Estudio sobre el papel de los receptores cannabinoides CB1 y CB2 en la neuroinflamación inducida por estrés

Resumen

Stress exposure elicits excitotoxicity due to the massive release of glutamate in some brain areas. Many changes caused by stress response effectors are not damaging to the neurons; one possible mechanism involved as neuroprotective pathway is led by prostaglandin 15d-PGJ2 and its nuclear receptor PPAR?. Furthermore, cannabinoids affect anxiety and stress responsivity. To elucidate the possible regulatory role of cannabinoid receptors 1 and 2 (CB1 and CB2) in stress-induced excitotoxicity and n euroinflammation (1) wild-type (WT), CB1 knockout mice (CB1-KO), CB2 knockout mice (CB2-KO), mice overexpressing CB2 receptor (CB2 ) were exposed to immobilization/acoustic stress and (2) to activate CB1 and CB2, the selective CB1 agonist ACEA and t he selective CB2 agonist JWH-133 were utilized. Stress exposure increased CB1 mRNA and protein expression in the prefrontal cortex in a mechanism related to NMDA receptor activation. ACEA pretreatment prevented stress-induced: (1) up-regulation of C B1 mRNA and protein, (2) decrease in glutamate uptake and EAAT2 expression, (3) increase in consecutive proinflammatory molecules TNF-? and MCP-1, NF-?B, NOS-2 and COX-2, (4) increase in lipid peroxidation; although having no effect on plasma cortico sterone. A possible related mechanism could be the ACEA modulation of the pathway 15d-PGJ2/PPAR?. Western Blot and immunohistochemical studies revealed no differences in CB2 protein and mRNA expression after stress exposure. Daily JWH-133 and CB2 re ceptor over-expression prevented stress-induced (1) increase in TNF-? and MCP-1, NF-?B, NOS-2, COX-2 and PGE2 levels, (2) increase in lipid peroxidation and nitric oxide by-products; although having no effect on glutamate uptake and plasma corticoste rone. A lack of CB2 exacerbated stress-induced neuroinflammatory responses. Stress exposure induced an increase in palmitoylethanolamide content and had no effect on anandamide, oleoylethanolamide, N-acylphosphatidylethanolamine phospholipase-D and f atty acid amide hydrolase levels. Concerning 2-arachidonyl-glycerol,we showed a reduction in its levels in parallel with a decrease of diacylglycerol lipase-? and an increase of monoacylglycerol lipase. Para aclarar el posible papel del receptor CB1 y CB2 en la modulación de la excitotoxicidad y neuroinflamación inducidas por estrés, ratones CB1 doble mutantes CB1, doble mutantes CB2, ratones que sobreexpresan el receptor CB2 y controles WT fueron expuestos a inmovilización subcrónica y a estr