Article

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

ABSTRACT

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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    • "Therefore, the contribution of peripheral steroids to the steroid milieu in the CNS is important and alterations in the peripheral steroidogenesis may influence neuronal activity in the brain. Although the steroid transport between the brain and periphery may be slowed by globulin binding, the steroid– globulin complex decreases the steroid clearance and has little influence on the total steroid amount transported to the brain [19] [24]. In spite of the substantially higher circulating levels of steroid sulfates when compared to their unconjugated counterparts , the levels of sulfated steroids in brain tissues are lower when compared with their unconjugated analogues [13] [18] [26] most probably due to their less polarity and the efflux transport via organic anion transporting polypeptide. "
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    ABSTRACT: Alzheimer's disease (AD) represents more than half of total dementias. Various factors including altered steroid biosynthesis may participate in its pathophysiology. We investigated how the circulating steroids (measured by GC-MS and RIA) may be altered in the presence of AD. Sixteen women with AD and 22 age- and BMI-corresponding controls aged over 65 years were enrolled in the study. The steroid levels (47 steroids and steroid polar conjugates) and their ratios in AD female patients indicated increased CYP11A1 activity, weakened activity of the CYP17A1C17,20 lyase metabolic step and attenuated sulfotransferase SULT2A1 activity at higher activity of the CYP17A1 17-hydroxylase step. The patients showed diminished HSD3B2 activity for C21 steroids, abated conversion of 17-hydroxyprogesterone to cortisol, and significantly elevated cortisol. The women with AD had also attenuated steroid 7α-hydroxylation forming immunoprotective Δ(5)-C19 steroids, attenuated aromatase activity forming estradiol that induces autoimmunity and a shift from the 3β-hydroxy-5α/β-reduced C19 steroids to their neuroinhibitory and antiinflammatory GABAergic 3α-hydroxy- counterparts and showed higher levels of the 3α-hydroxy-5α/β-reduced C21 steroids and pregnenolone sulfate (improves cognitive abilities but may be both protective and excitotoxic). Our preliminary data indicated functioning of alternative "backdoor" pathway in women with AD showing higher levels of both 5α/β-reduced C21 steroids but reduced levels of both 5α/β-reduced C21 steroids, which implied that the alternative "backdoor" pathway might include both 5α- and 5β-reduced steroids. Our study suggested relationships between AD status in women based on the age of subjects and levels of 10 steroids measured by GC-MS.
    Full-text · Article · Dec 2015 · The Journal of steroid biochemistry and molecular biology
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    • "They are indeed small molecules that easily cross the blood–brain-barrier by transmembrane diffusion. Moreover, they rapidly diffuse throughout the nervous tissues because of their low molecular weight and their physicochemical lipid solubility [52] [53]. An additional important feature of progesterone is its qualification as a multifunctional molecule, which means that it acts in a concerted manner on multiple targets. "
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    ABSTRACT: Since the first pioneering studies in the 1990s, a large number of experimental animal studies have demonstrated the neuroprotective efficacy of progesterone for brain disorders, including traumatic brain injury (TBI). In addition, this steroid has major assets: it easily crosses the blood-brain-barrier, rapidly diffuses throughout the brain and exerts multiple beneficial effects by acting on many molecular and cellular targets. Moreover, progesterone therapies are well tolerated. Notably, increased brain levels of progesterone are part of endogenous neuroprotective responses to injury. The hormone thus emerged as a particularly promising protective candidate for TBI and stroke patients. The positive outcomes of small Phase 2 trials aimed at testing the safety and potential protective efficacy of progesterone in TBI patients then provided support and guidance for two large, multicenter, randomized and placebo-controlled Phase 3 trials, with more than 2000 TBI patients enrolled. The negative outcomes of both trials, named ProTECT III and SyNAPSE, came as a big disappointment. If these trials were successful, progesterone would have become the first efficient neuroprotective drug for brain-injured patients. Thus, progesterone has joined the numerous neuroprotective candidates that have failed in clinical trials. The aim of this review is a reappraisal of the preclinical animal studies, which provided the proof of concept for the clinical trials, and we critically examine the design of the clinical studies. We made efforts to present a balanced view of the strengths and limitations of the translational studies and of some serious issues with the clinical trials. We place particular emphasis on the translational value of animal studies and the relevance of TBI biomarkers. The probability of failure of ProTECT III and SyNAPSE was very high, and we present them within the broader context of other unsuccessful trials.
    Full-text · Article · Nov 2015 · The Journal of steroid biochemistry and molecular biology
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    • "They are indeed small molecules that easily cross the blood–brain-barrier by transmembrane diffusion. Moreover, they rapidly diffuse throughout the nervous tissues because of their low molecular weight and their physicochemical lipid solubility [52] [53]. An additional important feature of progesterone is its qualification as a multifunctional molecule, which means that it acts in a concerted manner on multiple targets. "
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    ABSTRACT: Levels of steroids in the adult central nervous system (CNS) show marked changes in response to stress, degenerative disorders and injury. However, their analysis in complex matrices such as fatty brain and spinal cord tissues, and even in plasma, requires accurate and precise analytical methods. Radioimmunoassays (RIA) and enzyme-linked immunosorbent assays, even with prepurification steps, do not provide sufficient specificity, and they are at the origin of many inconsistent results in the literature. The analysis of steroids by mass spectrometric methods has become the gold standard for accurate and sensitive steroid analysis. However, these technologies involve multiple purification steps prone to errors, and they only provide accurate reference values when combined with careful sample workup. In addition, the interpretation of changes in CNS steroid levels is not an easy task because of their multiple sources: the endocrine glands and the local synthesis by neural cells. In the CNS, decreased steroid levels may reflect alterations of their biosynthesis, as observed in the case of chronic stress, post-traumatic stress disorders or depressive episodes. In such cases, return to normalization by administering exogenous hormones or by stimulating their endogenous production may have beneficial effects. On the other hand, increases in CNS steroids in response to acute stress, degenerative processes or injury may be part of endogenous protective or rescue programs, contributing to the resistance of neural cells to stress and insults. The aim of this review is to encourage a more critical reading of the literature reporting steroid measures, and to draw attention to the absolute need for well-validated methods. We discuss reported findings concerning changing steroid levels in the nervous system by insisting on methodological issues. An important message is that even recent mass spectrometric methods have their limits, and they only become reliable tools if combined with careful sample preparation. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Steroids
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