Systemic Nitrosative/Oxidative Stress in Patients With Acute Brain Injury

BACKGROUND:

Acute brain injury due to traumatic brain injury (TBI), intracerebral haemorrhage (ICH), and aneurysmal subarachnoid haemorrhage (SAH) is a major cause of mortality and permanent disability worldwide. Irrespective of its aetiology, acute brain injury is associated with a widespread activation of cellular and biochemical processes which can aggravate the damage after the primary injury - this is termed secondary brain injury.

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 (e.g. in acute brain injury), 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, 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, others argue that an overproduction of NO mediated by iNOS is maladaptive response leading to aggravated tissue injury due to nitrosative stress.

The investigators hypothesise that acute brain injury is associated with an immediate elevation in circulating biomarkers of oxidative stress and a reduction in the bioavailability of NO due to formation of peroxynitrite (nitrosative stress), and that this represents an important mechanism behind the development of secondary brain injury. This decrease in NO availability 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. However, it is further hypothesised that the initial decrease in NO availability is followed by an iNOS-mediated increase in NO metabolites in the subsequent days after injury. The present explorative study will attempt to characterise these changes and their role in patients with acute brain injury.