Damião P. Sousa

Phytol, a diterpene alcohol, inhibits the inflammatory response by reducing cytokine production and oxidative stress

Studies have shown that diterpenes have anti‐inflammatory and redox‐protective pharmacological activities. The present study aimed to investigate the anti‐inflammatory properties of phytol, a diterpene alcohol, in a mouse model of acute inflammation, and phytol effect on leukocyte recruitment, cytokines levels, and oxidative stress. The anti‐inflammatory activities of phytol were assessed by measuring paw edema induced by different inflammatory agents (e.g., λ‐carrageenan, compound 48/80, histamine, serotonin, bradykinin, and prostaglandin E2 [PGE2]), myeloperoxidase (MPO) activity, peritonitis model and cytokine levels. Further, oxidative stress was evaluated by determining glutathione (GSH) levels and malondialdehyde (MDA) concentration. The results showed that phytol (7.5, 25, 50, and 75 mg/kg) significantly reduced carrageenan‐induced paw edema, in a dose‐dependent manner. In addition, phytol (75 mg/kg) inhibited compound 48/80‐, histamine‐, serotonin‐, bradykinin‐ and PGE2‐induced paw edema. It also inhibited the recruitment of total leukocytes and neutrophils; decreased MPO activity, tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) levels, and MDA concentration; and increased GSH levels during carrageenan‐induced acute inflammation. These results suggest that phytol attenuates the inflammatory response by inhibiting neutrophil migration that is partly caused by reduction in IL‐1β and TNF‐α levels and oxidative stress.

Carvacryl acetate, a derivative of carvacrol, reduces nociceptive and inflammatory response in mice

AIMS The present study aimed to investigate the potential anti-inflammatory and anti-nociceptive effects of carvacryl acetate, a derivative of carvacrol, in mice. MAIN METHODS The anti-inflammatory activity was evaluated using various phlogistic agents that induce paw edema, peritonitis model, myeloperoxidase (MPO) activity, pro and anti-inflammatory cytokine levels. Evaluation of antinociceptive activity was conducted through acetic acid-induced writhing, hot plate test, formalin test, capsaicin and glutamate tests, as well as evaluation of motor performance on rotarod test. KEY FINDINGS Pretreatment of mice with carvacryl acetate (75 mg/kg) significantly reduced carrageenan-induced paw edema (P<0.05) when compared to vehicle-treated group. Likewise, carvacryl acetate (75 mg/kg) strongly inhibited edema induced by histamine, serotonin, prostaglandin E2 and compound 48/80. In the peritonitis model, carvacryl acetate significantly decreased total and differential leukocyte counts, and reduced levels of myeloperoxidase and interleukin-1 beta (IL-1β) in the peritoneal exudate. The levels of IL-10, an anti-inflammatory cytokine, were enhanced by carvacryl acetate. Pretreatment with carvacryl acetate also decreased the number of acetic acid-induced writhing, increased the latency time of the animals on the hot plate and decreased paw licking time in the formalin, capsaicin and glutamate tests. The pretreatment with naloxone did not reverse the carvacryl acetate-mediated nociceptive effect. SIGNIFICANCE In conclusion, the current study demonstrated that carvacryl acetate exhibited anti-inflammatory activity in mice by reducing inflammatory mediators, neutrophil migration and cytokine concentration, and anti-nociceptive activity due to the involvement of capsaicin and glutamate pathways.

Nerolidol exhibits antinociceptive and anti-inflammatory activity: involvement of the GABAergic system and proinflammatory cytokines.

Nerolidol, an acyclic sesquiterpene found as a major constituent of several essential oils, has several pharmacological activities, but its action in pain processes has never been studied. The purpose of our research was to evaluate the antinociceptive and anti‐inflammatory activities of nerolidol, as well as possible mechanisms of action, in experimental mouse models of pain. Antinociceptive activity was evaluated using the acetic acid‐induced writhing test, the formalin test, and the hot‐plate test. The nerolidol‐treated group showed lesser acetic acid‐induced abdominal contractions than the control group in all of the three doses tested (200, 300, and 400 mg/kg, p.o.). The formalin test doses of 300 and 400 mg/kg p.o. inhibited licking time, in both the first phase and the second phase. In the hot‐plate test, nerolidol did not alter latency at any of the observed time points. Motor coordination, evaluated through the rotarod test, was not hindered in animals treated with nerolidol. Regarding the mechanism of action, the antinociceptive activity of nerolidol is related to the GABAergic system, and not to the opioidergic or ATP‐sensitive K+ channels. Treatment with nerolidol reduced carrageenan‐induced paw edema. In the model of carrageenan‐induced peritonitis, nerolidol decreased the influx of polymorphonuclear cells and also reduced levels of tumor necrosis factor (TNF‐α) in peritoneal lavage. Nerolidol reduced production of interleukin 1 beta (IL‐1β) in LPS‐stimulated, peritoneal macrophages. Thus, these results showed that nerolidol has antinociceptive activity with possible involvement of the GABAergic system, and anti‐inflammatory activity, attributed to the suppression of TNF‐α and IL‐1β proinflammatory cytokines.

Isopropoxy‐Carvacrol, a Derivative Obtained from Carvacrol, Reduces Acute Inflammation and Nociception in Rodents

Monoterpenes, compounds mainly presented in essential oils, have important pharmacological actions. Isopropoxy‐carvacrol (IPC) is a derivative of the monoterpene carvacrol, and its pharmacological properties have not yet been investigated. The aim of this study was to analyse the acute anti‐inflammatory and antinociceptive properties of IPC. Mice (25–30 g) and rats (150–230 g) were pre‐treated (i.p.) with IPC at the doses of 10, 30 or 100 mg/kg or vehicle (Tween 80, 0.5%), 30 min. before injection of the phlogistic agents. Both the first and the second phases of formalin‐induced nociception were significantly reduced by IPC (100 mg/kg). Injection of carrageenan in mice paw reduced the threshold of stimulus intensity, applied with an analgesymeter, necessary to cause paw withdrawal, which was significantly reduced by 100 mg/kg of IPC. The area under curve (0–4 hr) of rat paw oedema induced by injection of carrageenan was also significantly diminished by the administration of IPC (100 mg/kg). Administration of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) markedly increased mice ear oedema and myeloperidase (MPO) activity. Topical co‐administration of IPC (0.3–3 mg/ear) during the induction did not affect TPA‐induced ear oedema, but significantly decreased MPO activity in the ears, when compared with the vehicle. In in vitro experiments, IPC reduced lipoperoxidation induced by different stimuli, showed nitric oxide scavenger activity and did not interfere with murine macrophage viability in concentrations up to 100 μg/mL. These results demonstrate that IPC exerts acute anti‐inflammatory and antinociceptive activities, suggesting that it may represent an alternative in the development of new future therapeutic strategies.

AVALIAÇÃO DA TOXICIDADE AGUDA E DO EFEITO ANSIOLÍTICO DE UM DERIVADO SINTÉTICO DA CARVONA

Objective: To evaluate the safety of cyano-carvone by means of acute toxicity studies and to investigate its anxiolytic potential. Material and Methods: Swiss male mice were treated with cyano-carvone (v.o) in escalating doses from 25 to 2000 mg/kg and observed for 14 days as regards behavioral changes and mortality rate. After this time period, hematological, biochemical and morphological analyses of the main macroscopic organs were carried out. In addition, other groups of animals were treated with doses of 25, 50 and 75 mg/kg in order to assess locomotor activity, anxiolytic effect and motor coordination. Results: In the Hippocratic test, the compound did not cause any deaths among the mice, thus the LD50 was not determined and clinical signs that emerged were discrete, reversible and observed only in higher doses. Accordingly, hematological and biochemical analyses did not show significant alterations. In the behavioral analysis, it was found a reduction of locomotor activity and a greater number of entries in open arms, as well as a longer time spent with open arms, suggesting an anxiolytic effect. In the Rota-rod test it was observed no change in the permanence time on the spinning rod, as well as no changes were detected for the number of falls. Conclusion: This study demonstrated that cyano-carvone has no acute toxicity, and suggests a possible anxiolytic effect that needs to be further investigated in order to elucidate its mechanism of action. DESCRIPTORS: Anxiety. Monoterpenes. Acute Toxicity. Central Nervous System.

PROSPECÇÃO TECNOLÓGICA DO MIRTENOL: UM MONOTERPENO COM ATIVIDADE FARMACOLÓGICA SOBRE O SISTEMA NERVOSO CENTRAL

O objetivo deste trabalho foi realizar uma investigacao das patentes nacionais e internacionais relacionadas ao monoterpeno (-)-mirtenol quanto as suas atividades e aplicacoes, especialmente, no campo da psicofarmacologia. A pesquisa foi desenvolvida atraves de ampla exploracao em tres bases de dados de depositos de patentes, sendo uma nacional e duas internacionais. A prospeccao tecnologica possibilitou verificar que este monoterpeno apresenta-se patenteado em diversos paises, dentre eles o Brasil, cujas empresas sao as maiores proprietarias intelectuais, tendo indicacao como antisseptico, antimicrobiano e flavorizante em bebidas e alimentos; entretanto, poucas sao suas aplicacoes na terapeutica humana, especialmente, sobre o sistema nervoso central, cuja primeira patente e brasileira e encontra-se em processo final de registro. Palavras-chave : patentes; prospeccao tecnologica; monoterpeno; mirtenol.

Carvacryl acetate, a novel semisynthetic monoterpene ester, binds to the TRPA1 receptor and is effective in attenuating irinotecan‐induced intestinal mucositis in mice

We aimed to determine whether carvacryl acetate acts as a TRPA1 receptor agonist and its effects against irinotecan (CPT‐11) induced intestinal mucositis in mice.