Abstract WP340: Dimethyl Fumarate Controls Inflammation-Associated Brain Damage under Hypoxia through Nrf2 Mechanism

Abstract

Introduction: Cerebral ischemia triggers a complex cascade of pathophysiological changes including the activation of resident cells, production of inflammatory mediators and infiltration of inflammatory cells. Clinical and experimental studies have revealed that inflammatory interaction following cerebral ischemia is closely related to the pathogenesis and the extent of ischemic brain injury. Therefore, targeting inflammation modulation has emerged as a promising therapeutic strategy. Dimethyl fumarate (DMF) is a typical transcriptional factor Nrf2 activator that exhibits an encouraging anti-inflammatory property. However, the effect of DMF on inflammation-associated ischemic brain injury is still inconclusive. Hypothesis: Here, we present that Nrf2 can serve as a modulator that links inflammation and subsequent brain injury following ischemia. Methods: Adult Nrf2 knockout and WT mice were pretreated with DMF for 7 days and were subjected to cerebral hypoxia-ischemia (HI) surgery. The infarct volume, neurobiological deficits, reactive gliosis, inflammatory mediators, and Nrf2 target protein were examined after HI. Results: DMF significantly reduced the ischemia-induced infarct volume, brain edema (P≤0.05, n=4-6) and neurological deficits (P≤0.05, n=7-11) in WT, but not Nrf2 -/- , mice at both 6h and 24h after HI. In both ischemic striatum and cortex, the inflammation associated reactive gliosis in astrocyte and microglia at a spatiotemporal pattern was significantly attenuated by DMF in ischemic-WT mice (P≤0.05, n=4-6), correlating well with the Nrf2-dependent neuroprotection by DMF. Meanwhile, DMF dramatically suppressed the expression levels of pro-inflammatory mediators and enhanced the expression levels of Nrf2 downstream cytoprotective proteins (P≤0.05, n=4-5), thereby supporting the Nrf2-mediated neuroprotection by DMF in this process. Conclusion: Overall, this proof-of-principle study provided the direct in vivo evidence that Nrf2 activation by DMF suppresses the neuro-inflammation and leads to long-last neuroprotection against ischemic brain damage.