RESUMO
BACKGROUND: Although never evaluated for efficacy, n-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) are commercially offered as treatment for irritable bowel syndrome (IBS). OBJECTIVE: This study was designed to investigate, in a mast cell-dependent model for visceral hypersensitivity, whether this pathophysiologic mechanism can be reversed by dietary LCPUFA treatment via peroxisome proliferator-activated receptor γ (PPARG) activation. METHODS: Maternally separated rats were subjected to hypersensitivity-inducing acute stress at adult age. Reversal was attempted by protocols with tuna oil-supplemented diets [4% soy oil (SO) and 3% tuna oil (SO-T3) or 3% SO and 7% tuna oil (SO-T7)] and compared with control SO diets (7% or 10% SO) 4 wk after stress. The PPARG agonist rosiglitazone was evaluated in a 1 wk preventive protocol (30 mg · kg⻹ · d⻹). Erythrocytes were assessed to confirm LCPUFA uptake and tissue expression of lipoprotein lipase and glycerol kinase as indicators of PPARG activation. Colonic mast cell degranulation was evaluated by toluidine blue staining. In vitro, human mast cell line 1 (HMC-1) cells were pretreated with rosiglitazone, eicosapentaenoic acid, or docosahexaenoic acid, stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore or compound 48/80 and evaluated for tumor necrosis factor α (TNF-α) and ß-hexosaminidase release. RESULTS: Stress led to visceral hypersensitivity in all groups. Hypersensitivity was not reversed by SO-T3 or control treatment [prestress vs. 24 h poststress vs. posttreatment area under the curve; 76 ± 4 vs. 128 ± 12 (P < 0.05) vs. 115 ± 14 and 82 ± 5 vs. 127 ± 16 (P < 0.01) vs. 113 ± 19, respectively]. Comparison of SO-T7 with its control showed similar results [74 ± 6 vs. 103 ± 13 (P < 0.05) vs. 115 ± 17 and 66 ± 3 vs. 103 ± 10 (P < 0.05) vs. 117 ± 11, respectively]. Erythrocytes showed significant LCPUFA uptake in the absence of colonic PPARG activation. Rosiglitazone induced increased PPARG target gene expression, but did not prevent hypersensitivity. Mast cell degranulation never differed between groups. Rosiglitazone and LCPUFAs significantly reduced PMA/calcium ionophore-induced TNF-α release but not degranulation of HMC-1 cells. CONCLUSION: Dietary LCPUFAs did not reverse stress-induced visceral hypersensitivity in maternally separated rats. Although further research is needed, claims concerning LCPUFAs as a treatment option in IBS cannot be confirmed at this point and should be regarded with caution.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Colo/inervação , Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/uso terapêutico , Óleos de Peixe/uso terapêutico , Síndrome do Intestino Irritável/dietoterapia , Animais , Animais Recém-Nascidos , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Eritrócitos/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/metabolismo , Feminino , Óleos de Peixe/administração & dosagem , Óleos de Peixe/metabolismo , Hipoglicemiantes/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/inervação , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/imunologia , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/fisiologia , Privação Materna , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Ratos Long-Evans , AtumRESUMO
Beyond the current hypothesis of depression, several new biological substrates have been proposed for this disorder. The present study investigated whether the anti-inflammatory drugs celecoxib and piroxicam have antidepressant activity in animal models of depression. After acute administration, we observed antidepressant-like effects of celecoxib (10 mg/kg) and piroxicam (10 mg/kg) in the modified forced swim test in rats. Piroxicam increased serotonin and norepinephrine levels in the hippocampus. Prolonged (21-day) treatment with celecoxib (10 mg/kg) and piroxicam (10 mg/kg) rescued sucrose preference in a chronic mild stress model of depression. Additionally, the chronic mild stress-induced reduction of hippocampal glutathione was prevented by treatment with celecoxib and piroxicam. Superoxide dismutase in the hippocampus was increased after chronic mild stress compared with the non-stressed saline group. The non-stressed celecoxib and piroxicam groups and stressed piroxicam group exhibited an increase in hippocampal superoxide dismutase activity compared with the stressed saline group. Lipid hydroperoxide was increased in the stressed group treated with vehicle and non-stressed group treated with imipramine but not in the stressed groups treated with celecoxib and piroxicam. These results suggest that the antidepressant-like effects of anti-inflammatory drugs might be attributable to enhanced antioxidant defenses and attenuated oxidative stress in the hippocampus.
Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Piroxicam/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antidepressivos/farmacologia , Celecoxib , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Privação de Alimentos , Glutationa/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Norepinefrina/metabolismo , Piroxicam/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Estresse Fisiológico/efeitos dos fármacos , Sacarose/administração & dosagem , Sulfonamidas/farmacologia , Superóxido Dismutase/metabolismo , Natação/psicologia , Fatores de Tempo , Privação de ÁguaRESUMO
This study evaluates the antipyretic activity of nimesulide, a cyclooxygenase (COX-2) selective inhibitor in rats. The effects of nimesulide on lipopolysaccharide (LPS)-induced cerebrospinal prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)) and on plasma tumor necrosis factor-alpha (TNF-alpha) levels were also evaluated. Male Wistar rats received an i.p. injection of LPS, or i.c.v. injections of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), TNF-alpha, macrophage inflammatory protein-1alpha (MIP-1alpha), arachidonic acid, PGE(2), PGF(2alpha), corticotrophin-releasing factor (CRF) or endothelin-1 (ET-1). Nimesulide or indomethacin administered i.p 30 min prior LPS, IL-1beta, IL-6, TNF-alpha or arachidonic acid reduced the febrile response and PGE(2) or PGF(2alpha) levels in LPS-febrile rats but did not modify PGE(2)-induced fever. Nimesulide, but not indomethacin, reduced the fever induced by MIP-1alpha, PGF(2alpha), CRF or ET-1. Plasma TNF-alpha levels in LPS-treated rats were also reduced by nimesulide. These findings confirm that the antipyretic effect of nimesulide differs from the antipyretic scenario with the non-selective cyclooxygenase blocker indomethacin. Additional mechanisms, including inhibition of increased plasma TNF-alpha, may contribute to its antipyretic activity in rats.
Assuntos
Analgésicos não Narcóticos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Febre/prevenção & controle , Sulfonamidas/farmacologia , Animais , Ácido Araquidônico/metabolismo , Quimiocina CCL3 , Quimiocina CCL4 , Hormônio Liberador da Corticotropina/metabolismo , Dinoprosta/líquido cefalorraquidiano , Dinoprosta/metabolismo , Dinoprostona/líquido cefalorraquidiano , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Endotelina-1/metabolismo , Febre/sangue , Febre/líquido cefalorraquidiano , Febre/induzido quimicamente , Indometacina/farmacologia , Injeções Intraperitoneais , Injeções Intraventriculares , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Proteínas Inflamatórias de Macrófagos/metabolismo , Masculino , Ratos , Ratos Wistar , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Leaves of Arctium lappa contain several mono- and dicaffeoylquinic acids, as evaluated by liquid chromatography-mass spectrometry. In order to investigate the protection on gastric mucosa against ulcers, rats were treated with fractions from leaf extract prior to ethanol-induced ulcers. The original fraction obtained as ethanol soluble fraction from hot aqueous extract was able to protect de gastric mucosa, and this effect was retained in the ethyl acetate fraction, obtained from liquid/liquid fractionation. The main compound in this fraction was isolated and chemically characterized by nuclear magnetic resonance and mass spectrometry, assisted by isopropylidene derivatization which gave rise a mass increment of 40 units. Therefore, the underivatized compound that had m/z 515.119 [M-H](-) was shifted to m/z 555.151, being confirmed as 1,3-O-dicaffeoylquinic acid, which presented an ED50 of 57 µg kg(-1) on gastric protection, lesser than the therapeutic concentration of omeprazole (40 mg kg(-1)).