Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage

Abstract

Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH.

Heme: The Lord of the Iron Ring

“…Increased tissue iron content after injury can also induce iron-dependent programmed cell death, known as ferroptosis, which has been shown to play an important role in nerve damage after TBI [88][89][90]. During ferroptosis, heme-iron interacts with hydrogen peroxide producing hydroxyl radicals, which cause lipid peroxidation and glutathione depletion [91,92]. It is important to highlight that nerves may be particularly vulnerable to ferroptosis due to their cellular organization into bundles of axons and dendrites, as well as to contain unusually large amounts of cholesterol and polyunsaturated fatty acids in the cell membrane [52].…”

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

“…There are a variety of defense mechanisms, including detoxification and antioxidant enzymes, to counteract the over-production of free radicals after ICH. Many of these enzymes are under the control of the Nrf2/ARE pathway which is currently regarded as the major system in cellular antioxidant response ( Zhao et al, 2007 ; Loan et al, 2022 ). Nrf2 was reported to increase significantly at 2 h, peaking at 24 h in the perihematomal region in rats with ICH ( Shang et al, 2013 ).…”

Special Issue “Role of NRF2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches II”

“…Within the context of vascular dementia, spontaneous intracerebral hemorrhage (ICH) following traumatic brain injury can be devastating. Therefore, Loan et al [5] carried out a comprehensive review analyzing the involvement of the recruitment of microglia and monocyte-derived cells to the area where ICH occurs and investigating the potential role of NRF2 throughout this entire process. Additionally, although to date there are no clinical trials with NRF2 activators in IHC patients, the authors suggested early-phase trials for IHC monitor safety given the older age of this kind of patient.…”