A Naphthoquinone from Sinningia canescens Inhibits Inflammation and Fever in Mice.

We previously showed that plants from the genus Sinningia are a source of antiinflammatory and analgesic compounds with different mechanisms of action. The present study evaluated the antiinflammatory, antinociceptive, and antipyretic effects of a crude extract (CE) from Sinningia canescens, its fractions, and 6-methoxy-7-hydroxy-α-dunnione (MHD) in mice. These effects were evaluated using carrageenan (Cg)-induced paw edema, acetic acid- and formalin-induced nociception, mechanical hyperalgesia, lipopolysaccharide (LPS)-induced fever, and plasma cytokine levels. The CE and dichloromethane and hexane fractions reduced Cg-induced paw edema and hyperalgesia, LPS-induced fever, and plasma tumor necrosis factor-α (TNF-α) levels. The CE also reduced acetic acid-induced writhing and the second phase of formalin-induced nociception but did not alter thermal nociception or motor performance. Partition with solvents showed that the antiinflammatory, antihyperalgesic, and antipyretic activities were present in dichoromethane and hexane fractions, and the major compound isolated from these fractions was MHD. Oral and intraplantar MHD administration reduced paw edema. Oral MHD administration also reduced prostaglandin E2-induced hyperalgesia but did not alter hyperalgesia that was induced by dopamine and dibutyryl cyclic adenosine monophosphate. Treatment with glibenclamide, a KATP channel blocker, did not alter the analgesic effect of MHD. Lipopolysaccharide-induced fever and TNF-α, interleukin-1ß, and interleukin-6 levels were inhibited by MHD. Altogether, these data suggest that the CE has antiinflammatory, analgesic, and antipyretic activity, and these actions are at least partially related to MHD. These results also suggest that MHD acts by blocking cytokine synthesis and/or blocking prostaglandin activity.

Effects of Binge-Like Ethanol Exposure During Adolescence on the Febrile Response in Rats.

BACKGROUND: Ethanol (EtOH) exposure during different phases of life may increase the risk of infections and cause alterations in the central nervous system. The present study investigated the effects of binge-like EtOH exposure in adolescent rats on the febrile response that was induced by lipopolysaccharide (LPS) and interleukin-1ß (IL-1ß). METHODS: Male rats were exposed to EtOH from postnatal days 25 to 38 in a binge-like pattern. Fever was induced by LPS (5 and 50 µg/kg, intraperitoneally) and evaluated on postnatal days 51 and 63, or by IL-ß (3 ng) and evaluated on postnatal day 51. Hematological parameters, the status of peritoneal macrophages, and plasma and cerebrospinal IL-1ß levels were also evaluated on postnatal day 51. RESULTS: EtOH exposure during adolescence did not alter normal body temperature. However, a significant reduction in the febrile response that was induced by LPS at both doses was observed on postnatal day 51. However, no changes in the febrile response were observed on postnatal day 63 in EtOH-exposed animals. The febrile response that was induced by intracerebroventricular IL-1ß also significantly decreased in animals that received binge-like EtOH exposure during adolescence. Acute oral treatment with EtOH 24 h prior to LPS administration did not alter the febrile response that was induced by LPS. Binge-like EtOH exposure during adolescence did not alter hematological parameters or the number or viability of peritoneal macrophages. Binge-like EtOH exposure did not alter plasma IL-1ß levels but reduced the cerebrospinal fluid levels of this cytokine. CONCLUSIONS: These results suggest that binge-like EtOH exposure during adolescence causes changes in the central nervous system that can impair the febrile response that can be observed after the cessation of EtOH exposure. These changes were reversible and appeared to involve the LPS/IL-1ß system.

Involvement of Central Endothelin ETA and Cannabinoid CB1 Receptors and Arginine Vasopressin Release in Sepsis Induced by Cecal Ligation and Puncture in Rats.

We previously reported that endothelin-1 (ET-1) reduced the frequency of spontaneous excitatory currents in vasopressinergic magnocellular cells through the activation of endothelin ETA receptors in rat brain slices. This effect was abolished by a cannabinoid CB1 receptor antagonist, suggesting the involvement of endocannabinoids. The present study investigated whether the blockade of ETA or CB1 receptors during the phase of increased levels of ET-1 after severe sepsis increases the survival rate of animals concomitantly with an increase in plasma arginine vasopressin (AVP) levels. Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). Treatment with the CB1 receptor antagonist rimonabant (Rim; 10 and 20 mg/kg, orally) 4 h after CLP (three punctures) significantly increased the survival rate compared with the CLP per vehicle group. Intracerebroventricular treatment with the ETA receptor antagonist BQ123 (100 pmol) or with Rim (2 µg) 4 and 8 h after CLP but not the ETB receptor antagonist BQ788 (100 pmol), also significantly improved the survival rate. Sham-operated and CLP animals that were treated with Rim had significantly lower core temperature than CLP animals. However, oral treatment with Rim did not change bacterial count in the peritoneal exudate, neutrophil migration to the peritoneal cavity, leucopenia or increased plasma interleukin-6 levels induced by CLP. Both Rim and BQ123 also increased AVP levels 12 h after CLP. The blockade of central CB1 and ETA receptors in the late phase of sepsis increased the survival rate, reduced body temperature and increased the circulating AVP levels.