Role of the Nrf2‐ARE pathway in early brain injury after experimental subarachnoid hemorrhage

Abstract

The nuclear factor erythroid 2-related factor 2 and antioxidant-response element (Nrf2-ARE) pathway is a key regulator for modulating inflammation and oxidative damage, which are involved in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that Nrf2-ARE pathway play neural protective roles in traumatic brain injury, cerebral ischemia, and intracerebral hemorrhage models; however, it has not been investigated whether, and to what degree, the Nrf2-ARE pathway is induced by SAH, and the role of the Nrf2-ARE pathway in development of EBI following SAH remains unknown. Experiment 1 sought to investigate the time course of Nrf2-ARE activation in the cortex in the early stage of SAH. In experiment 2, we assessed the effect of sulforaphane (SUL; a specific Nrf2 activator) on regulation of the Nrf2-ARE pathway in the SAH model and evaluated the impact of SUL on EBI after SAH. The rat SAH model was used injection of 0.3 ml fresh arterial, nonheparinized blood into the prechiasmatic cistern over 20 sec. As a result, Nrf2 and its target gene product, heme oxygenase-1 (HO-1), were up-regulated in the cortex after SAH and peaked at 24 hr post-SAH. After intraperitoneal SUL administration, the elevated expression of Nrf2-ARE-related factors such as Nrf2, HO-1, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutathione S-transferase-α1 (GST-α1) was detected in the cortex at 48 hr following blood injection. In the SUL-treated group, early brain damage such as brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and motor deficits was significantly ameliorated compared with vehicle-treated SAH rats. Our results suggest that the Nrf2-ARE pathway is activated in the brain after SAH, playing a beneficial role in EBI development, possibly through inhibiting cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.

Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1

“…In contrast, induction of HO-1 exerts potent protective effects in numerous preclinical disease models including sepsis, trauma, vascular proliferative disease, acute lung and liver injury, and cancer (1)(2)(3)(4)(5). A number of recent reports have demonstrated the benefits of HO-1 in the CNS, including the eye (6) and brain (7)(8)(9)(10)(11)(12). In the brain, expression of each HO isoform follows a distinct spatial and cell-specific distribution pattern.…”

Nrf2 Activation, an Innovative Therapeutic Alternative in Cerebral Ischemia

“…In both studies, the protective effects of sulforaphane were associated with its well-known capacity to induce the expression of HO-1 mRNA and protein through Nrf2/ARE pathway. Other in vivo studies support the ability of sulforaphane as inducer of phase II enzymes in brain increasing HO-1, NQO1 and GST mRNA levels (Chen et al, 2011). It has also shown in in vitro studies that pretreatment and post-treatment with sulforaphane reduced hippocampal death of astrocytes and neurons induced by transient exposure to O 2 and glucose deprivation.…”

“…Nrf2 has been detected in neuronal and glial cells (Chen et al, 2011;Li et al, 2011;Shah et al, 2010;Yang et al, 2009). Previous studies using gel-shift assay found that ischemic brains selectively upregulates ARE-mediated gene expression, whereas binding activities of other stress response elements were unchanged, including metal response element, interleukin-6, and STAT (signal transducer and activator of transcription) response elements (Campage et al, 2000).…”

Expression of NF‑E2‑related factor 2 in a rat dural arteriovenous fistula model

“…It is part of the Kelch-like ECH-associated protein 1-Nrf2-antioxidant response element (Keap1-Nrf2-ARE) signaling pathway and regulates numerous genes associated with ARE, including heme oxygenase-1 (HO-1) and NAD(P)H: quinine oxidoreductase 1 (NQO1) (16,17). Nrf2 contributes to the protection of tissues from damage induced by the outside environment, including damage arising from inflammation, trauma, ischemia, hemorrhage and cancer (18,19). Other studies have identified an association between Nrf2 and angiogenesis (20) and it was demonstrated that the absence of Nrf2 may suppress cancer cell angiogenesis and migration in vivo and in vitro (21)(22)(23).…”