Nrf2 activation in the human brain after stroke due to supratentorial intracerebral haemorrhage: a case–control study

Abstract

AimsPharmacological activation of the antioxidative transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) improves outcomes in experimental models of intracerebral haemorrhage (ICH). However, the Nrf2 pathway has not been previously studied in humans after ICH. Our study aims to address this gap.MethodsWe selected cases with fatal ICH from a prospective community-based inception cohort study and age-matched and sex-matched controls who died suddenly of non-neurological disease. We used immunohistochemistry to quantify Nrf2 (% total area stained overall and % of nuclei stained) and CD68 expression in controls and perihaematomal, ipsilateral and contralateral brain tissue from cases. We measured downstream haem oxygenase-1 (HMOX1) and NAD(P)H dehydrogenase quinone 1 [NQO1] expression using RNA in situ hybridisation.Results26 ICH cases (median age: 82 (IQR 76–86); 13 (50%) male) and eight controls (median age: 79 (IQR 77–80); 3 (37.5%) male) were included. We found no significant differences in overall % of Nrf2 staining between ICH cases and controls. However, the mean % of nuclei staining for Nrf2 seemed higher in perihaematomal compared with contralateral regions, although this was only statistically significant >60 days after ICH (25% (95% CI 17% to 33%) vs 14% (95% CI 11% to 17%), p=0.029). The percentage of perihaematomal tissue staining for CD68 was higher >60 days after ICH (6.75%, 95% CI 2.78% to 10.73%) compared with contralateral tissue (1.45%, 95% CI 0.93% to 1.96%, p=0.027) and controls (1.08%, 95% CI 0.20% to 1.97%, p=0.0008). RNA in situ hybridisation suggested increased abundance of HMOX1 and NQO1 transcripts in perihaematomal versus distant ipsilateral brain tissue obtained <7 days from onset of ICH.ConclusionsWe found evidence of Nrf2 activation in human brain tissue after ICH. Pharmacological augmentation of Nrf2 activation after ICH might be a promising therapeutic approach.

Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage

“…Moreover, haem interacts with a nuclear export signal present on Bach1 and Bach2, resulting in their export from the nucleus by the nuclear exporter Crm1 [ 152 ]. Additionally, oxidative stress increases the transactivation potential of the Nrf2 Neh5 domain, which is another potential Keap1-independent mode of Nrf2 activation after ICH [ 153 ]. The net effect of these processes is that Nrf2 is activated in tissue close to the haematoma surface in patients with ICH [ 153 ].…”

“…Additionally, oxidative stress increases the transactivation potential of the Nrf2 Neh5 domain, which is another potential Keap1-independent mode of Nrf2 activation after ICH [ 153 ]. The net effect of these processes is that Nrf2 is activated in tissue close to the haematoma surface in patients with ICH [ 153 ]. Notably Nrf2 localisation after ICH is submaximal [ 153 ].…”

The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke

“…Microglia can also switch between the M1 and M2 phenotypes in response to changes in environmental conditions. Following ischemic stroke, oxidative stress triggers the activation of the antioxidative transcription factor nuclear erythroid related factor 2 (Nrf2) pathway ( 28 ). The Nrf2 pathway promotes microglia polarization to the anti-inflammatory M2 phenotype by increasing expression of anti-inflammatory genes such as NQO1 and HMOX1 ( 28 ).…”

“…Following ischemic stroke, oxidative stress triggers the activation of the antioxidative transcription factor nuclear erythroid related factor 2 (Nrf2) pathway ( 28 ). The Nrf2 pathway promotes microglia polarization to the anti-inflammatory M2 phenotype by increasing expression of anti-inflammatory genes such as NQO1 and HMOX1 ( 28 ). Enhancing Nrf2 pathway activity using various pharmacological compounds has been found to improve stroke outcomes in several preclinical studies ( 29 , 30 ).…”

The Role of Concomitant Nrf2 Targeting and Stem Cell Therapy in Cerebrovascular Disease

“…Nrf2 plays a vital role in managing excessive oxidative stress following stroke, with a vital role in heme and iron metabolism, antioxidant proliferation, glutathione regeneration, thioredoxin, and protein recycling [ 23 , 24 ]. The major producers of Nrf2 in the brain include microglia and macrophages [ 25 , 26 ]. In fact, microglia and astrocytes produce an extreme amount of Nrf2 within 24 h following an induced middle cerebral artery occlusion (MCAO) [ 27 ].…”