RESUMEN
Reactive oxygen species (ROS) were shown to play a role in altering blood-brain barrier (BBB) permeability and formation of brain edema induced by trauma and/or ischemia. 2-arachidonoyl glycerol (2-AG), a novel, potent vasodilatory and cytoprotective endocannabinoid has been implicated to act as an antioxidative agent. This study examines: 1) the possible 2-AG modulation of BBB injury and edema formation induced by closed head injury (CHI); and 2) comparable effects between 2-AG and 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TPL), a known antioxidant nitroxide on endothelial Ca2+ and cytoskeletal responses to H2O2 (ROS). 2-AG treatment reduced the CHI-induced increase in BBB permeability and brain edema. The endothelial H2O2-stimulated Ca2+ mobilization and cytoskeleton (vimentin) rearrangement was modified by either 2-AG or TPL. These findings provide evidence of 2-AG antioxidant activity and are consistent with the involvement of ROS in the pathomechanism of CHI-induced BBB injury and brain edema.
Asunto(s)
Antioxidantes/farmacología , Ácidos Araquidónicos/farmacología , Barrera Hematoencefálica , Edema Encefálico/etiología , Moduladores de Receptores de Cannabinoides/farmacología , Endocannabinoides , Glicéridos/farmacología , Traumatismos Cerrados de la Cabeza/complicaciones , Traumatismos Cerrados de la Cabeza/fisiopatología , Sistema Vasomotor/efectos de los fármacos , Animales , Barrera Hematoencefálica/efectos de los fármacos , Calcio/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Óxidos N-Cíclicos/farmacología , Citoesqueleto/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Depuradores de Radicales Libres/farmacología , Peróxido de Hidrógeno/farmacología , Masculino , Ratones , Ratones Endogámicos , Oxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Marcadores de SpinRESUMEN
Traumatic brain injury triggers the accumulation of harmful mediators that may lead to secondary damage. Protective mechanisms to attenuate damage are also set in motion. 2-Arachidonoyl glycerol (2-AG) is an endogenous cannabinoid, identified both in the periphery and in the brain, but its physiological roles have been only partially clarified. Here we show that, after injury to the mouse brain, 2-AG may have a neuroprotective role in which the cannabinoid system is involved. After closed head injury (CHI) in mice, the level of endogenous 2-AG was significantly elevated. We administered synthetic 2-AG to mice after CHI and found significant reduction of brain oedema, better clinical recovery, reduced infarct volume and reduced hippocampal cell death compared with controls. When 2-AG was administered together with additional inactive 2-acyl-glycerols that are normally present in the brain, functional recovery was significantly enhanced. The beneficial effect of 2-AG was dose-dependently attenuated by SR-141761A, an antagonist of the CB1 cannabinoid receptor.