoxicity lipopolysaccharide |
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