Abstract
Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation and therefore represents a promising target for stroke intervention. However, the long-term effects of Nrf2 and the standardized Korean red ginseng (ginseng), a potent Nrf2 natural inducer, on permanent cerebral ischemic damage have not yet been reported. Wildtype (WT) and Nrf2−/− adult mice were pretreated with either vehicle or ginseng and were subjected to permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrocytes and microglia, and the water regulatory protein aquaporin 4 (AQP4) were examined at 28 days after stroke. When compared with the WT matched controls, the Nrf2 disruption significantly enlarged the infarct volume (40.4 ± 10.1%) and exacerbated the progression of reactive gliosis and AQP4 protein levels after pdMCAO. In contrast, ginseng significantly reduced the infarct volume and attenuated the reactive gliosis and AQP4 in the ischemic WT mice (47.3 ± 6.9%), but not in the Nrf2−/− mice (25.5 ± 5.6%). In conclusion, Nrf2 plays an important role in the long-term recovery of permanent cerebral ischemic damage and the neuroprotection of ginseng.
Highlights
Cerebral ischemia is a devastating disease with a high incidence of mortality and disability [1]
We sought to determine whether caneventually impede the long-term recoveryfunctional of permanent distal middle cerebral artery occlusion (pdMCAO)-caused brain. lesions and whether
Ginseng treatment conferred long-lasting neuroprotection against ischemic cortical lesion (47.3 ± 6.9%), attenuated the progression of reactive gliosis, and ameliorated the ischemia-induced aquaporin 4 (AQP4) increase in WT mice after pdMCAO; these benefits were not observed in the absence of Nrf2, supporting the prolonged
Summary
Cerebral ischemia is a devastating disease with a high incidence of mortality and disability [1]. It is caused by permanent or transient occlusion of blood vessels and their branches, which eventually leads to brain infarction. The cerebral ischemia mouse model of permanent distal middle cerebral artery occlusion (pdMCAO) provides a highly reproducible and well-standardized cortical lesion with a minimal mortality rate and closely mimics ischemic stroke in humans; it has been widely used in preclinical and translational research, allowing us to investigate long-term outcomes after stroke [6,7,8]. Increasing evidence indicates that the transcriptional factor Nrf plays a vital role in the endogenous defense against brain oxidative stress and inflammation, two crucial mechanisms of cerebral ischemic
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