Blood-brain barrierAlterations in blood-brain barrier (BBB) permeability after acute injury result in the crossing of water, electrolytes, blood-borne substances, and potential free copy neurotoxic agents across the vascular system and into the brain parenchyma. Many studies have demonstrated the importance of brain and body temperature on the microvascular consequences of cerebral ischaemia and trauma. One study that assessed the effects of intra-ischaemic brain temperature (mild hypothermia) on BBB was shown to reduce extravasation of the protein tracer horseradish peroxidase [12]. Brain water content is significantly reduced with hypothermia after focal cerebral ischaemia [13,14]. Recent studies have assessed this with magnetic resonance imaging and found that reductions in the apparent diffusion coefficient of water (cellular oedema) are also attenuated by hypothermia [15].

In models of post-traumatic injury, hypothermia has also been shown to reduce BBB permeability. Hypothermia may be attenuating BBB permeability by altering matrix metalloproteinases, which are critical extracellular enzymes that can disrupt the BBB [16]. These modulating effects of hypothermia on BBB permeability are important beneficial mechanisms because of the association between BBB permeability, formation of vasogenic oedema, the extravasation of circulating inflammatory cells and adverse post-injury outcomes.Inflammation and oedemaThe inflammatory response after TBI is significantly modulated by hypothermia in laboratory and clinical studies.

As well as attenuating the increase in BBB permeability and leucocyte margination, the endogenous inflammatory response of the central nervous system (CNS) is reduced by hypothermia. Astrocytes and microglia respond to CNS injury by proliferating around the injury areas and releasing pro-inflammatory communication molecules as an endogenous repair mechanism. Hypothermia significantly attenuates the activation Batimastat of both astrocytes and microglia [17-20]. Combination therapy including the anti-inflammatory cytokine inter leukin-10 and hypothermia therapy was attempted in both TBI and focal cerebral ischaemia [21]. Synergistic effects were seen in focal cerebral ischaemia but not in TBI, suggesting that the cellular biology of inflammation in these two major CNS injuries has an influence on the effect of subsequent hypothermia. Another major aspect of the inflammatory response to CNS injury is the release of reactive oxygen species by astrocytes and microglia. Hypothermia reduces increases in tissue levels of superoxide, nitric oxide, and the hydroxyl radical [22,23].