RESUMEN
Closed head injury induces cerebral oxidative stress. The efficacy of a Mn (III) porphyrin catalytic antioxidant was assessed in a mouse closed head injury model. Mice were subjected to closed head injury and treated 15 min later with an i.v. bolus of vehicle or 3 mg/kg MnTE-2-PyP5+. Aconitase activity, Fluoro-Jade staining, glial fibrillary acidic protein immunoreactivity, and rotarod falling latencies were measured. Closed head injury altered all variables. MnTE-2-PyP5+ had no effect on any variable with the exception of attenuation of aconitase inactivation at 2 h post-closed head injury. In a second experiment, mice received 3 mg/kg or 6 mg/kg MnTE-2-PyP5+ or vehicle i.v. 15 min post-closed head injury. Rotarod and Morris water maze latencies were measured. Closed head injury altered performance in both tests. No statistically significant effect of MnTE-2-PyP5+ was observed. We conclude that single dose MnTE-2-PyP5+ does not alter outcome in this mouse closed head injury model.
Asunto(s)
Antioxidantes/farmacología , Traumatismos Cerrados de la Cabeza/prevención & control , Metaloporfirinas/farmacología , Aconitato Hidratasa/metabolismo , Animales , Antioxidantes/administración & dosificación , Antioxidantes/química , Peso Corporal/efectos de los fármacos , Corteza Cerebral/química , Corteza Cerebral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteína Ácida Fibrilar de la Glía/análisis , Traumatismos Cerrados de la Cabeza/metabolismo , Traumatismos Cerrados de la Cabeza/fisiopatología , Inmunohistoquímica , Inyecciones Intravenosas , Masculino , Manganeso/química , Aprendizaje por Laberinto/efectos de los fármacos , Metaloporfirinas/administración & dosificación , Metaloporfirinas/química , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Factores de TiempoRESUMEN
Although apolipoprotein E4 (APOE4) was initially identified as a susceptibility gene for the development of Alzheimer's disease, the presence of the APOE4 allele is also associated with poor outcome after acute brain injury. One mechanism by which apoE may influence neurological outcome is by downregulating the neuroinflammatory response. Because it does not readily cross the blood-brain barrier, the apoE holoprotein has limited therapeutic potential. We demonstrate that a single intravenous injection of a small peptide derived from the apoE receptor binding region crosses the blood-brain barrier and significantly improves histological and functional outcomes after traumatic brain injury (TBI). The development of an apoE-based intervention represents a novel therapeutic strategy in the management of acute brain injury.