MHTP, a synthetic alkaloid, attenuates combined allergic rhinitis and asthma syndrome through downregulation of the p38/ERK1/2 MAPK signaling pathway in mice.

The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-ß. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription.

4-Carvomenthenol ameliorates the murine combined allergic rhinitis and asthma syndrome by inhibiting IL-13 and mucus production via p38MAPK/NF-κB signaling pathway axis.

The aim of this study was to analyze the 4-carvomenthenol (carvo) oral treatment on the experimental model of the combined allergic rhinitis and asthma syndrome (CARAS). BALB/c mice were OVA-sensitized on day zero and 7th (50 µg/mL OVA in 10 mg/mL Al (OH)3) and OVA-challenged (5 mg/mL, 20 µL/animal) for three weeks. In the last week, the animals were dally challenged with aerosol of OVA and the carvo treatment (12.5, 25 or 50 mg/kg) occurred one hour before each OVA-challenge. Data were analyzed and p < 0.05 was considered significant. Carvo (12.5-50 mg/kg) decreased significantly the eosinophil migration into the nasal (NALF) and bronchoalveolar (BALF) cavities as well as on the nasal and lung tissues of sick animals. The treatment also decreased mucus production on both tissue sections stained with PAS (periodic acid-Schiff satin). In addition, the histological analyzes demonstrated that sick mice presented hyperplasia and hypertrophy of the lung smooth muscle layer followed by increasing of extracellular matrix and carvo (50 mg/kg) inhibited these asthmatic parameters. We analyzed the allergic rhinitis signals as nasal frictions and sneezing and observed that carvo decreased these two signals as well as serum OVA-specific IgE titer, type 2 cytokine synthesis, mainly IL-13, with increasing of IL-10 production. Decreasing of IL-13 production corroborated with decreasing of mucus production and these effects were dependent on p38MAPK/NF-κB(p65) signaling pathway inhibition. Therefore, these data demonstrated that a monoterpene of essential oils presents anti-allergic property on an experimental model of CARAS suggesting a new drug prototype to treat this allergic syndrome.

Anti-asthmatic and anxiolytic effects of Herissantia tiubae, a Brazilian medicinal plant.

Herissantia tiubae (HtE) is a Brazilian plant used in folk medicine to treat inflammatory diseases. Our aim was to determine whether the HtE has anti-inflammatory and anxiolytic effects in a murine model of asthma. Ovalbumin (OVA)-sensitized BALB/c mice were treated with HtE (50, 100, or 200 mg/kg) or dexamethasone before each OVA challenge. After the last challenge, animals were subjected to anxiety tests and respiratory measurements. Following euthanasia, we quantified immune cells in the bronchoalveolar lavage (BAL), serum IgE titer and cytokine levels, cellular infiltration and mucus content in the lung tissues, and cellular composition of the mediastinal lymph nodes. OVA challenge in sensitized animals caused: (1) reduction of mean respiratory and dominant respiratory rate (from 398 ± 12 to 286 ± 20 cicles per minute (cpm) and from 320 ± 14 to 162 ± 15 cpm, respectively); (2) increase in behavioral markers of anxiety tests; (3) substantial pro-inflammatory effects, including rise in OVA-specific IgE titer (from 0 to 1:2048) and these inflammatory effect diminished the titer to 1:512 after HtE treatment; rise in plasma IL-13 (from 13 ng/mL in saline to 227 ng/mL in OVA and HtE treatment restored to 1.29 ng/mL; rise in total BAL cell count (from 0.742 cells/mL in saline to 11.77 cells/mL in OVA), with prominent eosinophilia. H. tiubae extract affected respiratory parameters similarly to aminophylline, behavioral changes comparable to diazepam, and inflammation being as efficient as dexamethasone. H. tiubae extract (HtE) possesses both anti-inflammatory and anxiolytic properties in the murine model of asthma.

Anti-inflammatory activity and acute toxicity studies of hydroalcoholic extract of Herissantia tiubae

ABSTRACT Hydroalcoholic extract of aerial parts of Herissantia tiubae (K. Schum.) Brizicky, Malvaceae, was evaluated in experimental models of inflammation and toxicity. For toxicity assays, male and female Swiss mice were orally treated with hydroalcoholic extract of H. tiubae (2000 mg/kg) and analyzed by consumption of water and food, body weight, mortality and rates of major organ weights, as well as biochemical and hematological indexes. For anti-inflammatory effect, phlogistic agents such as carrageenan or acetic acid were used to evaluate paw edema, cell migration and cytokine production. It was also investigated the hydroalcoholic extract of H. tiubae in RAW 264.7 macrophage lineage by nitric oxide and cytokine productions. Swiss mice treated with hydroalcoholic extract of H. tiubae showed low toxicity and (50 or 100 mg/kg) was able to reduce significantly (p < 0.01, p < 0.001) polymorphonuclear cell migration, TNF-α and IL-1β production in the carrageenan-induced peritonitis. However the hydroalcoholic extract of H. tiubae (50, 100 or 200 mg/kg) did not reduce carrageenan-induced paw edema. Additionally, hydroalcoholic extract of H. tiubae did not present cytotoxicity at concentrations of 6.25, 12.5, 25 or 50 µg/ml but induced significantly decrease of NO, TNF-α and IL-6 production in macrophage lineage. This study suggests that hydroalcoholic extract of H. tiubae has anti-inflammatory activity by inhibiting cell migration mainly by decreasing the inflammatory cytokine levels at the inflamed site independently of the anti-edematogenic effect.