Brain Meets Body: The Blood-Brain Barrier as an Endocrine Interface

Veterans Affairs Puget Sound Health Care System and Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
Endocrinology (Impact Factor: 4.5). 07/2012; 153(9):4111-9. DOI: 10.1210/en.2012-1435
Source: PubMed


The blood-brain barrier (BBB) separates the central nervous system (CNS) from the peripheral tissues. However, this does not prevent hormones from entering the brain, but shifts the main control of entry to the BBB. In general, steroid hormones cross the BBB by transmembrane diffusion, a nonsaturable process resulting in brain levels that reflect blood levels, whereas thyroid hormones and many peptides and regulatory proteins cross using transporters, a saturable process resulting in brain levels that reflect blood levels and transporter characteristics. Protein binding, brain-to-blood transport, and pharmacokinetics modulate BBB penetration. Some hormones have the opposite effect within the CNS than they do in the periphery, suggesting that these hormones cross the BBB to act as their own counterregulators. The cells making up the BBB are also endocrine like, both responding to circulating substances and secreting substances into the circulation and CNS. By dividing a hormone's receptors into central and peripheral pools, the former of which may not be part of the hormone's negative feed back loop, the BBB fosters the development of variable hormone resistance syndromes, as exemplified by evidence that altered insulin action in the CNS can contribute to Alzheimer's disease. In summary, the BBB acts as a regulatory interface in an endocrine-like, humoral-based communication between the CNS and peripheral tissues.

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    • "Are these examples of widespread and ever present physiological systems that routinely function to allow circulating estrogens to activate only some neural pathways while allowing locally produced estrogens to only activate other cells and circuits? Circulating steroids are thought to readily cross the blood– brain-barrier (Pardridge, 1981; Banks, 2012) or are thought to circulate bound to proteins that restrict or enhance their delivery to the brain. According to the free hormone hypothesis (Mendel, 1989), only 'free' or unbound steroid hormone can reach receptors on target tissues. "
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    ABSTRACT: The specificity of estrogen signaling in brain is defined at one level by the types and distributions of receptor molecules that are activated by estrogens. At another level, as our understanding of the neurobiology of the estrogen synthetic enzyme aromatase has grown, questions have emerged as to how neuroactive estrogens reach specific target receptors in functionally relevant concentrations. Here we explore the spatial specificity of neuroestrogen signaling with a focus on studies of songbirds to provide perspective on some as-yet unresolved questions. Studies conducted in both male and female songbirds have helped to clarify these interesting facets of neuroestrogen physiology.
    General and Comparative Endocrinology 09/2014; 205. DOI:10.1016/j.ygcen.2014.03.043 · 2.47 Impact Factor
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    • "A major setback for drugs intended for brain disorders is the inability to access the brain due to the surrounding BBB, which prevents crossing of large hydrophilic substances to the brain [1]. The nervous system has a vital role to send and receive electrochemical signals for organs to communicate. "
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    ABSTRACT: The blood brain barrier (BBB) poses a problem to deliver drugs for brain malignancies and neurodegenerative disorders. Stem cells such as neural stem cells (NSCs) and mesenchymal stem cells (MSCs) can be used to delivery drugs or RNA to the brain. This use of methods to bypass the hurdles of delivering drugs across the BBB is particularly important for diseases with poor prognosis such as glioblastoma multiforme (GBM). Stem cell treatment to deliver drugs to neural tumors is currently in clinical trial. This method, albeit in the early phase, could be an advantage because stem cells can cross the BBB into the brain. MSCs are particularly interesting because to date, the experimental and clinical evidence showed 'no alarm signal' with regards to safety. Additionally, MSCs do not form tumors as other more primitive stem cells such as embryonic stem cells. More importantly, MSCs showed pathotropism by migrating to sites of tissue insult. Due to the ability of MSCs to be transplanted across allogeneic barrier, drug-engineered MSCs can be available as off-the-shelf cells for rapid transplantation. This review discusses the advantages and disadvantages of stem cells to deliver prodrugs, genes and RNA to treat neural disorders.
    Clinical and Translational Medicine 07/2014; 3(1):24. DOI:10.1186/2001-1326-3-24
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    • "The ME and the Arc are two discrete areas located in the third ventricular walls. The ME is one of the circumventricular organs where specialized ependimal cells, the tanycytes [6] [52], are present instead of the blood brain barrier, providing access to the portal vessels where different terminals originating in other hypothalamic areas release their factors [13] [26], and isolating it from the cerebrospinal fluid and the Arc [52]. NEI axons, like many others, such as those of the GnRH, project to the ME [3] [10]. "
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    ABSTRACT: We previously showed that short-term hypo- and hyperthyroidism induce changes in neuropeptide glutamic-acid-isoleucine amide (NEI) concentrations in discrete brain areas in male rats. To investigate the possible effects of hypo- and hyperthyroidism on NEI concentrations mainly in hypothalamic areas related to reproduction and behavior, female rats were sacrificed at different days of the estrous cycle. Circulating luteinizing hormone (LH), estradiol and progesterone concentrations were measured in control, hypothyroid (hypoT, treated with PTU during 7-9 days) and hyperthyroid (hyperT, L-T4 during 4-7 days) animals. Both treatments blunted the LH surge. Hypo- and hyperthyroidism increased estradiol concentrations during proestrus afternoon (P-PM), although hypoT rats showed lower values compared to control during proestrus morning (P-AM). Progesterone levels were higher in all groups at P-PM and in the hyperT during diestrus morning (D2). NEI concentrations were lower in hypoT rats during the estrous cycle except in estrus (E) in the peduncular part of the lateral hypothalamus (PLH). They were also reduced by both treatments in the perifornical part of the lateral hypothalamus (PeFLH) during P-PM. Hypothyroidism led to higher NEI concentrations during P-PM in the organum vasculosum of the lamina terminalis and anteroventral periventricular nucleus (OVLT+AVPV). The present results indicate that NEI concentration is regulated in a complex manner by hypo- and hyperthyroidism in the different areas studied, suggesting a correlation between NEI values and the variations of gonadal steroid levels during estrous cycle. These changes could be, in part, responsible for the alterations observed in the hypothalamic-pituitary-gonadal axis in these pathologies.
    Peptides 09/2013; 49. DOI:10.1016/j.peptides.2013.08.016 · 2.62 Impact Factor
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