Abstract
Introduction: Recently, based on the purported antioxidative and anti-inflammatory properties, dimethyl fumarate (DMF) has exhibited protective potential in various acute and chronic neurological conditions. Its effect on cerebral ischemia and underlying mechanisms remain inconclusive; furthermore, increasing evidence indicates the involvement of the transcriptional factor Nrf2. Hypothesis: DMF plays a beneficial role on hippocampal neuronal loss and reactive gliosis induced by hypoxia-ischemia (HI) through an Nrf2-dependent mechanism. Methods: Adult wildtype (WT) and Nrf2 -/- mice were pretreated with DMF for 7 days prior to HI. Results: At 24h after HI, DMF significantly reduced infarct volume (52.5±12.3%), brain edema (61.5±17.4%), and hippocampal CA1 neuronal degeneration, and induced expressions of Nrf2 target proteins in the WT (p<0.01), but not in the Nrf2 -/- mice. Such hippocampal neuroprotective benefits were also observed at 6h 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, the astrocytic water transport channel protein aquaporin 4 was also attenuated after HI in WT, but not Nrf2 -/- , mice treated with DMF. Conclusion: Together, DMF confers 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 insights into the cellular basis of an Nrf2-targeting strategy for stroke prevention and/or treatment. As DMF is already clinically approved for multiple sclerosis, it makes it a unique potential prototypical example of drug repurposing for treatment and/or prevention of stroke damage.
Published Version
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