Dimethylfumarate alleviates early brain injury and secondary cognitive deficits after experimental subarachnoid hemorrhage via activation of Keap1-Nrf2-ARE system

Abstract

S ubarachnoid hemorrhage (SAH) is a critical neurosurgical phenomenon that is often coupled with several interrelated complications such as acute/delayed cerebral vasospasm, brain edema, obstructive/communicating hydrocephalus, diffuse/focal cerebral ischemia or infarction, and lasting cognitive deficits. 22,25 In China, the SAH-related morbidity rate is about 1.75 per 10,000. 30Despite recent progress in microsurgical and endovascular surgical techniques, the outcome of patients who suffer an SAH remains disappointing.abbreviatioNs 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 = nuclear factor erythroid 2-related factor 2; PBS = phosphate-buffered saline; SAH = subarachnoid hemorrhage; SOD = superoxide dismutase; TNFα = tumor necrosis factor-α. 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 ml 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.

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

“…Once the cell encounters stimulation, such as oxidative stress, Nrf2 dissociates from Keapl, translocates into the nucleus, and binds to the ARE, subsequently inducing antioxidant enzyme expression, including NQO-1, HO-1, and SOD [25,32]. Mounting evidence from preclinical studies indicates that Nrf2 signaling activation can ameliorate SAH injury and that genetic elimination of Nrf2 aggravates SAH-induced secondary complications [59,60]. In fact, recent studies in other research areas have shown that SalB upregulates Nrf2 and HO-1 protein expression and enhances the ability of potential antioxidants [61,62].…”

Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease

“…Hmox1 is one of the ARE-containing genes heavily regulated by Bach1 because the Hmox1 promoter is known to have a large number of ARE sequences to which Nrf2 can bind to induce its expression preferentially (Kensler et al, 2007). The enzymatic activity of Hmox1 involves catalyzing the degradation of heme to produce carbon monoxide, iron, and biliverdin, which are well known cellular antioxidant and anti-inflammatory agents known to induce neuroprotective effects (Otterbein et al, 2003). To determine the potential association of Bach1 nuclear export and Hmox1-mediated underlying neuroprotective mechanisms, we studied the neuroprotective effects of DMF and MMF against MPP ϩ toxicity in N27 rat dopaminergic cells with or without the presence of ZnPP, a widely used inhibitor of Hmox1 activity (Liu et al, 2014).…”

“…The enzymatic activity of Hmox1 involves catalyzing the degradation of heme to produce carbon monoxide, iron, and biliverdin, which are well known cellular antioxidant and anti-inflammatory agents known to induce neuroprotective effects (Otterbein et al, 2003). To determine the potential association of Bach1 nuclear export and Hmox1-mediated underlying neuroprotective mechanisms, we studied the neuroprotective effects of DMF and MMF against MPP ϩ toxicity in N27 rat dopaminergic cells with or without the presence of ZnPP, a widely used inhibitor of Hmox1 activity (Liu et al, 2014). As shown in Figure 3B, MPP ϩ induced significant cell death in N27 cells after 24 h, which was attenuated by pretreatment with either DMF (10 M) or MMF (10 M).…”

“…Tecfidera is a Food and Drug Administration-approved oral formulation of dimethylfumarate (DMF) for multiple sclerosis (MS;Fox et al, 2012;Gold et al, 2012). DMF is highly active in combating oxidative stress and inflammation by activating the Nrf2 genetic program to promote axonal regeneration and neurological recovery in MS and in many preclinical models of neurodegenerative diseases (Ellrichmann et al, 2011;Linker et al, 2011;Iniaghe et al, 2015;Jing et al, 2015;Liu et al, 2015), making DMF a promising therapeutic drug. Here, we compared Nrf2-dependent neuroprotective mechanisms of DMF and its bioactive metabolite monomethylfumarate (MMF) against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental PD.…”

Long-Term Cognitive Deficits After Subarachnoid Hemorrhage in Rats

“…Short-term rodent recovery models are often used to explore post-SAH mechanisms that result in neurologic deficits [6][7][8]. Only recently has this work been extended to examine cognitive deficits [9][10][11][12][13]. Because post-SAH cognitive and memory deficits may persist for months to years in humans [3,14,15], there is need to optimize preclinical modeling to facilitate investigation of putative injury mechanisms and therapeutic interventions.…”