RESUMO
OBJECTIVE: Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice. DESIGN: Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARα or PPARγ antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs. RESULTS: PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARα, but not PPARγ, abolished PEA effects, in mice and in humans. CONCLUSIONS: Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARα action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/patologia , Endocanabinoides/uso terapêutico , Etanolaminas/uso terapêutico , Neuroglia/metabolismo , PPAR alfa/metabolismo , Ácidos Palmíticos/uso terapêutico , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Receptor 4 Toll-Like/metabolismo , Amidas , Anilidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo Sigmoide/química , Colo Sigmoide/patologia , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana , Dinoprostona/metabolismo , Endocanabinoides/farmacologia , Etanolaminas/farmacologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Indóis/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , PPAR alfa/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Ácidos Palmíticos/farmacologia , Reto/química , Reto/patologia , Índice de Gravidade de Doença , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
This minireview highlights the importance of cannabidiol (CBD) as a promising drug for the therapy of inflammatory bowel diseases (IBD). Actual pharmacological treatments for IBD should be enlarged toward the search for low-toxicityand low-cost drugs that may be given alone or in combination with the conventional anti-IBD drugs to increase their efficacy in the therapy of relapsing forms of colitis. In the past, Cannabis preparations have been considered new promising pharmacological tools in view of their anti-inflammatory role in IBD as well as other gut disturbances. However, their use in the clinical therapy has been strongly limited by their psychotropic effects. CBD is a very promising compound since it shares the typical cannabinoid beneficial effects on gut lacking any psychotropic effects. For years, its activity has been enigmatic for gastroenterologists and pharmacologists, but now it is evident that this compound may interact at extra-cannabinoid system receptor sites, such as peroxisome proliferator-activated receptor-gamma. This strategic interaction makes CBD as a potential candidate for the development of a new class of anti-IBD drugs.
Assuntos
Canabidiol/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêuticoRESUMO
Cannabidiol (CBD) is the main non-psychotropic component of the glandular hairs of Cannabis sativa. It displays a plethora of actions including anticonvulsive, sedative, hypnotic, antipsychotic, antiinflammatory and neuroprotective properties. However, it is well established that CBD produces its biological effects without exerting significant intrinsic activity upon cannabinoid receptors. For this reason, CBD lacks the unwanted psychotropic effects characteristic of marijuana derivatives, so representing one of the bioactive constituents of Cannabis sativa with the highest potential for therapeutic use.The present review reports the pharmacological profile of CBD and summarizes results from preclinical and clinical studies utilizing CBD, alone or in combination with other phytocannabinoids, for the treatment of a number of CNS disorders.
Assuntos
Canabidiol/farmacologia , Cannabis/química , Doenças do Sistema Nervoso Central/tratamento farmacológico , Animais , Canabidiol/uso terapêutico , Canabidiol/toxicidade , HumanosRESUMO
Activated microglia and astrocytes produce a large number of inflammatory and neurotoxic substances in various brain pathologies, above all during neurodegenerative disorders. In the search for new neuroprotective compounds, interest has turned to marijuana derivatives, since in several in vitro, in vivo, and clinical studies, they have shown a great ability to control neuroinflammation. Despite the emerging evidence regarding pharmacological activities of cannabinoids, their effective introduction into clinical therapy still remains controversial and strongly limited by their unavoidable psychotropicity. Since the psychotropic effect of cannabinoids is generally linked to the activation of the CB1 receptor on neurons, the aim of our review is to clarify the function of the two cannabinoid receptors on glial cells and the differential role played by them, highlighting the emerging evidence of a CB2-mediated control of neuroinflammation that could liberate cannabinoids from the slavery of their central side effects. Despite the emerging evidence regarding pharmacological activities of cannabinoids, however their effective introduction in the clinical therapy remains still controversial and strongly limited by their unavoidable psychotropicity. Since the psychotropic effect of cannabinoids is generally linked to the activation of CB1 receptor on neurons, aim of our review is to clarify the functioning of the two cannabinoid receptors on glial cells and the differential role played by them, highlighting the emerging evidence of a CB2-mediated control of neuro-inflammation that could liberate cannabinoids from the slavery of the central side effects.