Estudo farmacológico de 1,8-Cineol, um óxido terpênico presente em óleos essenciais de plantas

• Ano de defesa: 1999
• Autor(a) principal: Santos, Flávia Almeida
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Palavras-chave em Português: Plantas Medicinais; Eucalyptus; Essências e óleos essenciais
• Link de acesso: http://www.repositorio.ufc.br/handle/riufc/65659

1,8-cmeole (cineole), a terpene compound present in various essential oils of plants that belong to Eucalyptus, Rosemary and Psidium species was investigated for its local and systemic pharmacological effects in rats and mice. In the evaluation of local effects, we verified its capacity to induce inflammatory edema and local nociception following the subplantar injection and as well the pharmacological characterization of these effects. While establishing systemic effects we evaluated cineole. for a possible anti-inflammatory activity in the animal models of carrageenan-induced hind-paw edema, cotton pellet-induced granuloma and acetic acid induced-vascular permeability; analgesic activity in acetic acid-induced abdominal constrictions and formalin-induced nociceptive tests; antiulcer effect against ethanol and indomethacin-induced gastric lesions; antisecretory effect on gastric acid secretion in pylorus ligated rats and against cholera toxin-induced intestinal fluid accumulation; sedative and anticonvulsant effects in tail suspension and Chemical seizures tests in mice as well as its protection against mortality in GalN/LPS-induced sepsis in mice. Besides, we observed the effects of cineole on rat reproduction (estrus cycle, nidation and pregnancy) and established its acute toxicity. Subplantar injection of cineole at doses of 5, 10, and 20 pl in rats and at doses of 10 and 20 pl in mice produced a dose-related inflammatory edema and nociception, respectively. The inflammatory edema response-induced by 20 pl of cineole was found to be completely abolished in the group ofrats depleted oftheir mastocyte granules by compound 48/80 and not by capsaicin, a compound that depletes neuropeptides ffom sensory nerve endings. The paw edema response to cineole was also markedly inhibited by cyproheptadine (5 mg/kg), a histamine H! and 5-HT2 receptor antagonist. The lipid mediator antagonists, dexamethasone (0.5 mg/kg), phenylbutazone (100 mg/kg) and indomethacin (5 mg/kg) and the TNF / antagonist, thalidomide (15 mg/kg) were also found to be effective in the inhibition of paw edema induced by cineole whereas the lipoxygenase inhibitor, NDGA (75 mg/kg) and the PAF antagonist WEB 2170 (10 mg/Kg) were xxvi ineffective. NECA (0,1 mg/Kg), a non-selective adenosine Aj/A2 receptor agomsts was also effective in the inhibition of paw edema. Furthermore, cineole at a concentrations of 0.56, 1.67 and 5.58 mM caused degranulation of rat pentoneal mast cells in vitro, in a manner similar to compound 48/80 (0.05, 0.16, 0.48 p.M) which could be blocked by NECA (3.24 pM). The nociceptive effect of cineole was almost absent in mice pretreated with cyproheptadine (5 mg/kg) and by NECA (0,01 mg/kg). These observations suggest a key role for mast cell and adenosine in the mechanism of cineole-induced local edema and nociception. Systemic admimstration of cineole evidenced anti-inflammatory and antinociceptive effects in rats and mice. Significant anti-inflammatory effect was evident at an oral dose of 400 mg/kg in the models of carrageenan-induced rat hind-paw edema, cotton pellet-induced granuloma (rats) and acetic acid mduced vascular permeability (mice). Cineole inhibited acetic acid-induced abdominal constrictions as well as formalin-induced nociception in mice. In addition, cineole prevented alcohol (absolute) and indomethacin-induced gastric lesions at doses varying from 100 to 400 mg/kg. An antisecretory effect of cineole (400 mg/kg) was also evident in the experimental models of pyloric ligation-induced gastric acid secretion and cholera toxin-induced intestinal fluid accumulation in rats. Cineole at the same dose offered complete protection against GalN/LPSinduced mortality and liver damage in mice. Besides, cineole (400 mg/kg) demonstrated sedative and anticonvulsant properties in mice, evidenced by increase in immobilization time in tail suspension test and protection against mortality in pentylenetetrazol-induced convulsions test. Some of the systemic effects of cineole, such as sedation, analgesia and anticonvulsant activities simulated the effects produced by exogenous adenosine. However, these effects of cineole were not reversed by pretreatment of animais with methylxanthines, caffeine and theophylline or by 8-phenyltheophylline, an antagonist of adenosine Ai/A2 receptors which indicate that it is unlikely that endogenous adenosine has a role in the effects produced by cineole. Cineole manifested low toxic potential. Its oral LD50 in mice was found to be 3.85 ± 0.33 g/kg. Neither it adversely affected ovulatory cycle in rats nor it xxvii induced teratogenicity. Nevertheless cineole (400 mg/Kg) caused slight inhibition on pregnancy index and also attenuated fetal weights, only when admmistered on days 1 to 7 of pregnancy in rats. Some of the pharmacological effects, such as sedation, analgesia and anticonvulsant effects, observed in this study with cineole resembled those exerted by crude essential oils of Psidium species that contained large amounts of cineole. Cineole exhibited low toxicity potential; Nevertheless manifested a weak sedative effect at the oral dose of 400 mg/Kg but did not evoke ataxia or motor incoordination indicating absence of neuronal toxicity. Cmeole demonstrated local pro-inflammatory and pro-nociceptive effects wherein mast cells and endogenous adenosine seems to play a key role. Systemic administration of cmeole produced anti-inflammatory, antinociceptive, sedation, anticonvulsant effects. However, endogenous adenosine does not seem to participate in these effects. Cineole possibly is gastroprotective through a reducting gastric acid secretion and or by an increase of gastric mucus. Its antisecretory effect may have therapeutic implications in conditions such as gastric ulcer and diarrhoea. Cmeole offers protection against GalN/LPS-induced toxic hepatitis possibly through its capacity to inhibit mflammatory cytokines. No adverse effects of cmeole was observed on reproductive parameters offemale rats