RESUMEN
AIMS: Recently, we found carnosine protects against N-Methyl-D-Aspartate (NMDA) induced excitotoxicity through a histaminergic pathway. The aim of this study was to determine whether the carnosine-histidine-histamine pathway also played a protective role in subcortical ischemic vascular dementia (SIVD). METHODS: Adult male mice (C57BL/6 strain) were subjected to right unilateral common carotid arteries occlusion (rUCCAO) and treated with carnosine or histidine. Object recognition test, passive avoidance task, Morris water maze, and immunohistochemical analyses were performed after rUCCAO. RESULTS: We found that carnosine (200, 500 mg/kg) ameliorated white matter lesion and cognitive impairment evaluated by object recognition test, passive avoidance task, and Morris water maze test after rUCCAO in both wide-type mice and histidine decarboxylase knockout mice, which are lack of endogenous histamine. However, administration of histidine did not show the same effect. The myelin basic protein in the corpus callosum decreased obviously at day 37 after rUCCAO, which was largely reversed by carnosine (200, 500 mg/kg). Carnosine (200, 500 mg/kg) suppressed the activation of microglia and astrocyte as attenuating the elevation of glial fibrillary acidic protein (GFAP) and Iba-1 fluorescent intensity. Moreover, carnosine (200, 500 mg/kg) significantly attenuated the increase in reactive oxygen species generation after rUCCAO. CONCLUSION: These data suggest that the neuroprotective effect of carnosine on rUCCAO in mice is not dependent on the histaminergic pathway, but may be due to a suppression of reactive oxygen species generation, glia activation, and myelin degeneration.
Asunto(s)
Carnosina/farmacología , Demencia Vascular/tratamiento farmacológico , Histamina/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Cuerpo Calloso/efectos de los fármacos , Cuerpo Calloso/metabolismo , Demencia Vascular/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Histidina/farmacología , Histidina Descarboxilasa/genética , Histidina Descarboxilasa/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Proteína Básica de Mielina/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
Ischemic preconditioning protects against cerebral ischemia. Recent investigations indicated that acidic preconditioning (APC) protects against ischemia-induced cardiomyocytes injury. However, it is not clear whether APC can protect against cerebral ischemia. To address this issue, C57BL/6 mice were exposed 3 times at 10-min intervals to a normoxic atmosphere containing 20% CO(2) for 5 min before being further subjected to bilateral common carotid artery occlusion. APC reversed the ischemia-induced brain injury as revealed by improved performance in passive avoidance experiments and decreased neuron loss in the hippocampal CA1 region. Consistently, both APC-treated brain slices and primary cultured neurons were more resistant to oxygen-glucose-deprivation (OGD)-induced injury, in a pH- and time-dependent manner, as revealed by reversed cell/tissue viability. In addition, the APC treatment prevented OGD-induced mitochondrial transmembrane potential loss and apoptosis, which was inhibited by the mitochondrial permeability transport pore opener atractyloside. Taken together, these findings indicated that APC protects against ischemia-induced neuronal injury. The beneficial effects may be attributed, at least in part, to decreased mitochondria-dependent neuronal apoptosis.
