Endocannabinoids regulate the activity of astrocytic hemichannels and the microglial response against an injury: In vivo studies.
Anandamide (AEA) is an endocannabinoid (EC) that modulates multiple functions in the CNS and that is released in areas of injury, exerting putative neuroprotective actions. In the present study, we have used intravital microscopy to analyze the role of the EC system in the glial response against an acute insult. Our data show that AEA modulates astroglial function in vivo by increasing connexin-43 hemichannel (HC) activity. Furthermore, the genetic inactivation of the AEA-degrading enzyme, fatty acid amide hydrolase (FAAH), also increased HC activity and enhanced the microglial response against an acute injury to the brain parenchyma, effects that were mediated by cannabinoid CB1 receptors. The contribution of ATP released through an astrocytic HC was critical for the microglial response, as this was prevented by the use of the HC blocker flufenamic acid and by apyrase. As could be expected, brain concentrations of AEA, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were elevated in FAAH-null mice, while 2-arachidonoylglycerol (2-AG) concentrations remained unaltered. In summary, these findings demonstrate that AEA modifies glial functions by promoting an enhanced pro-inflammatory glial response in the brain.
Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, 28922 Alcorcón, Madrid, Spain.
Carmen
C
Vázquez
Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, 28922 Alcorcón, Madrid, Spain.
Rosa María
RM
Tolón
Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, 28922 Alcorcón, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
María Ruth
MR
Pazos
Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, 28922 Alcorcón, Madrid, Spain.
Marta
M
Moreno
Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Erin C
EC
Koester
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Benjamin F
BF
Cravatt
Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cecilia J
CJ
Hillard
Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, 28922 Alcorcón, Madrid, Spain; School of Biosciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain. Electronic address: jromerop@fhalcorcon.es.
Julián
J
Romero
D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001081:Apyrase / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism*; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D004983:Ethanolamines / Q000378:metabolism; D005439:Flufenamic Acid / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism; D007834:Lasers; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009829:Oleic Acids / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
D000255:Adenosine Triphosphate; D000577:Amides; D000581:Amidohydrolases; D000893:Anti-Inflammatory Agents; D001081:Apyrase; D001095:Arachidonic Acids; D018031:Connexin 43; D063388:Endocannabinoids; D004983:Ethanolamines; D005439:Flufenamic Acid; D005989:Glycerides; D009829:Oleic Acids; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C543076:GJA1 protein, mouse; C488250:oleoylethanolamide; C005958:palmidrol; C094503:glyceryl 2-arachidonate; C078814:anandamide
Astrocytes; Endocannabinoids; Hemichannels; Microglia; Multiphoton microscopy; Neuroprotection