Neuroprotective Role of the Nrf2 Pathway in Subarachnoid Haemorrhage and Its Therapeutic Potential

Abstract

The mechanisms underlying poor outcome following subarachnoid haemorrhage (SAH) are complex and multifactorial. They include early brain injury, spreading depolarisation, inflammation, oxidative stress, macroscopic cerebral vasospasm, and microcirculatory disturbances. Nrf2 is a global promoter of the antioxidant and anti-inflammatory response and has potential protective effects against all of these mechanisms. It has been shown to be upregulated after SAH, and Nrf2 knockout animals have poorer functional and behavioural outcomes after SAH. There are many agents known to activate the Nrf2 pathway. Of these, the actions of sulforaphane, curcumin, astaxanthin, lycopene, tert-butylhydroquinone, dimethyl fumarate, melatonin, and erythropoietin have been studied in SAH models. This review details the different mechanisms of injury after SAH including the contribution of haemoglobin (Hb) and its breakdown products. It then summarises the evidence that the Nrf2 pathway is active and protective after SAH and finally examines the evidence supporting Nrf2 upregulation as a therapy after SAH.

Figure 1

Nrf2 regulation. Nrf2 is a redox-sensitive transcription factor that is bound to KEAP1 under physiological condition. KEAP1 is an intracellular redox sensor and targets Nrf2 for ubiquitination. Following oxidative stress, four different mechanisms result in dissociation of KEAP1 from Nrf2. These four mechanisms are as displayed in order: (1) oxidation of cysteine residues by lower molecular weight reactive oxygen species, (2) covalent modification of cysteine residues by electrophiles such as NF-κB-induced cyclopentenone prostaglandins, (3) phosphorylation of Nrf2 at Ser40 by protein kinase C and PERK, and (4) protein-protein interaction between p62 and KEAP1. Free of KEAP1, Nrf2 translocates into the nucleus where it binds to antioxidant response elements in DNA to mediate transcription of key proteins. Nrf2 requires the binding partners MAF and CBP to initiate transcription. BACH1 competes for MAF and NF-κB competes for CBP. Overall, the equilibrium between the two transcriptions factors BACH1 and Nrf2 determines overall transcription of the downstream genes.