N-Methyl-(2S,4R)-trans-4-hydroxy-L-proline isolated Sideroxylon obtusifolium attenuates TPA-induced irritant contact dermatitis in mice.

Dermatitis is defined as a set of inflammatory diseases that affect the skin, with varied causes. Among the different types of dermatitis, contact dermatitis is the most prevalent. Although the current therapy is often effective, it is associated with adverse effects and the possibility of drug tolerance. N-Methyl-(2S, 4R)-trans-4-hydroxy-L-proline is a L-proline amino acid derivative found in the leaves of Sideroxylon obtusifolium, a species traditionally used to treat inflammatory diseases. The aim of this study was to investigate the topical anti-inflammatory effect of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritant contact dermatitis in mice. Topically administered NMP, at doses of 0.03 - 0.50 mg/ear, reduced TPA-induced ear edema and neutrophil migration, as evidenced by low tissue myeloperoxidase activity and verified by histological examination. In addition, NMP (0.06 mg/ear) reduced tissue levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß, INF-γ and MCP-1) and of the anti-inflammatory cytokine IL-10, and reduced gene expression of TNF-α, IL-6 and IL-1ß increased by TPA. The data suggest that N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline acts as a topical anti-inflammatory agent that decreases the expression of inflammatory cytokines, making it useful for the treatment of skin inflammation. Further investigations are necessary for its development as a therapeutic agent.

(-)-Myrtenol accelerates healing of acetic acid-induced gastric ulcers in rats and in human gastric adenocarcinoma cells.

The gastroprotective property of (-)-myrtenol, a monoterpenoid, has been demonstrated previously against acute gastric ulceration induced by ethanol. However, the healing property of (-)-myrtenol in a chronic gastric ulcer model remains to be verified. This study evaluated its healing efficacy and the mechanism involved using the rat model of chronic gastric ulcer induced by serosal injection of 80% acetic acid in vivo, and human gastric adenocarcinoma cells (AGS) in vitro. The results showed that compared to vehicle-treated ulcer controls, oral administration of (-)-myrtenol (50 and 100 mg/kg/day) for 7 days promoted ulcer healing, as indicated by significant decreases in ulcer area and volume. The macroscopic and microscopic findings confirmed the healing potential of (-)-myrtenol. The ulcer healing activity was also associated with significant increases in gastric mucin content, collagen deposition, number of cells with positive marking for proliferating cell nuclear antigen (PCNA), and by changes in the expression of the inflammatory parameters tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and cyclooxygenase (COX)-2, as well as a decrease of metalloproteinases (MMP-9 and MMP-2) activity. Furthermore, in vitro assays using the AGS cultures revealed that (-)-myrtenol favors wound healing activity via stimulation of cell proliferation and migration without altering the cell viability. Taken together, these findings indicate that (-)-myrtenol has gastro-cytoprotective and ulcer healing properties that can be further explored to develop a new therapeutic agent from a natural source for the treatment of gastric ulcer.

Gastroprotective effect of ethanol extracts of cladodes and roots of Pilosocereus gounellei (A. Weber ex K. Schum.) Bly. Ex Rowl (Cactaceae) on experimental ulcer models.

ETHNOPHARMACOLOGICAL RELEVANCE: Pilosocereus gounellei Cactaceae), popularly known as "xique xique", is a species native from Caatinga region of Northeast Brazil, which is used by traditional communities in folk medicine for a variety of health problems, especially inflammatory processes and gastritis. AIM OF THE STUDY: The present study investigates the possible gastric antiulceractivity of ethanol extracts obtained from the cladodes and roots of Pilosocereus gounellei (EECPG and EERPG, respectively) and mechanisms of action underlying this effect. MATERIALS AND METHODS: Mice were used for the evaluation of the acute toxicity, and mice and rats to study the gastroprotective activity. The gastroprotective action of EECPG and EERPG was analyzed in the absolute ethanol in mice, ischemia-reperfusion and cold restraint stress in rats. In the investigation of the gastroprotective mechanisms of EECPG and EERPG, the participation of the NO and prostaglandins, the levels of the non-protein sulfhydril groups (NP-SH) and the catalase activity using the ethanol-induced gastric mucosa lesion model and the quantification of the gastric mucus and the antisecretory activity through pylorus ligature model in rats were analyzed. RESULTS: The animals did not present any signs of acute toxicity for the EECPG and EERPG, and it was not possible to calculate the DL50. EECPG and EERPG (200 and 400 mg/kg) exhibited a significant gastroprotective effect in absolute ethanol, ischemia-reperfusion-induced and cold restraint stress gastric lesion models. Gastroprotection of EECPG and EERPG (200 mg/kg) was significantly decreased in pre-treated mice with L-NAME. Our studies revealed that EECPG and EERPG (200 mg/kg) prevented the decrease of the non-protein sulfhydril groups (NPSH) and increased the catalase levels in ethanol-treated animals. However, the gastric secretion parameters (volume, [H+], pH) did not show any alteration. CONCLUSIONS: Our results indicate that the ethanolic extract from the cladodes and roots of Pilosocereus gounellei exhibits a significant gastroprotection, because it inhibits the formation of gastric lesions using different models. The participation of the nitric oxide, prostaglandins, the non-protein sulfhydril groups (NP-SH), catalase seem to be involved in the gastroprotection activity of the EECPG and EERPG. Nevertheless, this activity does not seem to be related to antisecretory mechanisms.

ß-Cyclodextrin-complexed (-)-linalool produces antinociceptive effect superior to that of (-)-linalool in experimental pain protocols.

Many plants produce (-)-linalool, a plant-derived monoterpene alcohol, including members of the Lamiaceae (mints) and Lauraceae family (laurels, cinnamon, rosewood). The anti-inflammatory and analgesic effects of (-)-linalool have been widely suggested for various studies. Poor chemical stability and short half-life restrain the clinical applications of some essential oil and monoterpenes, including (-)-linalool. However, ß-cyclodextrin (ß-CD) has been used to increase solubility and stability of lipophilic compounds and also to improve the pharmacological effects. In this study, the antinociceptive effect of (-)-linalool and (-)-linalool/ß-CD was examined using the acetic acid writhing reflex, formalin and hotplate tests in rodents. (-)-Linalool and (-)-linalool/ß-CD demonstrated strong antinociceptive activity in all the chemical- and heat-induced mice models (p < 0.01 or p < 0.001). These findings imply the involvement of both peripheral and central antinociceptive mechanisms. In peritonitis induced by carrageenan, isolated monoterpene or ß-CD complex also reduced total leucocyte migration and TNF-α levels in peritoneal fluid. The inclusion complexes, (-)-linalool/ß-CD, revealed that the antinociceptive effect was significantly (p < 0.01) improved when compared with (-)-linalool alone. Such results were unlikely to be provoked by any motor abnormality. Together, our results suggest that ß-CD might represent an important tool for improvement of analgesic and anti-inflammatory profiles of (-)-linalool and other water-insoluble compounds, such as lipophilic monoterpenes or essential oils.

Gastroprotective activity of carvacrol on experimentally induced gastric lesions in rodents.

The present study aimed to investigate the gastroprotective activity of carvacrol, a monoterpene present in essential oils from several species of medicinal and aromatic plants, by using different models of acute gastric lesions in rodents and also evaluate possible mechanisms involved in this action. For this study, absolute ethanol-, acidified ethanol-, ischemia and reperfusion-, and nonsteroidal anti-inflammatory drug-induced models of gastric lesions in mice and rats were used. The roles of nonprotein sulfhydryl groups, catalase, nitric oxide (NO), ATP-sensitive potassium channels (K(ATP) channels), and prostaglandins in carvacrol-induced gastroprotective effect were investigated. In addition, the effects of carvacrol on gastric secretion and mucus in pylorus-ligated rats were also determined. The results of the present study demonstrated that carvacrol promoted a marked gastroprotection in all models investigated, possibly mediated by endogenous prostaglandins, increase of mucus production, K(ATP) channels opening, NO synthase activation, and antioxidant properties. These findings markedly substantiate further studies to investigate the therapeutic potential of carvacrol as an effective gastroprotective agent and its safety profile in medicinal use.