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

Edward Christopher; James J M Loan; Neshika Samarasekera; Karina McDade; Jamie Rose; Jack Barrington; Jeremy Hughes; Colin Smith; Rustam Al-Shahi Salman

doi:10.1136/bmjno-2021-000238

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

BMJ Neurol Open. 2022 Feb 19;4(1):e000238. doi: 10.1136/bmjno-2021-000238. eCollection 2022.

Authors

Edward Christopher¹, James J M Loan^{2

3}, Neshika Samarasekera^{2

3}, Karina McDade⁴, Jamie Rose^{4

5}, Jack Barrington^{3

5}, Jeremy Hughes⁶, Colin Smith⁴, Rustam Al-Shahi Salman^{2

3}

Affiliations

¹ The University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, UK.
² Division of Clinical Neurosciences, NHS Lothian, Edinburgh, UK.
³ Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
⁴ Academic Neuropathology, The University of Edinburgh, Edinburgh, UK.
⁵ UK Dementia Research Institute, The University of Edinburgh, Edinburgh, UK.
⁶ Centre for Inflammation Research, The University of Edinburgh, Edinburgh, UK.

Abstract

Aims: Pharmacological 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.

Methods: We 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.

Results: 26 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.

Conclusions: We found evidence of Nrf2 activation in human brain tissue after ICH. Pharmacological augmentation of Nrf2 activation after ICH might be a promising therapeutic approach.

Keywords: histopathology; neuropathology; stroke.

Abstract

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