Blood–Brain Barrier - Clinical Tree

Introduction

The blood–brain barrier (BBB) maintains the brain parenchyma and blood components in separate compartments. In addition, by allowing glucose transport it helps fuel neuronal function. Maintenance of the integrity of this closed compartment comprises a dynamic combination of vascular, cellular, molecular, and ionic factors. Structurally, this barrier is composed of endothelial cells supported mainly by astrocytes and pericytes. BBB endothelial cells also have a transport function that acts to maintain a constant parenchymal milieu. Endothelial cells transport amino acids, participate to ionic homeostasis, and allow a controlled exchange of solute and water. Importantly, a variety of traumatic and nontraumatic inflammatory insults to the BBB may lead to a loss of the closed compartment and consequences of such.

The anesthesiologist must be aware that interventions such as cardiopulmonary bypass, cerebral arteriography, and osmotic BBB opening have all been linked to impairment of cerebral homeostasis in patients. We will focus our text to the effects of anesthetics on the BBB and clinical implications of the same.

Permeability at the Blood–Brain Barrier

Structurally, the brain microvasculature is lined with endothelial cells that are secured together by tight junctions (TJs). These TJs provide a means to regulate movement of substances into and out of the brain. The lipid bilayer of these endothelial cells allows movement and determines permeability across the BBB. Substances do not cross through the alternative paracellular route.

Translated into clinical practice, this unique structure means that the BBB does not allow a majority of CNS drugs to enter the brain parenchyma. Interestingly anesthetics are an important exception in that they freely exert CNS effects, and it has been proven that the lipophilicity of these agents drives them to cross the BBB. The log octanol/water partition coefficient has a significant role in predicting how and if compounds will cross the BBB.

Typically this coefficient is determined using an aqueous substance (water) and a hydrophobic substance (octanol). Compounds with a high log (P) favor hydrophobic compartments and will cross a lipid bilayer while compounds with a low log (P) will tend to stay in hydrophilic compartments (e.g., serum) and will not cross the BBB. As a general rule, compounds with a log (P) > 0 will cross the BBB rapidly with the major limiting factor being supply of the drug. On the other hand, compounds with a log (P) < −1 are limited in their ability to cross the BBB. Importantly, log (P) is a velocity, and therefore a higher value is necessary for a clinically relevant effect. It is indeed in actuality a pharmacokinetic property that allows anesthetic agents to move from blood to brain.

Also, compounds with similar log (P)s can have differing ability to cross the BBB. To cross the BBB efficiently, a number of conditions must be met: (1) Larger compounds (greater than 400 Da) require some additional transport mechanism to cross the BBB. These are too large to pass through TJs or directly across the lipid bilayer. (2) Many drugs have changes in ionization states that affect the ability of a drug to cross the BBB. (3) Hyperthermia enhances while hypothermia impedes BBB permeability. (4) Highly regulated mechanisms of transport by BBB endothelial cells. This type of facilitated transport is dependent on membrane receptors and is the major mechanism of transport regulation across the BBB (most notably glucose).

Cellular and Molecular Effects of Anesthetics on the Blood–Brain Barrier

Anesthetic agents may interact in several different ways with the BBB. This is because the same anesthetic agent establishes a different relationship with the target, signaling pathway, and pathology involved. Both direct and indirect effects of anesthetic agents on the molecular components of BBB integrity may affect these signaling pathways. At the cellular level several changes may be important such as tight and adherens junctions, vasodilation, endothelial cell survival, and neuroinflammation. Therefore, anesthetic action at the BBB depends upon the extent to which the agent modulates these pathways of signal transmission and in addition the systemic cerebral milieu in which it is administered.

Anesthesia and Nitric Oxide Signaling

Anesthetics have a varied effect on nitric oxide (NO) signaling pathways. NO is a signaling molecule and potent vasodilator that has been effective in ischemic preconditioning and, at low levels, shown to induce neuroprotection mediated by the BBB. NO has important downstream effects such as vascular regulation, mediation of neuroinflammation, and regulation of endothelial cell survival.

Volatile anesthetics result in potent cerebral vasodilation that in turn can induce endothelial stretching, increasing the gap between neighboring endothelial cells, and hence BBB permeability. These agents act in part via modulation of NO signaling (via nitric oxide synthase iNOS) and regulation of ATP-sensitive K ⁺ channels in vascular smooth muscle cells.

Let us look at isoflurane as a specific example. Isoflurane can induce nitric oxide synthase (iNOS)-dependent cerebral vasodilation and also neuroprotection via NO downstream effects. But as both the agents, on the flip side, NO and isoflurane are known to stimulate prostanoid production, this may potentially result in increased inflammation. Some other studies have also noted the proapoptotic effects of NO donors in vitro that lead to disruption of the cerebral endothelial cell monolayer and increased leukocyte adhesion in the presence of NO. Some of these effects may be attenuated by propofol administration.

Volatile anesthetics are important regulators of cardiovascular output, vascular tone, and cerebral blood flow. This may be a mechanism of BBB perturbation (via endothelial stretching) and a potential experimental confounder when assessing other molecular mechanisms influencing permeability.

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