Anandamide Reduces the Toxic Synergism Exerted by Quinolinic Acid and Glutaric Acid in Rat Brain Neuronal Cells.
The endocannabinoid system (ECS) regulates several physiological processes in the Central Nervous System, including the modulation of neuronal excitability via activation of cannabinoid receptors (CBr). Both glutaric acid (GA) and quinolinic acid (QUIN) are endogenous metabolites that, under pathological conditions, recruit common toxic mechanisms. A synergistic effect between them has already been demonstrated, supporting potential implications for glutaric acidemia type I (GA I). Here we investigated the possible involvement of a cannabinoid component in the toxic model exerted by QUIN + GA in rat cortical slices and primary neuronal cell cultures. The effects of the CB1 receptor agonist anandamide (AEA), and the fatty acid amide hydrolase inhibitor URB597, were tested on cell viability in cortical brain slices and primary neuronal cultures exposed to QUIN, GA, or QUIN + GA. As a pre-treatment to the QUIN + GA condition, AEA prevented the loss of cell viability in both preparations. URB597 only protected in a moderate manner the cultured neuronal cells against the QUIN + GA-induced damage. The use of the CB1 receptor reverse agonist AM251 in both biological preparations prevented partially the protective effects exerted by AEA, thus suggesting a partial role of CB1 receptors in this toxic model. AEA also prevented the cell damage and apoptotic death induced by the synergic model in cell cultures. Altogether, these findings demonstrate a modulatory role of the ECS on the synergic toxic actions exerted by QUIN + GA, thus providing key information for the understanding of the pathophysiological events occurring in GA I.
['Kotlar|Ilan|I|', 'Rangel-López|Edgar|E|', 'Colonnello|Aline|A|', 'Aguilera-Portillo|Gabriela|G|', 'Serratos|Iris N|IN|', 'Galván-Arzate|Sonia|S|', 'Pedraza-Chaverri|José|J|', 'Túnez|Isaac|I|', 'Wajner|Moacir|M|', 'Santamaría|Abel|A|']
D000818:Animals D001095:Arachidonic Acids D001549:Benzamides D063386:Cannabinoid Receptor Agonists D002219:Carbamates D002470:Cell Survival D002478:Cells, Cultured D002540:Cerebral Cortex D004357:Drug Synergism D063388:Endocannabinoids D005260:Female D005977:Glutarates D008297:Male D009474:Neurons D010880:Piperidines D053284:Polyunsaturated Alkamides D011247:Pregnancy D011720:Pyrazoles D017378:Quinolinic Acid D051381:Rats D011920:Rats, Inbred WF D043882:Receptors, Cannabinoid
toxic synergism endocannabinoid system glutaric acidemia type I CB1 receptor neurodegeneration neuroprotection