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Review
. 2012;18(25):3624-44.
doi: 10.2174/138161212802002625.

Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke

Patrick T Ronaldson  1 , Thomas P Davis
Affiliations
Review

Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke

Patrick T Ronaldson et al. Curr Pharm Des. 2012.

Abstract

The blood-brain barrier (BBB) is a critical regulator of brain homeostasis. Additionally, the BBB is the most significant obstacle to effective CNS drug delivery. It possesses specific charcteristics (i.e., tight junction protein complexes, influx and efflux transporters) that control permeation of circulating solutes including therapeutic agents. In order to form this "barrier," brain microvascular endothelial cells require support of adjacent astrocytes and microglia. This intricate relationship also occurs between endothelial cells and other cell types and structures of the CNS (i.e., pericytes, neurons, extracellular matrix), which implies existence of a "neurovascular unit." Ischemic stroke can disrupt the neurovascular unit at both the structural and functional level, which leads to an increase in leak across the BBB. Recent studies have identified several pathophysiological mechanisms (i.e., oxidative stress, activation of cytokine-mediated intracellular signaling systems) that mediate changes in the neurovascular unit during ischemic stroke. This review summarizes current knowledge in this area and emphasizes pathways (i.e., oxidative stress, cytokine-mediated intracellular signaling, glial-expressed receptors/targets) that can be manipulated pharmacologically for i) preservation of BBB and glial integrity during ischemic stroke and ii) control of drug permeation and/or transport across the BBB. Targeting these pathways present a novel opportunity for optimization of CNS delivery of therapeutics in the setting of ischemic stroke.

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Conflict of interest statement

Disclosure

Part of the information that appears in this article has been adapted from Ronaldson & Davis. Therapeutic Delivery. 2: 1015–1041 (2011).

Figures

Figure 1
Figure 1
Basic molecular organization of tight junction protein complexes at the blood-brain barrier. Adapted from Ronaldson & Davis. Therapeutic Delivery. 2: 1016–1041 (2011).
Figure 2
Figure 2
Endothelial localization of drug transporters known to be involved in transport of opioids at the blood-brain barrier. Adapted from Ronaldson & Davis. Therapeutic Delivery. 2: 1016–1041 (2011).
Figure 3
Figure 3
Effect of TEMPOL on H/R-mediated disruption of the tight junction. ROS and subsequent oxidative stress are known to disrupt assembly of critical TJ proteins such as occludin. Our results show that administration of TEMPOL, by scavenging ROS, prevents disruption of occludin oligomeric assemblies. Furthermore, TEMPOL attenuates the increase in sucrose leak across the BBB observed in animals subjected to H/R stress. Taken together, our studies with TEMPOL demonstrate that the TJ can be targeted pharmacologically in an effort to preserve BBB functional integrity during ischemic stroke.
Figure 4
Figure 4
The transforming growth factor-β (TGF-β) signalling pathway. Intracellular signalling molecules associated with TGF-β signalling at the blood-brain barrier. Signals elicited by the TGF-β pathway involve two cell surface receptors at the brain microvascular endothelium, which are designated activin receptor-like kinase (ALK)-1 and ALK-5. ALK1 transduces signals via phosphorylation of Smad proteins -1, -5, and -8 while ALK5 signals by phosphorylation of Smad2 and Smad3. Once phosphorylated, these Smad proteins bind to the common Smad (i.e., Smad4), thereby forming a protein complex that can translocate to the nucleus and affect transcription.
Figure 5
Figure 5. Opportunities for targeting the BBB to optimize CNS drug delivery
Results from our recent studies demonstrate that CNS drug delivery can be modified by targeting specific molecular structures of the BBB during pathophysiological stress such as H/R. TJ functional integrity can be maintained by scavenging ROS with an antioxidant drug such as TEMPOL. Targeting the TJ provides an opportunity to prevent blood-to-brain solute leak during ischemic stroke, thereby enabling control of CNS drug concentrations. In situations where increased uptake of therapeutics into the brain may be desirable, transporters such as Oatp1a4 can be targeted. Oatp1a4 facilitates brain delivery of drugs that may exhibit efficacy in treatment of ischemic stroke such as statins and opioid peptide analgesics. The TGF-β signalling pathway offers an opportunity to control both TJs and transporters by targeting TGF-β receptors (i.e., ALK1, ALK5) with small molecule therapeutics such as SB431542. Although P-gp is also a critical determinant of CNS drug delivery, caution must be exercised when targeting this transporter to enable greater uptake of therapeutic agents into brain parenchyma. This warning arises from evidence obtained from several laboratories including our own that have shown that enhanced brain delivery of drugs can lead to CNS toxicity and unexpected adverse drug reactions.
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