Adequate neuronal function requires a highly regulated extra-cellular environment, wherein the concentrations of ions such as sodium, potassium and calcium must be maintained within very narrow ranges. The brain accounts for approximately 20% of oxygen consumption in humans, and is also extremely sensitive to a wide range of chemicals that are circulating without harm to peripheral organ systems. It is therefore paramount that the interface between the central nervous system and the peripheral circulatory system (that is, the BBB) functions as a dynamic regulator of ion balance, as a facilitator of nutrient transport, and as a barrier to potentially harmful molecules.

Intuitively, the disruption of this barrier may flood the brain with neurotoxic substances. Subsequently, it is commonly thought that the breakdown of the BBB is a key causative factor of sepsis-associated delirium 678. The stimulation of cerebrovascular endothelial cells with septic plasma induced dissociation of tight junction proteins such as occludin from the cytoskeletal network, and subsequently increased the size-selective transendothelial solute flux 9.

In patients, vasogenic oedema can be demonstrated by magnetic resonance imaging within the Wirchow–Robin spaces, within the posterior cerebral hemispheres and, less frequently, as diffuse white matter oedema. Various mediators cause BBB hyperpermeability, such as bradykinin, IL-1β, TNFα and complement 6. Recent experiments suggest that upregulation of C3 induced a breakdown in the BBB and increased gliosis, increased the water content, and upregulated Toll-like receptor 4 with subsequent alterations in TNF, inducible nitric oxide synthase and aquaporin 4 10.

Extending these findings, Flierl and colleagues were able to prevent the damage to the BBB by systemic administration of an anti-C5a neutralising antibody 1. Unfortunately, they did not look at neuronal activation or damage to confirm any neuroprotection. Of note, interfering with complement activation either by blocking C5a or its receptor 11, or by inhibitor of the alternative complement pathway, attenuates neuronal death in experimental traumatic brain injury 12.

To survive stress, the brain must be alerted, must identify the stressors and must mount an appropriate response. The limbic system, the hypothalamic–pituitary axis and the locus coeruleus/noradrenergic system are tightly interconnected to orchestrate homeostasis in stress. These structures are all behind the BBB. The circulating inflammatory mediators may reach these brain areas via the circumventricular organs that lack a BBB or by active transport across the BBB 6.

It is also possible that specific systems are in place to open the BBB as a normal response to severe infection. Indeed, by increasing the BBB permeability, C5a may ease pathogen-associated molecular pattern access to brain sensing areas such as paraventricular and amygdala cells. Upregulation of C5a therefore allows the stress system to mount an appropriate response. This assumption is supported by at least three major facts. Firstly, blockade of C5a markedly reduced the activation of the hypothalamic–pituitary cells 5 and decreased the corticotrophin and corticosterone levels 1. This effect correlated with decreased expression of pathogen-associated molecular pattern 5 and of cytokines 15. The resulting inappropriate hypothalamic–pituitary adrenal axis is probably detrimental in sepsis 13. Secondly, in patients with sepsis, magnetic resonance imaging studies showed that increased BBB permeability is an early, common, and transient phenomenon 8. Patients who did survive to sepsis recovered a normal brain. Thirdly, C5-deficient mice or those pretreated with a C5a receptor antagonist are unable to mount a febrile response to intraperitoneal endotoxin challenge 14.

Furthermore, C3 is also broadly upregulated during sepsis, and may act as a gatekeeper – protecting the brain from any live circulating microorganisms while the BBB is rendered permeable. Neuronal excitation involving the excitatory glutamate receptors may be an important underlying mechanism in sepsis-induced altered neurotransmission 6. Recent reports suggested that C5a induced neuroprotection against glutamate-mediated apoptosis through inhibition of caspase 3 activity, through the mitogen-activated protein kinase transduction pathway, and through regulation of the glutamate receptor GluTR2 15. C5 blockade may therefore inhibit select neuroprotective actions of the complement cascade, and may possibly exacerbate neuro-excitatory mechanisms.

Future studies should investigate neuron survival in the stress system following C5a antibodies, or C5a receptor antagonists or blockade of the alternative complement pathway in experimental sepsis.

BBB: blood–brain barrier; IL: interleukin; TNF: tumour necrosis factor.

The author declares that they have no competing interests.