Reactive Gliosis Contributes to Nrf2-Dependent Neuroprotection by Pretreatment with Dimethyl Fumarate or Korean Red Ginseng Against Hypoxic-Ischemia: Focus on Hippocampal Injury
Recently, dimethyl fumarate (DMF) and Korean red ginseng (ginseng), based on their purported antioxidative and anti-inflammatory properties, have exhibited protective potential in various neurological conditions. Their effects on cerebral ischemia and underlying mechanisms remain inconclusive; however, increasing evidence indicates the involvement of the transcriptional factor Nrf2. This study evaluated the preventive effects of DMF and ginseng on hippocampal neuronal damage following hypoxia-ischemia (HI) and assessed the contributions of reactive gliosis and the Nrf2 pathway. Adult wild type (WT) and Nrf2−/− mice were pretreated with DMF or ginseng for 7 days prior to HI. At 24 h after HI, DMF or ginseng significantly reduced infarct volume (52.5 ± 12.3% and 47.8 ± 10.7%), brain edema (61.5 ± 17.4% and 39.3 ± 12.8%), and hippocampal CA1 neuronal degeneration, and induced expressions of Nrf2 target proteins in WT, but not Nrf2−/−, mice. Such hippocampal neuroprotective benefits were also observed at 6 h and 7 days after HI. The dynamic attenuation of reactive gliosis in microglia and astrocytes correlated well with this sustained neuroprotection in an Nrf2-dependent manner. In both early and late stages of HI, astrocytic dysfunctions in extracellular glutamate clearance and water transport, as indicated by glutamine synthetase and aquaporin 4, were also attenuated after HI in WT, but not Nrf2−/−, mice treated with DMF or ginseng. Together, DMF and ginseng confer robust and prolonged Nrf2-dependent neuroprotection against ischemic hippocampal damage. The salutary Nrf2-dependent attenuation of reactive gliosis may contribute to this neuroprotection, offering new insight into the cellular basis of an Nrf2-targeting strategy for stroke prevention or treatment.
KeywordsAstrocyte Astrogliosis Microglia Oxidative stress Stroke Transcriptional factor
L.L. and S.D. designed the project and experiments. L.L., M.K.V., M.G.K., V.F., and T.G.F. performed the experiments, the data collection, and the analysis. H.K. provided the Korean red ginseng and participated in the discussion. L.L. and S.D. wrote the manuscript. All authors discussed the manuscript and reviewed the final version.
This study was supported in part by the National Institutes of Health (R01AT007429 and R01NS046400, S.D.) and the American Heart Association (16POST31220032, L.L.).
Compliance with Ethical Standards
All procedures were approved by the University of Florida Institutional Animal Care and Use Committee. We conducted the experiments according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.
Conflict of Interest
The authors declare that they have no conflict of interest.
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