European journal of pharmacology
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Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used for treatment of arthritis. However, their long-term use has been associated with considerable morbidity, limiting their application. Thus, there remains a need to develop new drugs for the effective and safe relief of chronic inflammatory pain. ⋯ The activity of tissue myeloperoxidase, the tissue TNF-alpha level and the serum haptoglobin level was increased by intraplantar CFA injection. However, chronic administration of EPFCA3, MPFCA4 or dipyrone was not able to alter the relation between these parameters and inflammation. Our results suggest that EPFCA3 and MPFCA4 are good candidates for the development of new drugs for pain treatment.
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Using an adaptation of published behavioral protocols, we determined that acute exposure to the cholinergic compounds nicotine and carbamylcholine decreased planarian motility in a concentration-dependent manner. A tobacco cembranoid (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R-cembranoid), also decreased planarian motility. Experiments in the presence of 1 microM 4R-cembranoid did increase the IC50 for nicotine- but not carbamylcholine-induced decrease in planarian motility. ⋯ In experiments where planarians were pre-exposed to 100 microM nicotine for 24 h in the presence of 1 microM 4R-cembranoid, the withdrawal-like effects were significantly reduced. These results indicate that the 4R-cembranoid might have valuable applications for tobacco abuse research. This experimental approach using planarians is useful for the initial screening of compounds relevant to drug abuse and dependence.
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Sympathomimetic drugs (MDMA; ecstasy) induce a potentially catastrophic hyperthermia that involves free fatty acid (FFA) activation of mitochondrial uncoupling proteins (UCP). Insulin is an important regulator of plasma FFA levels, although its role in thermogenesis is unclear. The aims of the present study were 1) to characterize the pharmacodynamic effects of MDMA on plasma insulin and glucose, 2) to examine the effects of insulin on MDMA-induced thermogenesis and 3) to examine MDMA-induced thermogenesis in an animal model of insulin resistance, the obese Zucker rat. ⋯ Insulin resistant, fa/fa (obese) Zucker rats demonstrated an attenuated thermogenic response to MDMA (40 mg/kg, s.c.). Consistent with the role for FFA in UCP3 expression, immunoblot analysis showed significantly increased levels of UCP3 protein obese compared to lean Zucker skeletal muscle. In conclusion, the results of the present study suggest a potential role of insulin signaling in sympathomimetic-induced thermogenesis.
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Peripheral nerve injury, which gives rise to persistent chronic pain, has become an area of intense research activity, largely because it represents a disorder with a high unmet medical need. In this study, serum biomarkers of the spinal nerve ligation model were successfully investigated with the metabolomic method. The regulatory effect of gabapentin, a novel clinical antineuralgia drug, on biomarker levels in serum was also investigated. ⋯ In addition, another multivariate method, the orthogonal partial least-squares analysis (OPLS), was used to monitor the real biological variability and to detect potential biomarkers in the spinal nerve ligation model. The results demonstrated that the spinal nerve ligation model had several discriminating ions compared with the control model. Among the detectable metabolites, levels of norepinephrine were increased in the spinal nerve ligation model and were decreased to control levels by gabapentin.
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Clinical Trial
Berberine-induced decline in circulating CD31+/CD42- microparticles is associated with improvement of endothelial function in humans.
Elevated circulating endothelial microparticles (EMPs) are associated with endothelial dysfunction. This study is to investigate whether berberine-induced fall in circulating EMPs facilitates improvement of endothelial function in healthy subjects. Fourteen healthy subjects received 1-month berberine therapy (1.2 g/d) and 11 healthy subjects served as control. ⋯ The EMPs in vitro led to diminished eNOS protein expression in HUVECs and this EMP-mediated detrimental effect was markedly inhibited by berberine. Berberine-induced decline in circulating CD31(+)/CD42(-) microparticles contributes to upregulation of endothelial function in healthy subjects. Deceasing EMPs may be a novel therapeutic target for the improvement of endothelial dysfunction in humans.