Blood brain barrier: Fluid Transfer

The blood brain barrier (BBB) is a specialized barrier that renders the environment of the central nervous system (CNS) separate from other compartments of the body. The unique environment provided by the BBB enables the specialized activity of neurons; BBB breakdown is the result of pathologic conditions and leads to further neuronal dysfunction. The unique requirements of the CNS require the BBB to limit the free exchange of some solutes that would be freely exchanged through other anatomic compartments. The restriction of solute transport limits how fluids can transfer across the BBB.

The BBB is formed by endothelial cells that line cerebral micro vessels. 1 It restricts the entry of many substances dissolved in blood because of specialized tight junctions (TJ) between adjacent endothelial cells. BBB TJ are maintained by the interaction of specialized cytoskeleton and linking proteins not expressed in other endothelium, examples include : Claudins, occludins, and junctional adhesion molecules.2 Small gaseous and lipophilic molecules can diffuse freely through the BBB, however most charged compounds (peptides, proteins) must take the trans-cellular route and gain entry by means of specific transporters or carriers. These specialized TJ even restrict the flow of small ions such as Na+, K+, Ca2+, and Cl-. Inextricably linked to the transport of ions, water transport across the BBB is also tightly regulated. Water crosses the BBB primarily via Aquaporin 4 (AQP4) expressed in astrocyte end-feet.3 When the BBB is functioning optimally it provides an ideal environment for neuronal function. Several pathological conditions can diminish the ability of the BBB to screen what gets into the brain, this leads to neurotoxicity and cerebral edema.4

BBB disruption is mediated by a number of soluble factors which are associated with diverse pathologic conditions, these include : glutamate, endothelin-1, NO, MIP-2, TNFα, MIP2, bradykinin, histamine, and free radicals among others.5 Hypoxic and ischemic insults lead to disruption of TJ by events set in motion by VEGF, NO, and various cytokines. VEGF expression induces fenestration in unfenestrated endothelial cells in the BBB.6 Sepsis can mediate BBB disruption via perivascular edema and astrocyte end-foot edema, rupture, and detachment.7 The BBB in the area surrounding a brain tumor is poorly developed. This is the result of failure to express critical TJ proteins. In glioblastoma, claudin-1 is found to be absent and claudin-5 and occludin significantly downregulated.8 Similar events occur in astrocytoma and metastatic adenocarcinoma leading to improperly formed TJ.9 The consequence of these events is the increased permeability to a variety of (potentially neurotoxic) solutes, and cerebral edema. AQP4 is significantly upregulated in several forms of brain tumor contributing to water influx and disruption of delicate neural homeostasis.10 Edema caused by disruption of the BBB leads to brain swelling and potentially life threatening increases in intracranial pressure (ICP).

Elevated ICP is a potentially life threatening condition as increased ICP can decrease cerebral perfusion and cause traumatic herniation of the brainstem through the foramen magnum. Many conditions that cause severe elevation in ICP set up dangerous positive feedback loops where damage to the BBB causes edema and elevated ICP; this in turn causes ischemia and further breakdown of the BBB leading to further increase in ICP. Treatment of these conditions centers on decreasing the volume of one or more of the three intracranial components: brain parenchyma, blood, and CSF. While elevation of the head or opening of a lumbar drain can remove blood or CSF from within the skull relatively quickly reducing the size of the brain parenchyma is slightly more laborious. Both hypertonic saline and mannitol therapy function on the principle of administering hyperosmotic solutions containing solute that will not cross the BBB. The result is hyperosmotic blood that pulls water down its concentration gradient out of the brain. This can be life saving by reversing the cycle of elevated ICP and restoring brain perfusion. The unique barrier between the brain and other body compartments is the basis for this therapy’s effectiveness and the veil that provides the specific environment for optimal CNS function.