Role of central endothelin-1 in hyperalgesia, anhedonia, and hypolocomotion induced by endotoxin in male rats.

Sickness syndrome is an adaptive response that can be distinguished by specific signs and symptoms, such as fever and generalized hyperalgesia. Endothelin-1 (ET-1) is produced by inflammatory stimuli, including lipopolysaccharide, and involved in the pathogenesis of inflammation and pain by acting through ETA and ETB receptors. ET-1 also induces fever by acting on the central nervous system. The present study investigated the role of ET-1 in sickness syndrome responses, including hyperalgesia, anhedonia, and hypolocomotion. Intracerebroventricular ET-1 administration induced mechanical and thermal hyperalgesia in rats, which was ameliorated by the ETA receptor antagonist BQ123 and exacerbated by the ETB receptor antagonist BQ788. A cyclooxygenase blocker did not alter hyperalgesia that was induced by ET-1. Lipopolysaccharide administration induced hyperalgesia, and both BQ123 and BQ788 abolished this mechanical hyperalgesia, but the thermal response was only partially blocked. The blockade of ETA receptors in the hypothalamus also abolished lipopolysaccharide-induced mechanical hyperalgesia, and the ETB receptor antagonist did not influence this response. Lipopolysaccharide also induced anhedonia, reflected by lower sucrose preference, and reduced locomotor activity. Both antagonists restored locomotor activity, but only BQ788 reversed the reduction of sucrose preference. These results indicate that ET-1 and both ETA and ETB receptors are involved in various responses that are related to sickness syndrome, including hyperalgesia, anhedonia, and hypolocomotion, that is induced by LPS. Hypothalamic ETA but not ETB receptors are involved in mechanical hyperalgesia that is observed during lipopolysaccharide-induced sickness syndrome.

Effects of silymarin on angiogenesis and oxidative stress in streptozotocin-induced diabetes in mice.

The present study evaluated the effects of acute treatment with silymarin, an extract that is obtained from Silybum marianum, on angiogenesis, oxidative stress, and inflammation in normoglycemic and diabetic mice. Diabetes was induced by streptozotocin (80 mg/kg, intraperitoneal) in male Swiss mice, 6 weeks of age. A polyether-polyurethane sponge was surgically implanted in the back of the mice as a model of healing in both diabetic and normoglycemic animals that were treated with oral silymarin or water for 10 days. The pancreas, liver, kidneys, blood, and sponges were collected and analyzed. Diabetes led to impairments of antioxidant defenses, reflected by a reduction of pancreatic superoxide dismutase and hepatic and renal catalase and an increase in pancreatic lipoperoxidation. An inflammatory process was observed in diabetic mice, reflected by an increase in pancreatic tumor necrosis factor α (TNF-α) and the infiltration of inflammatory cells in islets. The number of vessels was lower in the implanted sponges in diabetic mice. Silymarin treatment attenuated this damage, restoring antioxidant enzymes and reducing pancreatic TNF-α and inflammatory infiltration. However, silymarin treatment did not restore angiogenesis or glycemia. In conclusion, treatment with silymarin red uced oxidative stress and inflammation that were induced in the model of streptozotocin-induced diabetes in several organs, without apparent toxicity. Silymarin may be a promising drug for controlling diabetic complications.