Cerebral Nitrosative/Oxidative Stress in Aneurysmal Subarachnoid Haemorrhage

BACKGROUND:

Aneurysmal subarachnoid haemorrhage (SAH) carries a high morbidity and mortality. This is in large part due to the development of secondary brain injury, including the complication delayed cerebral ischaemia (DCI), which affects 30% of initial survivors. The mechanisms behind secondary brain injury after SAH are incompletely understood.

Nitric oxide (NO) is a potent endogenous vasodilator produced from arginine by the enzyme nitric oxide synthase (NOS), which exists in three isoforms: endothelial, neuronal, and inducible NOS (eNOS, nNOS and iNOS). In conditions of inflammation and oxidative stress, free radicals may react with NO to form peroxynitrite (ONOO-), which is highly reactive and can directly damage biological macromolecules such as lipids and proteins. This phenomenon, i.e. an increased production of reactive nitrogen species potentially leading to cellular damage, is termed nitrosative stress.

It is widely believed that oxidative/nitrosative stress and associated disturbances in the metabolism of NO are involved in the development of secondary brain injury after SAH, but the exact role of these mechanisms remains incompletely understood. While some authors believe that NOS dysfunction and a resultant low NO bioavailability is an important cause of secondary brain injury (and a key mechanism behind DCI), others argue that an overproduction of NO mediated by iNOS is maladaptive response leading to aggravated tissue injury due to nitrosative stress.

The transcerebral (i.e., arterial to jugular venous) exchange of NO metabolites and its interrelationship with oxidative stress has never been studied in patients with SAH. The investigators hypothesise that SAH is associated with an initial reduction in the cerebrovascular bioavailability of NO due to scavenging by free radicals. This could contribute to a vicious cycle, in which a resulting increase in microvascular resistance, cerebral hypoperfusion, and brain tissue hypoxia further increases free radical production and NO depletion, ultimately leading to ischaemic brain injury and poor outcome.