A definitive guide to the blood-brain barrier

The mechanisms that maintain a “privileged” environment within the brain have been the subject of intense scrutiny for decades (1–4). While numerous authoritative reviews and primary research articles (6,001 listed in a search limiting the topic only to APS-sponsored publications) have appeared over the years, a recent entry into the literature stands out for its comprehensive nature and its focus on both the physiology and pathophysiology of the barrier (5). This highly readable and well-illustrated document details the mechanisms that establish the barrier, consequences of barrier dysfunction, and strategies for bypassing the barrier for therapeutic purposes.

In addition to a comprehensive discussion of the blood-brain barrier, this review details three prominent mechanisms that allow peripheral factors such as hormones, cytokines, and metabolic byproducts to enter into the central nervous system (CNS). First, the brain contains circumventricular organs that lack a conventional blood-brain barrier. Namely, the organum vasculosum lamina terminalis (OVLT), the subfornical organ (SFO), the median eminence, and neurohypophysis within the forebrain and the area postrema and adjacent nucleus tractus solitarius (NTS) within the hindbrain all contain fenestrated capillary endothelium that allow substances to pass from the periphery into the CNS. Although there is controversy over how far those entering factors can diffuse, there is no doubt that they can, via these sites, influence neuronal function. Second, the projection of afferent nerves into the CNS provides a neuronal delivery system whereby these peripheral neurons release factors directly onto central targets. For example, vagal nerves can communicate the peripheral hormonal and metabolic milieu to the CNS by release of relevant factors from vagal afferent nerve terminals within the CNS. Third, circulating factors such as leptin can bypass the barrier and enter the CNS via selective transport proteins. Other circulating vasoactive compounds as well as toxins and metabolic byproducts likely use similar communication mechanisms to directly influence the CNS despite the presence of a blood-brain barrier.

The review by Sweeney et al. (5) details anatomic and cellular properties of the barrier between the periphery and the CNS and discusses mechanisms that compromise this critical barrier. This review provides novel and important commentary on recently discovered genetic underpinnings of barrier dysfunctions and development of modern imaging and molecular approaches to elucidate causes of barrier breakdown that promote development of neurological disorders. These recent observations of how the barrier functions in healthy and disease states provide the foundation for researchers to develop protections for the integrity of the barrier and mechanisms to bypass the barrier for targeted therapies.

Researchers interested in understanding how multiple organ systems regulate total body homeostasis in healthy and disease states will find this review to be a valuable resource for insights into consequences of function and dysfunction of the blood-brain barrier.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

W.K.S. drafted manuscript; W.K.S. edited and revised manuscript; W.K.S. approved final version of manuscript.