title: Cannabinoids prevent the opposite regulation of astroglial connexin43 hemichannels and gap junction channels induced by pro-inflammatory treatments.
abstract: Brain injuries as well as neurodegenerative diseases, are associated with neuro-inflammation characterized by astroglial and microglial activation and/or proliferation. Recently, we reported that lipopolysaccharide (LPS)-activation of microglia inhibits junctional channels and promotes hemichannels, two connexin43 functions in astrocytes. This opposite regulation is mediated by two pro-inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, released from activated microglia. Because cannabinoids (CBs) have anti-inflammatory properties and their receptors are expressed by glial cells, we investigated on primary cortical cultures the effects of CB agonists, methanandamide and synthetic CBs on (i) cytokines released from LPS-activated microglia and (ii) connexin43 functions in astrocytes subjected to pro-inflammatory treatments. We observed that CBs inhibited the LPS-induced release of interleukin-1 beta and tumor necrosis factor-alpha from microglia. Moreover, the connexin43 dual regulation evoked by the pro-inflammatory treatments, was prevented by CB treatments. Pharmacological characterizations of CB actions on astrocytic connexin43 channels revealed that these effects were mainly mediated through CB1 receptors activation, although non-CB1/CB2 receptors seemed to mediate the action of the methanandamide. Altogether these data demonstrate that in inflammatory situations CBs exert, through the activation of different sub-types of glial CB receptors, a regulation on two functions of connexin43 channels in astrocytes known to be involved in neuron survival.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U840, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Froger
authors.forename: Juan A
authors.initials: JA
authors.lastname: Orellana
authors.forename: Martine
authors.initials: M
authors.lastname: Cohen-Salmon
authors.forename: Pascal
authors.initials: P
authors.lastname: Ezan
authors.forename: Edwige
authors.initials: E
authors.lastname: Amigou
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
authors.forename: Christian
authors.initials: C
authors.lastname: Giaume
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018031:Connexin 43 / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004996:Ethidium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020714:Maximum Tolerated Dose; D051379:Mice; D017628:Microglia / Q000737:chemistry; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D018031:Connexin 43; D017630:Connexins; D017077:Culture Media, Conditioned; D003511:Cyclohexanols; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; C088155:methanandamide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D004996:Ethidium; D000077285:Rimonabant