Biological Activities of Morita-Baylis-Hillman Adducts (MBHA).

BACKGROUND: The Morita-Baylis-Hillman reaction (MBHR) is considered one of the most powerful and versatile methodologies used for carbon-carbon bond formation. The reaction is defined as the condensation between an electrophilic carbon sp² and the α position of an olefin, carrying an electron-withdrawing group, in the presence of a catalyst. The advantages of the reaction are the high atom economy and mild reaction conditions. Under ideal conditions, this reaction leads to the formation of multifunctional products, called Morita-Baylis-Hillman adducts (MBHA), a class of relevant molecules that exhibit a variety of biological activities. OBJECTIVE: Considering the importance of these compounds, this review brought together several studies regarding the biological activities of MBHA, to point out the use of these molecules as future therapeutic agents. METHODS: We searched for scientific articles available in the main databases, published between 1999 and 2022, using the descriptors: Morita-Baylis-Hillman adducts, Morita-Baylis-Hillman reaction, biological activity, and biological potentiality. RESULTS: Thirty-five articles showed the variety of biological activities of MBHA, including molluscicidal, antitumor, herbicidal, and fungicidal, antileishmanial, antioxidant, antimalarial, anti-tumor inflammatory, vasorelaxant, antichagasic, antimicrobial, and anti-inflammatory activities. CONCLUSION: Therefore, these compounds are promising candidates to become drugs for the treatment of a variety of diseases, following further studies to understand the effective mechanisms of action of MBHA.

Milonine attenuates the lipopolysaccharide-induced acute lung injury in mice by modulating the Akt/NF-κB signaling pathways.

Acute lung injury is an inflammation that triggers acute respiratory distress syndrome with perialveolar neutrophil infiltration, alveolar-capillary barrier damage, and lung edema. Activation of the toll-like receptor 4 complex (TLR4/MD2) and its downstream signaling pathways are responsible for the cytokine storm and cause alveolar damage. Due to the complexity of this pulmonary inflammation, a defined pharmacotherapy has not been established. Thus, this study evaluated the anti-inflammatory potential of milonine, an alkaloid of Cissampelos sympodialis Eichl, in an experimental model of lung inflammation. BALB/c mice were lipopolysaccharide-challenged and treated with milonine at 2.0 mg/kg. Twenty-four hours later, the bronchoalveolar fluid, peripheral blood, and lungs were collected for cellular and molecular analysis. The milonine treatment decreased the cell migration (mainly neutrophils) to the alveoli, the pulmonary edema, and the cytokine levels (IL-1ß, IL-6, TNF-α). The systemic IL-6 level was also reduced. The milonine docking analysis demonstrated hydrophobic interaction at TLR4/MD2 groove with Ile124 and Phe126 amino acids. Indeed, the alkaloid downregulated the kinase-Akt and NF-κB through TLR4/MD2. Therefore, milonine is an effective inflammatory modulator being a potential molecule for the treatment of lung inflammation.

4-Carvomenthenol, a monoterpene of essential oils, and its underlying effects on anti-inflammatory activity and immediate hypersensitivity reaction

Abstract The monoterpene 4-carvomenthenol (Carvo) is found in essential oils of plant. Here, we evaluate the Carvo oral pretreatment in acute inflammatory experimental models and in silico molecular docking. Mice pretreated with Carvo were challenged and submitted to the protocols: paw edema, peritonitis, scratching behavior and anaphylactic shock reaction. Besides, we used histamine H1 receptor, cyclooxygenases (COX-1 and COX-2) and phospholipase A2, as targets for molecular docking analysis. Carvo inhibited the carrageenan-induced paw edema and decreased the peritoneal influx of polymorphonuclear cells on carrageenan-challenged mice without interfering with the mononuclear cell influx. Moreover, Carvo diminished the histamine, PGE2 and compound 48/80 induced paw edematogenic effect. The monoterpene also diminished the mice scratching behavior and, surprisingly, avoided the animal death caused by compound 48/80 in 30 min. Through the docking analysis, Carvo showed favorable binding energy to the histamine H1 receptor. This study demonstrates that Carvo attenuated the allergic inflammatory process, decreasing edema, cell migration, activation of mast cells and the histamine release, probably due to interaction of Carvo with the histamine H1 receptor, ameliorating the itching and the anaphylactic shock reaction. Therefore, the results of this study indicate that Carvo has anti-inflammatory properties by reducing the histamine effects.

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.

The Control and Prevention of COVID-19 Transmission in Children: A Protocol for Systematic Review and Meta-analysis.

BACKGROUND: The pandemic following the rapid spread of the new SARS-CoV-2 virus has hit all continents and caused thousands of deaths worldwide. Evidence has been published on epidemiological and clinical characteristics of population groups considered at risk; however, information for the other population groups, especially for the child population, is needed. In this context, this protocol describes a systematic review that will aim to identify the evidence on control and prevention of COVID-19 transmission among children and adolescents, as well as to describe the epidemiological profile and clinical and immunological characteristics of COVID-19 in this population. METHODS: This protocol will be developed in accordance with PRISMA-P. The searches will be conducted in PubMed, Web of Science, ScienceDirect, EMBASE, and Scopus, seeking clinical trials. Observational studies and case reports with Children and adolescents (≤19 years) infected with SARS-CoV-2 will be included whether they report information on the control of prevention and COVID-19 transmission. Two independent researchers will perform the selection of articles, removal of duplication, and screening by Rayyan QCRI application. Cochrane's RoB 2.0, ROBINS-I, and CASP tools will be used to assess the risk of bias. Meta-analysis, subgroup analyses, and/or descriptive analyses will be carried out based on the data conditions included. RESULTS: A high-quality synthesis of the available evidences on the epidemiological profile, the clinical and immunological characteristics involved in children, and adolescents diagnosed with COVID-19, as well as the participation of this population in the transmission dynamics of SARS-CoV-2 will be provided. CONCLUSION: This systematic review has an important relevance in the current context because it has a great potential to help the development of new control and prevention strategies in the pediatric population. RECORD OF SYSTEMATIC REVIEW: CRD42020179263.

MHTP, a synthetic tetratetrahydroisoquinoline alkaloid, attenuates lipopolysaccharide-induced acute lung injury via p38MAPK/p65NF-κB signaling pathway-TLR4 dependent.

INTRODUCTION: This study investigated the mechanism of action of a synthetic tetrahydroisoquinoline alkaloid, MHTP, in an experimental model of acute lung injury (ALI) in two distinct moments: 72 h and 10 days. METHODOLOGY: To realize this study, 2.5 mg/kg of lipopolysaccharide (LPS) was intranasally administered in BALB/c mice, and nasal instillation of MHTP (1.25; 2.5; 5.0; 10 or 20 mg/kg) was administrated at 1, 24, and 48 h after LPS challenge. The data were statistically analyzed and p < 0.05 was considered statistically significant. RESULTS: MHTP treatment (2.5, 5.0, 10 or 20 mg/kg) significantly decreased neutrophil migration into the bronchoalveolar lavage fluid (BALF), tissue inflammatory cell infiltration, edema, and hemorrhage as well as collagen fiber deposition on the perialveolar regions at both moments. TNF-α and IL-6 levels were significantly diminished in the MHTP-treated animals at 72 h and maintained them, at a basal level, at 10-day observation. These effects of MHTP are due to downregulating p38MAPkinese/p65NFκB signaling pathway-TLR4 dependent. Also, the MHTP treatment promoted a survival rate at 100% and improved their body weights during the 10-day observation. Unlike, the LPS group (non-treated LPS challenged animals) presented less than 50% of surviving rate at 72 h and the animals that survived did not improve their physiological state at 10-day observation. CONCLUSIONS: These data showed for the first time the beneficial and effective activity of a nasal treatment with a synthetic tetrahydroisoquinoline alkaloid on an experimental model of ALI and pointed out the molecular mechanism related to it.

Combined allergic rhinitis and asthma syndrome (CARAS).

Combined allergic rhinitis and asthma syndrome (CARAS) is a concept of "one airway - one disease" or "unified airway disease ". The upper and lower airway inflammation characterizes allergic rhinitis and asthma, respectively and both diseases have shown an intimate connection in their genesis, coexistence and similarities as triggered by the same etiological agents; the same inflammatory cell profile and share therapeutic treatment. This review highlights the concept of CARAS by its phenotype, endotype and biomarker classification. Indeed, rhinitis is divided into four major phenotypes: allergic rhinitis; infectious rhinitis; non-infective/non-allergic rhinitis and mixed rhinitis. On the other hand, asthma has no common consensus yet; however, the most accepted classification is based on the stage of life (early- or late- onset asthma) in which the clinical symptoms are presented. Experimental researches where animals develop a syndrome similar to CARAS have been contributed to better understand the pathogenesis of the syndrome. Therefore, the aim of this review is to clarify current terms related to CARAS as definition, phenotypes, endotypes/biomarkers, physiopathology and treatments.

MHTP, 2-Methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol, a Synthetic Alkaloid, Induces IFN-γ Production in Murine Model of Ovalbumin-Induced Pulmonary Allergic Inflammation.

MHTP [2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol], a synthetic isoquinolinic alkaloid, presented anti-inflammatory activity in several experimental models of acute inflammation as lipopolysaccharide (LPS)-induced acute lung injury and phlogistic agent-induced edema and presented low preclinical toxicity. The aim of this study was to determine the MHTP effect on ovalbumin (OVA)-induced pulmonary allergic inflammation. In other to realize this study, female BALFB/c mice were sensitized and challenged with OVA (OVA group) and treated with MHTP (MHTP group) by nasal instillation. Inflammatory, allergic, and immunomodulatory parameters such as migration of inflammatory cells to the lung tissue, pulmonary histological analysis, serum level of IgE-allergen specific, cytokine secretion, and lung T cell population characterization were analyzed and the data were considered statistically significant with p < 0.05. OVA-sensitized and OVA-challenged and MHTP (5.0 mg/kg)-treated mice presented reduction on total leukocyte migration into the bronchoalveolar lavage (BALF) dependent of lymphocyte and eosinophil migration (p < 0.001 and p < 0.01) as compared with the OVA group. Flow cytometric analysis showed that MHTP treatment decreased the percentage of granulocytes (p < 0.001) into the BALF and lung tissue histological analyzes demonstrated that the MHTP treatment decreased leukocyte migration and mucus production. In addition, treatment with MHTP decreased the number of CD3+CD4+ T cells independently of CD8+ T cell reduction into the BALF. The treatment also reduced significantly (p < 0.05) the serum level of IgE-OVA specific followed by reduction of IL-4, IL-13, and IL-17 production. Surprisingly, the MHTP treatment increased significantly (p < 0.05) the IFN-γ production in the BALF of these animals. Therefore, the results presented here showed that MHTP treatment, by nasal instillation, in a mouse model of OVA-induced pulmonary allergy has anti-allergic and immunomodulatory effects dependent on a Th1-skewed cytokine production that ameliorate the pulmonary allergic inflammation.

Comparison of behavioral, neuroprotective, and proinflammatory cytokine modulating effects exercised by (+)-cis-EC and (-)-cis-EC stereoisomers in a PTZ-induced kindling test in mice.

Epoxy-carvone (EC) has chiral centers that allow generation of stereoisomers, including (+)-cis-EC and (-)-cis-EC, whose effects in the kindling tests have never been studied. Accordingly, this study aims to comparatively investigate the effect of stereoisomers (+)-cis-epoxy-carvone and (-)-cis-epoxy-carvone on behavioral changes measured in scores, in the levels of cytokines (IL-1ß, IL-6, and TNFα) and neuronal protection in the face of continuous treatment with pentylenetetrazol. Swiss mice were divided into five groups (n = 10), receiving vehicle, (+) - cis-EC, (-) - cis-EC (both at the dose of 30 mg/kg), and diazepam (4 mg/kg). Thirty minutes after the respective treatment was administered to the animals one subconvulsive dose of PTZ (35 mg/kg). Seven subconvulsives treatments were made on alternate days, in which each treatment several parameters were recorded. In the eighth treatment, the animals receiving the highest dose of PTZ (75 mg/kg) and were sacrificed for quantification of cytokines and histopathologic analysis. All drugs were administered by intraperitoneal route. In the kindling test, (+)-cis-EC and (-)-cis-EC reduced the average scores. The stereoisomer (+)-cis-EC decreased levels of proinflammatory cytokines IL-1ß, IL-6, and TNFα, whereas comparatively (-)-cis-EC did not reduce IL-1ß levels. Histopathological analysis of the mice hippocampi undergoing this methodology showed neural protection for treated with (+)-cis-EC. The results suggest that the anticonvulsant effect of (+)-cis-EC possibly takes place due to reduction of proinflammatory cytokines involved in the epileptogenic process, besides neuronal protection, yet further investigation of the mechanisms involved is required.

Author Correction: Ouabain attenuates ovalbumin-induced airway inflammation.

In the original publication, author missed to include the financial support from CAPES/PROCAD-2013. The complete funding text should read as follows.

Ouabain attenuates ovalbumin-induced airway inflammation.

PURPOSE: Ouabain, an Na+/K+-ATPase inhibitor hormone, presents immunomodulatory actions, including anti-inflammatory effect on acute inflammation models. METHODS: In the present study, the effect of ouabain in a model of allergic airway inflammation induced by ovalbumin (OVA) was assessed. RESULTS: Initially, it was observed that ouabain treatment inhibited cellular migration induced by OVA on bronchoalveolar lavage fluid (BALF), mostly granulocytes, without modulating macrophage migration. In addition, it was observed, by flow cytometry, that ouabain reduces CD3high lymphocytes cells on BALF. Furthermore, treatment with ouabain decreased IL-4 and IL-13 levels on BALF. Ouabain also promoted pulmonary histological alterations, including decreased cell migration into peribronchiolar and perivascular areas, and reduced mucus production in bronchioles regions observed through hematoxylin-eosin (HE) and by periodic acid-Schiff stain, respectively. Allergic airway inflammation is characterized by high OVA-specific IgE serum titer. This parameter was also reduced by the treatment with ouabain. CONCLUSIONS: Therefore, our data demonstrate that ouabain negatively modulates allergic airway inflammation induced by OVA.

Milonine, a Morphinandienone Alkaloid, Has Anti-Inflammatory and Analgesic Effects by Inhibiting TNF-α and IL-1ß Production.

Milonine is a morphinandienone alkaloid from Cissampelos sympodialis Eichl (Menispermaceae), a plant used in Brazil to treat inflammatory disorders. In this study, we evaluated the anti-inflammatory and analgesic activity of milonine (MIL) by using classical experimental models of inflammation and nociception. The results showed that MIL reduced the paw edema formation induced by lipopolysaccharide, prostaglandin E2, and bradykinin, without interfering with the serotonin-induced edema. With respect to the nociception experiments, MIL decreased the exudate into the peritoneum induced by acetic acid, maintaining the tissue morphology. The alkaloid was able to inhibit the peritonitis induced by carrageenan, decreasing mainly the migration of polymorphonuclear cells, without altering the mononuclear cell number, and reduced the levels of TNF-α and IL-1ß in the peritoneum. In addition, MIL was able to decrease the frequency of abdominal writhing induced by acetic acid but did not increase the latency time of the animals in the hot plate test. MIL significantly reduced the nociceptive behavior of paw licking induced by formalin only at the second phase of the test. In conclusion, we demonstrate that milonine has anti-inflammatory and anti-nociceptive activities by inhibiting mediators essential for the inflammatory process.

Milonine, an Alkaloid of Cissampelos sympodialis Eichl. (Menispermaceae) Inhibits Histamine Release of Activated Mast Cells.

Milonine is an alkaloid of Cissampelos sympodialis Eichl. (Menispermaceae), a plant used in the northeast of Brazil to treat allergies such as asthma, rhinitis, and other conditions. Previously, several alkaloids were isolated from its roots and leaves with pharmacological properties in asthma and acute inflammation models. Therefore, the aim of this study was to evaluate the milonine effect on mast cells degranulation in vivo and in vitro. Swiss mice (n = 8) were used in models of paw edema induced by carrageenan, compound 48/80, or histamine. One hour before challenge, the animals were treated with milonine (at different doses) or standard drugs and, at different time points, the edema formation was measured. In addition, other different methods, such as anaphylactic shock reaction and scratching behavior models both induced by compound 48/80, a mast cell degranulator, were used to assess milonine effect histamine release in vivo. Moreover, milonine effect on mast cell degranulation in vitro was also carried out. Firstly, it was observed that milonine significantly decreased the carrageenan edema formation only at the beginning of the reaction (i.e., up to 2 h after challenge). Furthermore, this alkaloid decreased the edema induced by compound 48/80, maintained the paw tissue integrity, without modulating histamine-induced paw edema. In anaphylactic shock reaction, milonine increased the time of animal survival when compared with compound 48/80 group. Milonine also significantly decreased the scratching behavior induced by compound 48/80 with decreasing of mast cell degranulation in vitro. Therefore, these data indicated that milonine presents anti-allergic properties by decreasing mast cell degranulation rather than acting on histamine effect.

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.

Profile of patients receiving medical care at a reference, support, and treatment center for psoriasis patients at a university hospital.

Psoriasis is a chronic, inflammatory, immune-mediated disease affecting 1-3% of the population worldwide. This work seeks to draw a profile of patients with psoriasis, analyzing socioeconomic, anthropometric, and clinical aspects. For this, medical records from 81 individuals who received medical care in a university hospital in 2014 were consulted. It was observed that the patients were mostly dark-skinned black adult men, with a low education level and a low income, who were sedentary, former smokers, obese, with an increase in waist circumference, and who did not consume alcohol. Psoriasis vulgaris predominated, beginning mainly on the scalp, hands, and feet. In addition, many presented some type of associated comorbidity and had relatives with psoriasis.

Cissampelos sympodialis has anti-viral effect inhibiting dengue non-structural viral protein-1 and pro-inflammatory mediators

ABSTRACT Dengue is the most important viral infection transmitted among humans by arthropod-borne. There are currently no vaccines or specific therapeutical treatment. Therefore, immunomodulatory compounds from plants have been widely examined for their antiviral effects. Cissampelos sympodialis Eichler, Menispermaceae, has scientifically proven to present immunomodulatory activities. Here we assessed the antiviral activity of leaf hydroalcoholic extract, warifteine or methylwarifteine from C. sympodialis in an in vitro dengue virus infection model. The results demonstrated that leaf hydroalcoholic extract or warifteine/methylwarifteine treatment did not reduce dengue virus-Ag+ hepatocyte (Huh-7 cell) rates in present experimental conditions. However, we assessed the potential antiviral effect of leaf hydroalcoholic extract or warifteine/methylwarifteine on dengue virus-infection by the production of inflammatory molecules, TNF-α, MIF, IL-8 and PGE2. Dengue virus infection enhanced TNF-α, MIF, IL-8 and PGE2 production in infected Huh-7 cells and leaf hydroalcoholic extract but not warifteine/methylwarifteine treatments, significantly reduced these molecules in infected cells. In dengue virus-infected Huh-7 cells, non-structural protein-1 is produced and leaf hydroalcoholic extract significantly inhibited it independently of alkaloids. Our findings imply that leaf hydroalcoholic extract may attenuate dengue virus infection in Huh-7 cells by inhibiting the enhanced of pro-inflammatory mediators and non-structural protein-1 production induce by dengue virus independently of warifteine/methywarifteine its major compound.

Gamma-Terpinene Modulation of LPS-Stimulated Macrophages is Dependent on the PGE2/IL-10 Axis.

Gamma-terpinene is a monoterpene present in the essential oils of several plants, including those from the Eucalyptus genus. This molecule was recently described as anti-inflammatory and microbiocidal, but little is known about the mechanisms behind its effects. The aim of the present study was to investigate the effect of gamma-terpinene on the lipopolysaccharide-induced production of cytokines by murine peritoneal macrophages. Gamma-terpinene treatment was found to reduce the production of proinflammatory cytokines, such as interleukin-1ß and interleukin-6, and enhance that of the anti-inflammatory cytokine interleukin-10. This was accompanied by increased levels of the enzyme cycloxygenase-2 and its product, the lipid mediator prostaglandin E2. Inhibition of cycloxygenase-2 with nimesulide abolished the potentiating effect of gamma-terpinene on interleukin-10 production. Moreover, nimesulide treatment also abrogated the inhibitory effect of gamma-terpinene on interleukin-1ß and interleukin-6. Furthermore, in macrophages from mice deficient in the interleukin-10 gene, gamma-terpinene failed to inhibit interleukin-1ß and interleukin-6 production. These results suggest that this monoterpene promotes the prostaglandin E2/interleukin-10 axis, which inhibits the production of these proinflammatory cytokines.

Gamma-Terpinene Modulates Acute Inflammatory Response in Mice.

The monoterpene gamma-terpinene is a natural compound present in essential oils of a wide variety of plants, including the Eucalyptus genus, which has been reported to possess anti-inflammatory activity. The goal of this study was to evaluate the effect of gamma-terpinene on several in vivo experimental models of acute inflammation. Swiss mice were pretreated with gamma-terpinene and subjected to protocols of paw edema with different phlogistic agents such as carrageenan, prostaglandin-E2, histamine, or bradykinin. The microvascular permeability was measured by intraperitoneal injection of acetic acid and measuring the amount of protein extravasation. Carrageenan-induced peritonitis was used to analyze the effect of gamma-terpinene on inflammatory cell migration and cytokine production. We also developed an acute lung injury protocol to define the anti-inflammatory effect of gamma-terpinene. Mice pretreated with gamma-terpinene displayed reduced paw edema induced by carrageenan from 1-24 h after challenge. A similar reduction was observed when gamma-terpinene was administered after stimulation with PGE2, bradykinin, and histamine. Treatment with gamma-terpinene also inhibited fluid extravasation in the acetic acid model of microvascular permeability. In a carrageenan-induced peritonitis model, gamma-terpinene treatment reduced neutrophil migration as well as the production of interleukin-1ß and tumor necrosis factor-α when compared to nontreated animals, and in the acute lung injury protocol, gamma-terpinene diminished the neutrophil migration into lung tissue independently of the total protein extravasation in the lung. These data demonstrate that, in different models of inflammation, treatment with gamma-terpinene alleviated inflammatory parameters such as edema and pro-inflammatory cytokine production, as well as cell migration into the inflamed site, and that this monoterpene has anti-inflammatory properties.