An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis.
The aim of this study was to evaluate how endocannabinoids interact with excitotoxic processes both in vitro, using primary neural cell cultures, and in vivo, in the TMEV-IDD model of multiple sclerosis. First, we observed that neuronal cells respond to excitotoxic challenges by the production of endocannabinoid molecules which in turn exerted neuroprotective effects against excitotoxicity. The inhibitor of endocannabinoid uptake, UCM707, protected specifically against AMPA-induced excitotoxicity, by activating CB(1) and CB(2) cannabinoid receptors, as well as the nuclear factor, PPARgamma. This neuroprotective effect was reverted by blocking the glial glutamate transporter, GLT-1. Mice subjected to the model of multiple sclerosis showed a decrease in the expression of GLT-1. UCM707 reversed this loss of GLT-1 and induced a therapeutic effect. Our data indicate that the enhancement of the endocannabinoid tone leads to neuroprotection against AMPA-induced excitotoxicity and provides therapeutic effects in this model of multiple sclerosis.
Loría
F
F
Neuroimmunology Group, Department of Functional and Systems Neurobiology, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Petrosino
S
S
Hernangómez
M
M
Mestre
L
L
Spagnolo
A
A
Correa
F
F
Di Marzo
V
V
Docagne
F
F
Guaza
C
C
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005260:Female; D005663:Furans / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D047495:PPAR gamma / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D027342:Excitatory Amino Acid Transporter 2; D005663:Furans; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D018696:Neuroprotective Agents; D009498:Neurotoxins; D047495:PPAR gamma; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid