Efecto del tratamiento con el agonista cannabinoide win55212-2 en modelos experimentales de encelopatía hipóxico-isquémica neonatal

Resumen

7.-SUMMARY. 1.-INTRODUCTION. 1.1.-The endocannabinoid system. The endocannabinoid system is an endogenous neuromodulatory system involved in the control of synaptic transmission, memory and learning, nociception, appetite, movement, motivation and thermoregulation, among many other central and peripheral processes (Howlett et al. 2004; Mechoulam et al. 2002). Several members of the endocannabinoid system have been characterized so far, including two receptors (CB1 and CB2), their endogenous l igands (endocannabinoids), a transporter for the uptake of the endocannabinoids from the extracelular space and several enzymes involved in the biosynthesis and degration of the endocannabinoids. Within the brain, CB1 receptors are expressed primar ily by neurons and neural progenitor cells, although their expression has also been found in glial cells. CB2 receptors are not expressed in forebrain neurons, but they have been described in activated glial cells, neural progenitor cells and some ne uronal nuclei located in the brainstem and the cerebellum. Both CB1 and CB2 are Gi/o coupled receptors that modulate the activity of several plasma membrane proteins and intracelullar signaling molecules including adenilatecyclase (Howlett and Flemin g 1984), ion channels (Caulfield and Brown 1992; Gebremedhin et al. 1999; Mackie et al. 1995), phospholipases (Sugiura et al. 1996) and ceramide (Guzmán et al. 2001) (figure 1.3). Several endogenous ligands for the cannabinoid receptors have been is olated and pharmacologically characterized, the most abundant of which are anandamide (N-arachidonoyl ethanolamine) and 2-arachidonoylglycerol (figure 1.1). These eicosanoids can bind and activate both cannabinoid receptors. They are biosynthetized f rom phospholipids constituing the plasma membrane, and degradated inside the cells by the fatty acid amido hydrolase (FAAH) and/or the monoacylglycerol lipase (MGL) following their uptake by a specific endocannabinoid transporter (Di Marzo et al. 199 4). The exogenous cannabinergic ligands have been clasified according to their chemical structure and properties. Some of these ligands, as ?9-tetrahydrocannabinol (?9-THC), cannabinol and cannabidiol (figure 1.4), are bioactive principles present i n the plant Cannabis sativa or marihuana, whilst others have been chemically engineered in order to increase their activity of specificity for a subtype of cannabinoid receptor. This is the case of the compound tested in the present work, WIN 55212-2