Object: Oxidative stress and the inflammatory response are thought to promote brain damage in the setting of subarachnoid hemorrhage (SAH). Previous reports have shown that dimethylfumarate (DMF) can activate the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2-antioxidant-responsive element (Keap1-Nrf2-ARE) system in vivo and in vitro, which leads to the downregulation of oxidative stress and inflammation. The aim of this study was to evaluate the potential neuroprotective effect of DMF on SAH-induced brain injury in rats.
Methods: Rats were subjected to SAH by the injection of 300 μl of autologous blood into the chiasmatic cistern. Rats in a DMF-treated group were given 15 mg/kg DMF twice daily by oral gavage for 2 days after the onset of SAH. Cortical apoptosis, neural necrosis, brain edema, blood-brain barrier impairment, learning deficits, and changes in the Keap1-Nrf2-ARE pathway were assessed.
Results: Administration of DMF significantly ameliorated the early brain injury and learning deficits induced by SAH in this animal model. Treatment with DMF markedly upregulated the expressions of agents related to Keap1-Nrf2-ARE signaling after SAH. The inflammatory response and oxidative stress were downregulated by DMF therapy.
Conclusions: DMF administration resulted in abatement of the development of early brain injury and cognitive dysfunction in this prechiasmatic cistern SAH model. This result was probably mediated by the effect of DMF on the Keap1-Nrf2-ARE system.
Keywords: ARE = antioxidant-responsive element; DMF = dimethylfumarate; EBI = early brain injury; ELISA = enzyme-linked immunosorbent assay; EMSA = electrophoretic mobility shift assay; FJB = Fluoro-Jade B; GSH-Px = glutathione peroxidase; GST-α1 = glutathione S-transferase α1; HO-1 = heme oxygenase 1; IL = interleukin; Keap1 = Kelch-like ECH-associated protein 1; MDA = malondialdehyde; MWM = Morris water maze; NQO1 = quinone oxidoreductase 1; Nrf2; Nrf2 = nuclear factor erythroid 2-related factor 2; PBS = phosphate-buffered saline; SAH = subarachnoid hemorrhage; SOD = superoxide dismutase; TNFα = tumor necrosis factor–α; dimethylfumarate; subarachnoid hemorrhage; vascular disorders.