Neuro-oxidative-nitrosative stress in sepsis

Abstract

Neuro-oxidative-nitrosative stress may prove the molecular basis underlying brain dysfunction in sepsis. In the current review, we describe how sepsis-induced reactive oxygen and nitrogen species (ROS/RNS) trigger lipid peroxidation chain reactions throughout the cerebrovasculature and surrounding brain parenchyma, due to failure of the local antioxidant systems. ROS/RNS cause structural membrane damage, induce inflammation, and scavenge nitric oxide (NO) to yield peroxynitrite (ONOO(-)). This activates the inducible NO synthase, which further compounds ONOO(-) formation. ROS/RNS cause mitochondrial dysfunction by inhibiting the mitochondrial electron transport chain and uncoupling oxidative phosphorylation, which ultimately leads to neuronal bioenergetic failure. Furthermore, in certain 'at risk' areas of the brain, free radicals may induce neuronal apoptosis. In the present review, we define a role for ROS/RNS-mediated neuronal bioenergetic failure and apoptosis as a primary mechanism underlying sepsis-associated encephalopathy and, in sepsis survivors, permanent cognitive deficits.

Figure 1

A hypothetical model of brain dysfunction in sepsis. Reactive oxygen and nitrogen species (ROS/RNS), generated during the systemic inflammatory response, trigger lipid peroxidation chain reactions, due to the limited antioxidant capacity of the brain. Free radical-mediated structural membrane damage induces neuroinflammation; furthermore, free radicals (such as superoxide anion, O₂^•−) deplete ambient nitric oxide (^•NO) in the cerebrovascular bed to form peroxynitrite (ONOO⁻). The consequently reduced vascular bioavailability of NO acts in concert with the local inflammatory response to increase the expression of the inducible NO synthase (iNOS). ONOO⁻ irreversibly inhibits the mitochondrial electron transport chain, which increases the mitochondrial release of free radicals. Free radical-mediated uncoupling of oxidative phosphorylation compounds the mitochondrial dysfunction, and renders the neuron in a state of ‘cytopathic hypoxia,' thus leading to neuronal bioenergetic failure. Furthermore, free radicals trigger apoptosis by altering the intracellular Ca²⁺ homeostasis in the brain areas ‘at risk,' such as the cerebral cortex and hippocampus, which exacerbates the local inflammatory response further.

Figure 2

Ascorbate: the phantom menace? Catalytically active ferric (Fe³⁺) and ferrous (Fe²⁺) iron may be unlocked and released to the extracellular space upon cellular damage. Because of its relatively low one-electron reduction potential (E°′=+282 mV), ascorbate (AH⁻) is capable of donating an electron to Fe³⁺ thereby reducing it to Fe²⁺, which in turn reacts with hydrogen peroxide (H₂O₂) to form the hydroxyl radical (^•OH) through the Fenton reaction. ^•OH may consequently initiate lipid peroxidation chain reactions and cause structural membrane damage throughout the cerebrovasculature and brain parenchyma. A^•−, ascorbyl radical; L^•, lipid pentadienyl radical; OH⁻, hydroxide.