Cannabinoid CB2 receptors and spinal microglia are implicated in tingenone-mediated antinociception in mice

Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain, as well as and the involvement of the cannabinoid receptors type 2 (CB2) and spinal microglia in this process. Methods:Male Swiss mice were subjected to inflammatory pain induced by intraplantar injection of carrageenan. The nociceptive threshold was measured by von Frey filaments test. Tingenone was administered orally 60 min before carrageenan injection. To evaluate the involvement of CB2 receptor, endocannabinoids, and microglia, AM630 (a CB2 receptor antagonist), MAFP (an inhibitor of an enzyme that hydrolyses endocannabinoids), and minocycline (a microglial inhibitor) were given intrathecally 20 min before tingenone administration. In addition, an immunofluorescence assay was used to evaluate CB2 receptor and CD11B (a microglial marker) expression in the spinal cord dorsal horn. Results:Tingenone significantly reduced carrageenan-induced hyperalgesia, which was reversed by pretreatment with AM630. MAFP and minocycline potentiated and prolonged the tingenone-induced antinociception. CD11B expression was increased in the spinal cord dorsal horn of mice with inflammatory pain pretreated with tingenone, which was reduced by AM630, MAFP, and minocycline. Conclusions:CB2 receptors and endocannabinoids participate in the tingenone-induced antinociception which may involve the inhibition of microglia at spinal level.

Pharmacological potential of Maytenus species and isolated constituents, especially tingenone, for treatment of painful inflammatory diseases

ABSTRACT Uses of medicinal plants by people around the world significantly contribute and guide biologically active compounds research that can be useful in the combat against various diseases. Due to a great chemical and structural variety found in their vegetal structures it consolidates ethnopharmacology as an important science for the pharmaceutical section. Inserted in the diversity of medicinal plants, is the Maytenus genus, whose research has already revealed lots of isolated substances which are responsible for a great variety of biological activities, among which we cite analgesic and anti-inflammatory, for the treatment of inflammatory diseases such as rheumatoid arthritis, gastritis, ulcers and gastrointestinal disorders. The aim of this review article is to make a compendium of the Maytenus genus and its isolated chemical compounds, among them tingenone. The elucidation of its mechanism of action reveals promising sources for the development of new drugs specially targeted for the treatment of painful inflammatory diseases.

Antitumoral, mutagenic and (anti)estrogenic activities of tingenone and pristimerin

Cancer constitutes the second main mortality cause in the world, after cardiovascular diseases. In spite of the progresses in the chemotherapeutics treatments, many patients fail chemotherapy, mainly because of side effects or multi-drugs resistance, proving the need and importance of the research for new molecules with anticancer activity, more effective and with smaller adverse effects. Various compounds derived from plant secondary metabolites are commonly used in the chemotherapy against cancer and the natural products play an important role in the research for new molecules. Among several molecules of natural origin evaluated by MTT assay in murine tumor cell lines [breast (LM3) and lung (LP07)] the quinona-methide triterpenes tingenone and pristimerin showed marked cytotoxic activity presenting IC50 around 2 and 5 µM respectively. The structure-activity relationship suggests that rings A and B containing an α, ß-unsaturated carbonyl group are essential for the observed cytotoxic activity. The interaction between these positions and acetylcisteyne residues suggests a probable mechanism of action. The in vitro mutagenic activity was also evaluated by the Salmonella microsome assay (Ames test) for pristimerin and tingenone with and without metabolic activation (S9) in the strains TA98, TA97a, TA100 and TA102, none of which showed mutagenic potential in any strains. Estrogenic and anti-estrogenic activities were also studied by the e-screen assay in MCF-7 cells with negative results. The present data point to the importance of pristimerin and tingenone as representative of an emerging class of potential anticancer chemicals.