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Blood-Brain Barrier: Endogenous Modulation by Adrenal-Cortical Function
Abstract
The blood-brain barrier restricts the passage of molecules from the blood to the brain. The permeability of the barrier to iodine-125-labeled bovine serum albumin was examined in rats that had undergone adrenalectomy, adrenal demedullation, and corticosterone replacement. Adrenalectomy, but not adrenal demedullation, increased the permeability of brain tissue to the isotopically labeled macromolecule; corticosterone replacement reversed this effect. These results indicate that the blood-brain barrier may be hormonally regulated; that is, the pituitary-adrenal axis may physiologically modulate the permeability of the brain microvasculature to macromolecules.
... 131, Baud, 2007 #2152;Jobe, 2018 #2151} Evidence in adult subjects suggests that the BBB is under hormonal control. [132][133][134][135] Adrenalectomy increases BBB permeability, and corticosterone replacement reverses this effect on the barrier in adult rats. 133 These findings suggest that the pituitary-adrenalcortical axis may function as a physiologic regulator of barrier function. ...
... [132][133][134][135] Adrenalectomy increases BBB permeability, and corticosterone replacement reverses this effect on the barrier in adult rats. 133 These findings suggest that the pituitary-adrenalcortical axis may function as a physiologic regulator of barrier function. 133 It is well known that the pituitary-adrenal-cortical axis matures during fetal development and that endogenous cortisol concentrations increase particularly in the latter part of gestation. ...
... 133 These findings suggest that the pituitary-adrenalcortical axis may function as a physiologic regulator of barrier function. 133 It is well known that the pituitary-adrenal-cortical axis matures during fetal development and that endogenous cortisol concentrations increase particularly in the latter part of gestation. 136 In sheep, maternally administered exogenous antenatal glucocorticoids have been shown to reduce blood-brain permeability early (at 60%, 70%, and 80% of gestation) but not late (at 90% of gestation) in fetal development or in the neonatal period. ...
... Evidence in adult subjects suggests that the BBB is under hormonal control. [98][99][100][101] Adrenalectomy increases BBB permeability, and corticosterone replacement reverses this effect on the in anesthetized exteriorized acutely studied fetal sheep. 90 The brain-to-blood sucrose ratios exhibited rapid decreases in early gestation, followed by smaller decreases later in gestation through the first week of postnatal life. ...
... 130 Although mechanisms underlying the differences in regional vascular vulnerability have yet to be established, the vascular tree differs among brain barrier in adult rats. 99 These findings suggest that the pituitaryadrenal cortical axis may function as a physiologic regulator of barrier function. 99 It is well known that the pituitary-adrenal cortical axis matures during fetal development and that endogenous cortisol concentrations increase, particularly in the latter part of gestation. ...
... 99 These findings suggest that the pituitaryadrenal cortical axis may function as a physiologic regulator of barrier function. 99 It is well known that the pituitary-adrenal cortical axis matures during fetal development and that endogenous cortisol concentrations increase, particularly in the latter part of gestation. 102 In sheep, maternally administered exogenous antenatal glucocorticoids have been shown to reduce blood-brain permeability early (at 60%, 70%, and 80% of gestation) but not late (at 90% of gestation) in fetal development or in the neonatal period. ...
... In adult rats, adrenalectomy has been shown to increase blood-brain barrier permeability; corticosterone replacement reverses this effect on the barrier (20). These findings suggest that the entry of substances into the CNS may be responsive to circulating glucocorticoids and that the pituitary-adrenal cortical axis may function as a physiological regulator of bloodbrain barrier permeability (20). ...
... In adult rats, adrenalectomy has been shown to increase blood-brain barrier permeability; corticosterone replacement reverses this effect on the barrier (20). These findings suggest that the entry of substances into the CNS may be responsive to circulating glucocorticoids and that the pituitary-adrenal cortical axis may function as a physiological regulator of bloodbrain barrier permeability (20). In the normal adult rat, pharmacological doses of dexamethasone have been reported to reduce barrier permeability to AIB (39). ...
... In adult rats, changes in endogenous adrenocortical function have been shown to alter blood-brain barrier permeability (20). Adrenalectomy, but not adrenal demedullation, increased the permeability of brain tissue to albumin, and corticosterone replacement reversed these effects on the barrier (20). ...
Antenatal corticosteroid therapy reduces the incidence of intraventricular hemorrhage in premature infants. Enhanced microvascular integrity might provide protection against intraventricular hemorrhage. In the adult, there is evidence to suggest that the blood-brain barrier may be under hormonal control. We hypothesized that antenatal corticosteroids decrease blood-brain barrier permeability in the preterm ovine fetus. Chronically instrumented 120-day-gestation fetuses were studied 12 h after the last of four 6-mg dexamethasone (n = 5) or placebo (n = 6) injections had been given over 48 h to the ewes. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (K-i) for a-aminoisobutyric acid (AIB). K-i was significantly lower across brain regions in the fetuses of ewes that received antenatal dexamethasone compared with placebo (ANOVA; interaction, F = 2.54, P < 0.004). In fetuses of dexamethasone- and placebo-treated ewes, K-i (mu l . g brain wt(-1) . min(-1), mean +/- SD) was, respectively, 2.43 +/- 0.27 vs. 3.41 +/- 0.74 in the cortex, 4.46 +/- 0.49 vs. 5.29 +/- 0.85 in the cerebellum, and 3.70 +/- 0.49 vs. 5.11 +/- 0.70 in the medulla. We conclude that antenatal treatment with corticosteroids reduces blood-brain permeability in the ovine fetus.
... Evidence in adult subjects suggests that the BBB is under hormonal control. [98][99][100][101] Adrenalectomy increases BBB permeability, and corticosterone replacement reverses this effect on the in anesthetized exteriorized acutely studied fetal sheep. 90 The brain-to-blood sucrose ratios exhibited rapid decreases in early gestation, followed by smaller decreases later in gestation through the first week of postnatal life. ...
... 130 Although mechanisms underlying the differences in regional vascular vulnerability have yet to be established, the vascular tree differs among brain barrier in adult rats. 99 These findings suggest that the pituitaryadrenal cortical axis may function as a physiologic regulator of barrier function. 99 It is well known that the pituitary-adrenal cortical axis matures during fetal development and that endogenous cortisol concentrations increase, particularly in the latter part of gestation. ...
... 99 These findings suggest that the pituitaryadrenal cortical axis may function as a physiologic regulator of barrier function. 99 It is well known that the pituitary-adrenal cortical axis matures during fetal development and that endogenous cortisol concentrations increase, particularly in the latter part of gestation. 102 In sheep, maternally administered exogenous antenatal glucocorticoids have been shown to reduce blood-brain permeability early (at 60%, 70%, and 80% of gestation) but not late (at 90% of gestation) in fetal development or in the neonatal period. ...
... Cependant, la nicotine et la cotinine ont des effets différents sur les taux plasmatiques d'aldostérone et de prolactine (Andersson et al., 1993) et les fonctions endocriniennes sont modulables par les nAChRs (Fuxe et al., 1990). Ces hormones de l'axe hypophysesurrénale ont été impliquées dans la régulation endogène de la perméabilité de la barrière hématoencéphalique (Long et Holoday, 1985). Il est donc probable que la nicotine et la cotinine passent différemment la barrière hématoencéphalique. ...
... Le système nicotinique périphérique semble jouer un rôle plus prépondérant que le système nicotinique central. Le mécanisme intime de la modulation du passage n'est pas expliqué, mais il est probable qu'il résulterait d'un effet sur les hormones de la surrénale qui ont été rapportées responsables de la modulation de la perméabilité de la barrière hématoencéphalique (Long et Holoday, 1985). Les effets différents de la nicotine et de la cotinine sur ces hormones (Andersson et al., 1993) pourraient expliquer le passage plus restreint de la cotinine par rapport à la nicotine. ...
... It may be that because the slow release formulation produced a lower concentration over a longer time that the apparent impact on cell proliferation is ameliorated compared to a large single bolus injection due to the short half life of BrdU (approximately 15 minutes in vivo) or secondly it could be because the larger bolus injection restricted blood brain barrier (BBB) permeability (it has been suggested that glucocorticoids regulate BBB permeability to some degree (Long and Holaday, 1985)) and thus less BrdU entered the brain creating the impression of an even greater reduction in cell proliferation. The plasma levels of corticosterone obtained for the acute injections and chronic pellet implantation compared favourably with published values for similar dosing regimes (Inoue and Koyama, 1996) and the reduced adrenal gland weights seen at 7,14 and 21 days also confirmed a constant corticosterone elevation resulting in a reduction of endogenous corticosterone production. ...
Despite the fact that major depressive disorder (MDD) is expected to become the single largest cause of injury and illness in the world by 2020 little is known regarding the underlying cause of the disease or the mechanism of action of antidepressants although the HPA axis and neurogenesis may be of importance in both processess. In this thesis I have attempted to further elucidate the links between the mechanism of action of antidepressants, disruption of the HPA axis and neurogenesis with particular focus on members of the Bcl-2 family of pro- and anti-apoptotic proteins. Results showed that disruption of the HPA axis in mice by elevating corticosterone via a pellet implant method caused robust behavioural changes in the forced swim test (FST) (following acute and 7 day administration but not 14 or 21 day administration) and the light/dark box (following chronic but not acute administration which was normalised following corticosterone withdrawal) indicative of a "depressed phenotype". Chronic corticosterone treatment also significantly decreased hippocampal neurogenesis (attenuated by antidepressant treatment) but failed to alter expression of the anti- or pro-apoptotic proteins Bcl-2 and BAX respectively indicating a role for a disrupted HPA axis in reduced hippocampal neurogenesis but not in increased apoptosis via changes in Bcl-2 or BAX expression. Conversely, antidepressants increased hippocampal neurogenesis and selectively increased hippocampal Bcl-2 without a corresponding change in BAX. Treatment with receptor subtype selective 5-HT antagonists indicated the involvement of the 5-HT1A and 5-HT2C receptor subtypes in the effects on Bcl-2. Central administration of Bcl-2 and BAX peptide fragments modulated monoamine systems increasing 5-HT metabolism and produced an antidepressant effect in the FST. Taken together results suggest a potential involvement for the Bcl-2 family of proteins in the mechanism of action of antidepressants and further supports the suggestion that chronically disrupted HPA axis function influences hippocampal neurogenesis.
... wildtype animals (Uhr, Holsboer, & Muller, 2002). Other studies have shown that the permeability of the BBB to various steroids in vivo, or of model BBB systems in vitro, can be modulated by a number of factors including removal of adrenals by adrenalectomy (ADX) (Long & Holaday, 1985) and, potentially, antidepressants (Pariante et al., 2001). ...
Successful coping with stressful events involves adaptive and cognitive processes in the brain that make the individual more resilient to similar stressors in the future. Stressful events result in the secretion of glucocorticoids (GCs) from the adrenal glands into the blood stream. Early work proved instrumental for developing the concept that these hormones act in the brain to coordinate physiological and behavioral responses to stress through binding to two different GC-binding receptors. Once activated these receptors translocate to the nucleus where they act on target genes to facilitate (or sometimes inhibit) transcription. There are two types of receptors in the brain, the mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). This review summarizes recent work which provides new insights regarding the genomic action of these receptors, both under baseline conditions and following exposure to acute stress. This work is discussed alongside the extensive studies undertaken in this field previously and new, and exciting "big data" studies which have generated a wealth of relevant data. The consequence of these new insights will challenge existing assumptions about the role of MRs and GRs and pave the way for the implementation of novel and improved methodologies to identify the role these corticosteroid receptors have in stress-related behavioral adaptation.
... The critical pain-control hormones that are produced in glands outside the CNS are cortisol, pregnenolone, dehydroepiandrosterone (DHEA), progesterone, testosterone, estrogen, and thyroid (Table 1) . Among the primary pain-control functions of these hormones are immune and anti-inflammatory actions, cellular protection, tissue regeneration, glucose control, and modulation of CNS receptors, the blood-brain [19,33,37,42,[49][50][51][52][53]. ...
Severe pain has profound physiologic effects on the endocrine system. Serum hormone abnormalities may result and these serve as biomarkers for the presence of severe pain and the need to replace hormones to achieve pain control. Initially severe pain causes a hyperarousal of the hypothalamic-pituitary-adrenal system which results in elevated serum hormone levels such as adrenocorticotropin, cortisol, and pregnenolone. If the severe pain does not abate, however, the system cannot maintain its normal hormone production and serum levels of some hormones may drop below normal range. Some hormones are so critical to pain control that a deficiency may enhance pain and retard healing.
... As noted in the section on development of the cerebrovasculature, in the fetal lamb Stonestreet and colleagues have demonstrated increasing impermeability of the blood-brain barrier (BBB) from 0.6 to 0.9 gestation [165,166]. In part, BBB permeability is regulated by corticosteroids [588], and in the premature lamb this group also showed that antenatal dexamethazone administration significantly decreased BBB permeability [166,167]. As noted, these findings are of relevance to the beneficial effects of antenatal corticosteroids in lowering the risk of early onset intraventricular hemorrhage [589,590]. ...
As compared to the adult, the developing fetus and newborn infant are at much greater risk for dysregulation of cerebral blood flow (CBF), with complications such as intraventricular and germinal matrix hemorrhage with resultant neurologic sequelae. To minimize this dysregulation and its consequences presents a major challenge. Although in many respects the fundamental signal transduction mechanisms that regulate relaxation and contraction pathways, and thus cerebrovascular tone and CBF in the immature organism are similar to those of the adult, the individual elements, pathways, and roles differ greatly. Here, we review aspects of these maturational changes of relaxation/contraction mechanisms in terms of both electro-mechanical and pharmaco-mechanical coupling, their biochemical pathways and signaling networks. In contrast to the adult cerebrovasculature, in addition to attenuated structure with differences in multiple cytoskeletal elements, developing cerebrovasculature of fetus and newborn differs in many respects, such as a strikingly increased sensitivity to [Ca(2+)]i and requirement for extracellular Ca(2+) for contraction. In essence, the immature cerebrovasculature demonstrates both "hyper-relaxation" and "hypo-contraction". A challenge is to unravel the manner in which these mechanisms are integrated, particularly in terms of both Ca(2+)-dependent and Ca(2+)-independent pathways to increase Ca(2+) sensitivity. Gaining an appreciation of these significant age-related differences in signal mechanisms also will be critical to understanding more completely the vulnerability of the developing cerebral vasculature to hypoxia and other stresses. Of vital importance, a more complete understanding of these mechanisms promises hope for improved strategies for therapeutic intervention and clinical management of intensive care of the premature newborn.
... It has been shown that dexamethasone reduces cerebral capillary hypertension, in addition to maintaining integrity of the bloodbrain barrier by inhibiting transvascular endothelial permeability and increasing anti-inflammatory biomarkers in acute mountain sickness-susceptible individuals. [49][50][51] It is not unreasonable that ibuprofen's anti-inflammatory effects may be similarly protective against blood-brain barrier damage in the hypoxic edematous state. ...
Acute mountain sickness occurs in more than 25% of the tens of millions of people who travel to high altitude each year. Previous studies on chemoprophylaxis with nonsteroidal anti-inflammatory drugs are limited in their ability to determine efficacy. We compare ibuprofen versus placebo in the prevention of acute mountain sickness incidence and severity on ascent from low to high altitude.
Healthy adult volunteers living at low altitude were randomized to ibuprofen 600 mg or placebo 3 times daily, starting 6 hours before ascent from 1,240 m (4,100 ft) to 3,810 m (12,570 ft) during July and August 2010 in the White Mountains of California. The main outcome measures were acute mountain sickness incidence and severity, measured by the Lake Louise Questionnaire acute mountain sickness score with a diagnosis of ≥ 3 with headache and 1 other symptom.
Eighty-six participants completed the study; 44 (51%) received ibuprofen and 42 (49%) placebo. There were no differences in demographic characteristics between the 2 groups. Fewer participants in the ibuprofen group (43%) developed acute mountain sickness compared with those receiving placebo (69%) (odds ratio 0.3, 95% confidence interval 0.1 to 0.8; number needed to treat 3.9, 95% confidence interval 2 to 33). The acute mountain sickness severity was higher in the placebo group (4.4 [SD 2.6]) than individuals receiving ibuprofen (3.2 [SD 2.4]) (mean difference 0.9%; 95% confidence interval 0.3% to 3.0%).
Compared with placebo, ibuprofen was effective in reducing the incidence of acute mountain sickness.
... Evidence in adult subjects suggests that the blood-brain barrier is under endogenous hormonal control [30]. The pituitary-adrenal cortical axis matures during fetal development and cortisol concentrations increase particularly in the latter part of gestation [53]. ...
Maternal glucocorticoid treatment reduces blood-brain permeability early, but not late in fetal development, and pretreatment with glucocorticoids does not affect barrier permeability in newborn lambs. In addition, endogenous increases in plasma cortisol levels are associated with decreases in blood-brain barrier permeability during normal fetal development. Therefore, we tested the hypotheses that development as well as endogenous and exogenous glucocorticoids alters the expression of tight junction proteins in the cerebral cortex of sheep. Cerebral cortices from fetuses at 60%, 70%, and 90% of gestation, newborn and adult sheep were snap frozen after four 6-mg dexamethasone or placebo injections were given over 48-h to the ewes and adult sheep. Lambs were treated similarly with 0.25 mg/kg-dexamethasone or placebo. Tight junction protein expression was measured by Western immunoblot. Claudin-1 was higher (P<0.05) in fetuses at 60% of gestation than in newborn and adult sheep. Claudin-5 was higher at 60% than 70% of gestation, and than in newborn and adult sheep. ZO-1 was higher in newborn than adult sheep. ZO-2 was higher at 90% gestation, in newborn and adult sheep than 60% gestation. Claudin-5 was higher in dexamethasone than placebo-treated lambs, and ZO-2 was higher in fetuses of dexamethasone than placebo-treated ewes at 90% gestation. ZO-2 expression demonstrated a direct correlation with increases in plasma cortisol during fetal development. We conclude that claudin-1, claudin-5, ZO-1, and ZO-2 expression exhibit differential developmental regulation, exogenous glucocorticoids regulate claudin-5 and ZO-2 in vivo at some, but not all ages, and increases in endogenous fetal glucocorticoids are associated with increases in ZO-2 expression, but not with occludin, claudin-1, claudin-5 or ZO-1 expression in ovine cerebral cortices.
... A barreira hematocefálica tem sua permeabilidade modulada a outras substâncias pelos glicocorticóides, o que torna possível seu uso na terapia antiedema cerebral 42 . ...
Endothelial Rho proteins are essential signalling molecules that mediate endothelial responses to adherent leukocytes through ICAM-1, allowing them to migrate through brain endothelial monolayers. In order to be functionally active, Rho proteins are required to undergo post-translational prenylation. In vitro inhibition of brain endothelial protein isoprenylation with protein prenyl transferase inhibitors, resulted in a significant reduction in the ability of brain endothelial cells to support transendothelial migration of myelin basic protein (MBP)-specific T-lymphocytes. The effect of these inhibitors was specific for the process of migration and did not significantly affect the ability of T-lymphocytes to adhere to endothelial cells. Protein prenyl transferase inhibitors were also effective at inhibiting leukocyte migration into the CNS and attenuating clinical signs of disease in an in vivo model of neuroinflammation. Similar studies using the 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, lovastatin to limit the availability of isoprenoid groups for protein prenylation showed a significant reduction in both the transendothelial migration of MBP-specific T-lymphocytes and the infiltration of leukocytes into the CNS. These studies demonstrate the potential of pharmacologically targeting CNS endothelial cell signalling responses, and particularly limiting endothelial protein prenylation, as a means of attenuating leukocyte recruitment to the CNS and subsequent neuroinflammatory disease. Studies with VCAM-1 suggest that it may transduce intracellular signals in brain endothelial cells which may be important in the transvascular migration of monocytes.
It has been clear since the time of Ehrlich that the greater part of the CNS is not stained when Trypan blue is injected into the blood stream, even when other organs of the body are very heavily stained.
At the beginning of this decade, there was relatively little information available regarding the clinical symptomatology of Alzheimer’s disease (AD), the borders between “normal CNS aging” and AD, and the course of AD.
Chronic low back pain is one of the most common maladies of modern man. Many of these men have accompanying erectile dysfunction (ED). The cause(s) of erectile dysfunction in men with chronic low back pain is multifactorial. This article will review the causes of erectile dysfunction in men with chronic low back pain. We will also review the noninvasive evaluation that can easily be accomplished by most physicians caring for men with chronic low back pain and erectile dysfunction. Finally, we will review the treatment options that are effective in men with chronic low back pain who are affected with erectile dysfunction. The causes of ED in these men include the side effects of medication used to treat back pain, hormone deficiency, depression and other psychological causes, and neurologic causes. Treatment of ED for men with chronic back pain can be very successful.
It is probably no exaggeration to declare that the hypothalamus-neurohypophysial system (HNS) is the quintessence of neurosecretion and vasopressin (VP) the quintessential brain peptide. The system comprises magnocellular neurons, with cell bodies located in the hypothalamus, which project to and release their hormone in the neurohypophysis, a large storage organ outside the confines of the central nervous system (CNS). Most magnocellular VP and oxytocin (OX) neurons have their large cell bodies (25–30-μm diameter) segregated in the relatively discrete supraoptic nuclei (SON) and paraventricular nuclei (PVN) of the hypothalamus (Fig. 1). Since VP is released into the systemic circulation and stimulates distant target organs, it fits the definition of a true hormone, but it may have effects in the CNS as well. The unique anatomy of this system not only contributed to its early discovery but also facilitated subsequent experimental manipulation of this relatively accessible neurosecretory complex. Also, the discovery of the Brattleboro rat, which fails to produce hypothalamic VP in the homozygous form (see Valtin, 1982) and, to a much lesser extent, of mice with hereditary diabetes insipidus resulting from renal unresponsiveness to VP (Falconer et al., 1964), has provided animal models of great value.
In letzter Zeit mehren sich psychoneuroimmunologische Forschungsbefunde, die darauf hindeuten, dass bestimmte chronische Schmerzsyndrome mit Dysregulationen der Hypothalamus-Hypophysen-Nebennierenrindenachse und des sympathoadrenalen Systems einhergehen können. Es wird davon ausgegangen, dass diese möglicherweise durch psychischen Stress bedingbaren Dysfunktionen zu einer potenzierten Sekretion von Entzündungsmediatoren und damit zur Sensibilisierung von peripheren Schmerzrezeptoren sowie zentralen nozizeptiven Neuronen führen. Aus den aktuell vorliegenden Studien lässt sich jedoch nicht ohne weiteres eine kausale Beeinflussung des Schmerzgeschehens durch Mediatorhormone des Stresssystems folgern. Vor diesem Hintergrund wurde untersucht, ob sich Zusammenhänge zwischen Cortisol (Hydrocortison) und Schmerzempfindlichkeit humanexperimentell realisieren und psychophysisch quantifizieren lassen. Durch Prüfung der Idoneität diverser Modelle peripher- und zentralnervöser Entzündungsschmerzprozesse konnte eine prinzipiell ursächliche Beeinflussung des Schmerzgeschehens durch Cortisol nachgewiesen und Befunde aus klinischen Studien validiert werden. Die Experimentalbefunde deuten auf eine spezifische Regulation algetischer Prozesse hin, die sich vielfach von bekannten antiinflammatorischen Corticosteroideffekten abhebt. Daraus ableitbare Anwendungen für die Schmerztherapie insbesondere präemptive Analgesie werden diskutiert.
Objective
Millions of patients continue to require opioid analgesics for control of moderate to severe chronic pain, which is a disease that affects more Americans than cancer, heart disease, and diabetes combined. Common opioid adverse effects include constipation, sedation, and nausea. A lesser-known sequelae is opioid induced androgen deficiency (OPIAD). The objective of this review was to better characterize the effects of opioids on the endocrine system. Methods
Published data were evaluated to identify links between opioid use and hypogonadism, as well as to describe proposed physiological mechanisms. ResultsChronic opioid use may predispose to hypogonadism through alteration of the hypothalamic-pituitary-gonadal axis as well as the hypothalamic-pituitary-adrenal-axis. The resulting hypogonadism and hypotestosteronism may contribute to impaired sexual function, decreased libido, infertility, and osteoporosis- none of which may be clinically recognized as opioid related. ConclusionsOPIAD is a recognized consequence of long-term opioid therapy. Patients initiated or maintained on opioids should be queried about symptoms that might suggest hypogonadism including irregular menses, reduced libido, depression, fatigue, and hot flashes or night sweats. Some clinicians recommend assessment of baseline testosterone levels prior to initiating therapy. Additional data appear necessary to formulate guidelines regarding the diagnosis and management of OPIAD. Options include, rotating, reducing the dose or type, or cessation of opioid therapy or adding hormonal supplementation in the form of androgen replacement therapy. There are multiple formulations of testosterone available for replacement therapy, which is usually guided by laboratory measurements.
The present work investigated the possible relationship between central and peripheral oxytocin (OT) release during milking in experimental ewes. Ten multiparous ewes were divided into four groups according to milk ejection stimuli: exclusive machine milking (EM), mixed-management milking and suckling, lambs separated during the night and reunited with their mother after morning milking (MMS); mixed-management with manual milking (MMM), and exclusive suckling (ES) lambs also separated during the night. Simultaneous sampling of cerebrospinal fluid (CSF) and blood was performed during milking. The means, standard deviations, variation coefficients, and minimum and maximum CSF and plasma OT concentrations were the following, respectively: 257.88 ± 265.90 pg/ml, 103.11%, and 11.70 and 1000.00 pg/ml. No statistically significant correlations were found between OT concentrations in the CSF and plasma samples (EM: -0.26; ES: -0.19; MMM: 0.05; MMS: 0.04). The OT concentration in CSF was not influenced by milk ejection stimuli, although plasma OT was higher in the MMM (679.80 ± 25.63) and MMS (591.82 ± 30.56) groups compared with the EM and ES groups. Additionally, plasma OT concentrations were higher in the OME group (381.04 ± 22.09) compared with the AE group (218.82 ± 27.04). In conclusion, no positive correlations were found between central and peripheral OT concentrations during milking and suckling. Plasma OT concentrations differed as a function of milking management and had consequences for both milk ejection and production. Plasma but not CSF oxytocin concentrations were influenced by different milk ejection stimuli.
The blood-brain barrier maintains central nervous system homeostasis and limits the entry of blood-borne substances that could alter neuronal function and survival. The barrier exists predominantly at the endothelium of cerebral vascular microvessels. The cerebral vascular endothelium becomes highly specialized during the formation of the neurovascular unit early in embryonic development. The blood-brain barrier is present and functional early in fetal life. The tightness of the barrier gradually increases throughout gestation and in the newborn period. Alterations in the basolateral environment of the cerebral microvasculature can modify the blood-brain barrier properties by modulating the expression of the endothelial tight junctions and other biochemical properties of the cerebral vascular endothelium.Maturation of the blood-brain barrier late in gestation correlates with increases in endogenous corticosteroids and with exposure to exogenous corticosteroids. Several adverse fetal and neonatal conditions can alter the structure and function of the blood-brain barrier. Impairment of blood-brain barrier function in the perinatal period could increase the entry of bilirubin and other neurotoxic substances from the systemic circulation into the brain, thereby exacerbating and/or causing damage to the developing brain.
A number of factors have recently coalesced to bring hormone testing and treatment to the field of pain care. Uncontrolled, severe pain as well as opioid drugs have a profound impact on the endocrine system. Because pain is a potent stressor, it initially causes pituitary, adrenal, and gonadal hormones to elevate in the serum. If severe pain goes uncontrolled for too long, however, hormone levels deplete in the serum. The finding of abnormal (too high or low) serum hormone levels serve as biomarker of endocrinopathies, which helps inform the clinician that enhanced analgesia as well as hormone replacement may be necessary. Adequate, physiologic levels of some specific hormones are necessary for optimal analgesia, neuroprotection, and neurogenesis. Although not a substitute for opioids, some hormone replacements may minimize their use. We know that the central nervous system produces a group of hormones called neurohormones whose natural function is neuroprotection and neurogenesis. Their clinical use in centralized pain states is new, and early reports indicate that they may have considerable benefit for treatment.
There has been discussion over some years on the effects of drugs used against nerve gas poisoning on the central nervous system (CNS) following exposure to stress. A study in guinea-pigs, where animals were exposed to a 20 min forced swimming task in 30°C water four days after the start of continuous s.c. delivery (Alzet minipumps) of pyridostigmine or physostigmine has been completed. Following forced swimming, the animals received i.m. injection of soman (2 LD 50) and i.m. atropine, diazepam and one of four oximes (obidoxime, HI-6, Hlö-7 or P2S) 1 min after soman. The animals were observed for 30 min after administration of the triple therapy followed by decapitation. The level of acetylcholine (ACh) and the acetylcholinesterase (AChE) activity were measured in cortex, hippocampus and cerebellum and the AChE-activity was also measured in diaphragm, heart and in plasma (ChE). The animals were pre-treated with TOCP (100 mg/kg, s.c.) 24 hours before the forced swimming stress. Administration of pyridostigmine or physostigmine, which inhibited the plasma cholinesterase activities 15% and 19% in control animals, respectively, did not alter the level of ACh in cortex and hippocampus. The ACh level was, however, significantly reduced in the cortex and hippocampus in animals pre-treated with pyridostigmine or physostigmine followed by exposure to forced swimming stress. Furthermore, there was a significant difference between the animals given pyridostigmine and those given physostigmine followed by exposure to forced swimming stress, soman exposure (i.m.) and triple therapy. The level of ACh in cortex and hippocampus was only marginally increased in those animals pre-treated with physostigmine, while there was a significant increase in the level of ACh in animals pre-treated with pyridostigmine. There were, however, no major differences between the animal groups injected with one of the four different oximes in these experiments. The AChE-activity in the brain was only slightly altered following s.c. delivery of pyridostigmine or physostigmine in stressed and non-stressed animals. There was not a clear difference in the efficiency of the four oximes used following exposure to soman and forced swimming stress in reactivation of the AChE-activity in the brain. The inhibition of AChE by soman was, however, overall lower in animals treated with HI-6 (HI-6<obidoxime=P2S< Hlö-7). In plasma, diaphragm and heart there was a significantly larger inhibition of cholinesterase activities following soman and triple therapy and pre-treatment with pyridostigmine than after pre-treatment with physostigmine. Thus, a combination of pre-treatment with physostigmine and treatment with HI-6 resulted in a lower peripheral AChE-inhibition than after injection of the other oximes. These data from guinea-pigs imply that forced swimming stress might induce alterations in the brain and change the blood-brain barrier. Quaternary drugs may, therefore, pass into the brain during exposure to heavy stress. Furthermore, there was a significantly lower increase in brain ACh levels following the use of physostigmine as a pre-treatment drug than following the use of pyridostigmine. There was a less clear difference in the degree of inhibition of the AChE-activity following pre-treatment with the two carbamates in the peripheral tissues studied, but HI-6 was somewhat more efficient in reducing the cholinesterase inhibition than the other oximes. In plasma, diaphragm and heart, pre-treatment with physostigmine resulted in an overall lower inhibition of the cholinesterase activity than pre-treatment with pyridostigmine followed by exposure to soman and triple therapy. The inhibition of the cholinesterase activity was lower when using HI-6 than following injection of obidoxime, P2S or Hlö-7.
The objective of this study was to investigate behavioural changes in Holstein heifers caused by exogenous adrenocorticotropic hormone (ACTH) administration. Twelve 11-month-old heifers were submitted to either a single saline or ACTH injection and then the treatments were switched after 3 days (n=12 heifers/treatment). Heifers were in full view throughout the experimental period and recordings started immediately after ACTH and saline administration (injection corresponded to time 0min), with general activity patterns of each heifer recorded on videotape for 24h. Behavioural results during the first two experimental hours showed that heifers were less active and spent more time lying following ACTH than after saline treatment (P=0.04). Also, heifers spent significantly less time ruminating immediately following ACTH injection (P=0.05). However, feed intake measured after 4 and 24h was similar between treatments (P>0.05). Overall, there was no significant influence of ACTH treatment on frequency or duration of behaviours during the 4- and 24-h periods following injection (P>0.05). The rapid and minimal effect of ACTH injection on behaviour suggests that peripheral administration of ACTH can be used to measure reactivity of the adrenal cortex without inducing biologically significant consequences.
This chapter highlights neuropeptide receptors and astrocytes. It summarizes the capabilities of astrocytes to react to external and particularly to neuropeptide stimuli from the neuropil. The chapter focuses on astrocytes from the adult brain in situ on glial fibrillary acidic protein (GFAP)-positive astrocytes cultivated from murine brains. Glia cells exhibit a large variety of receptors on their surface, the activation of which results in either an increase or a decrease in the formation of cAMP and cGMP. The receptor-mediated reaction of astrocytes to external stimuli may consist in (1) modification of the pattern of membrane channels and, consequently, in the ional composition or the pH of the intercellular milieu, (2) metabolic changes, (3) synthesis and secretion of substances as well as changing uptake and clearance of neurotransmitters from the intercellular clefts, and (4) plastic remodeling of astrocytic form and processes altering the coverage of neurons with glia. The unique position of astrocytes as non-wired adaptable and slowly working parts of the information transmission system brain allows them to participate in the finely tuned modulation of the yes- or no-answer coming from synaptically linked neuronal chains.
Synthetic glucocorticoids have been used for several years in the treatment of brain edema 1. Labelled dexamethasone binds to the nucleus of capillary and choroid plexus endothelial cells 2, suggesting a local site of action. Another possibility is, of course, a suppression of pituitary adrenocorticotrophic hormone (ACTH) secretion; intracisternal administration of ACTH, 0~- or ~- melanocyte stimulating hormone (MSH) increases the penetration of labelled albumin, inulin, sucrose or mannitol from the blood into the cerebrospinal fluid of rabbits; i.v. injected ACTH, however, has little or no effect 3 . The active segment of ACTH and the MSH hormones does not appear to be ACTH 4--9, since administration of this fragment has an opposite effect 4. Long and Holaday have recently reported 5 that bilateral adrenalectomy, but not adrenal medullectomy, increases the penetration of [125I]labelled bovine seroalbumin into rat cerebellum, brainstem, and rostral, dorsal or ventral forebrain. The effect is reversed by corticosterone (0.5 mg kg -1, s.c.), and is not due to an increase in blood pressure, which is in fact diminished by adrenalectomy 5. These findings suggest that the pituitary-adrena l axis may regulate permeability of the bloodbrain barrier. They do not show whether the effect is due to a direct action of the adrenal steroids or to a feedback influence of these on ACTH secretion. However, the binding of dexamethasone to brain capillary or choroid plexus endothelial cells 2, and the relative ineffectiveness of i.v. ACTH on albumin penetration into the cerebrospinal fluid 3, suggests that it is more likely that adrenocortical steroids affect the blood-brain barrier through a direct action. This raises the possibility, however, that in circumstances in which the pituitaryadrenal axis becomes hyperactive, blood-brain barrier permeability to peptides or other relatively large molecules may increase. One such circumstance could be, for example, the period immediately following aversive behavioral training. The pituitary-adrena l axis is hyperactive for several minutes after training, and at that time numerous peptides given peripherally do affect brain processes involved in memory regulation 6.
To reach their central target areas corticosteroid hormones have to enter the brain by passing the blood-brain barrier (BBB), a dynamic barrier that protects the brain from peripheral influences. At this barrier, the efflux transporter P-glycoprotein (Pgp) is expressed, which hampers the uptake into the brain of a wide range of compounds including several glucocorticoids such as dexamethasone, prednisolone, and cortisol. Remarkably, corticosterone uptake is not affected by this Pgp.P-glycoprotein may play a crucial role as an intermediate between brain and periphery by controlling transport of corticosteroids at the BBB and thus exposure of corticosteroid receptors in brain. Indeed, low-dose dexamethasone treatment leads to dissimilarity in the potency of direct central and peripheral glucocorticoid actions. It suppresses pituitary-adrenal secretion at the pituitary level without replacing endogenous glucocorticoids in the brain.The lack of Pgp-mediated transport of corticosterone, in contrast to cortisol, suggests a more important role for corticosterone in modulating human brain function than hitherto recognized. In post-mortem human brain samples the ratio of corticosterone over cortisol is six times higher compared with the ratio in plasma.In the next years, modulation of glucocorticoid access by efflux transporters like Pgp will increasingly emerge as a new level of regulation of glucocorticoid actions in brain.
Sprague-Dawley rats were anesthetized and the mystatial vibrissae was injected with 0.3-120 pmol of 125I-labeled affinity-purified nonspecific rat IgG with and without additional unlabeled IgG in 50 μL of normal saline. Following a survival of 2 days, the rats were deeply anesthetized and perfused with saline and buffered formalin. The brains were removed and punch sample taken that included the facial nuclei. Uptake of radioiodinated IgG by the facial nucleus was determined by subtracting background activity, which was determined from the facial nucleus punch sample contralateral to the injection, from the ipsilateral facial nucleus. Uptake of radiolabeled IgG established a linear relationship with the amount of radiolabeled IgG injected, and only a very small amount was taken up (0.21 fmol per nmol injected). Addition of unlabeled IgG had no effect on the uptake of radiolabeled IgG. This evidence supports immunohistochemical evidence indicating that nonspecific serum IgG is taken up by motor neurons of the CNS with axons projecting the periphery. An increased understanding of this and other aspects of the relationship between the nervous system and the humoral immune system may provide insight concerning the pathogenesis of certain types of autoimmune nervous system disease.
This chapter describes the mechanism of macromolecular transport in newborn animals, focusing on the factors regulating gut closure. The neonatal mammalian small intestine has the capacity to transport macromolecules derived from breast milk. The transported macromolecules are biologically important in the neonate especially in hypogammaglobulinemic animals. Transport of macromolecules follows two different pathways: specific receptor mediated transcytosis and nonspecific transcytosis. Milk-born lactoferrin may have effects such as influence on iron metabolism, antibacterial action, mitogenic effects, and actions to potentiate the immunological system. The factors regulating gut closure are epidermal growth factor (EGF), insulin, secretin, prostaglandin, polyamines, and dietary fibre. The transfer of some macromolecules into the CSF via the blood circulation in suckling neonatal pigs is discussed in the chapter. The passage of macromolecules present in plasma into the brain is limited by the blood–brain barrier and blood cerebrospinal fluid barrier. It remains for future work to clarify if novel agents derived from milk contribute to the improvement of central nervous functions.
Current research evidence suggests that interactions between genetic and environmental factors contribute to modulate the susceptibility to degenerative disorders, including inflammatory and autoimmune diseases of the central nervous system (CNS). In this context, bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life, thereby influencing the predisposition to several disease entities. Glucocorticoids (GCs), the end products of the hypothalamic–pituitary–adrenocortical (HPA) axis, gender and signals generated by hypothalamic–pituitary–gonadal (HPG) axis are major players coordinating the development of immune system function and exerting powerful effects in the susceptibility to autoimmune disorders, including experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS). In particular, GCs exert their beneficial immunosuppressive and anti-inflammatory effects in inflammatory disorders of the CNS, after binding to their cytoplasmic receptors (GRs). Here we review our work using transgenic (Tg) mice with a dysfunctional GR from early embryonic life on programming vulnerability to EAE. The GR-deficiency of these Tg mice confers resistance to active EAE induction. The interplay between GCs, proinflammatory mediators, gender and EAE is summarized. On the basis of our data, it does appear that exposure to a defective GR through development programs major changes in endogenous neuroendocrine and immune mechanisms controlling the vulnerability to EAE. These studies highlight the plasticity of the HPA-immune axis and its pharmacological manipulation in autoimmune diseases of the CNS.
High levels of stress or stress hormones have been reported to exacerbate a variety of human disorders of the cardiovascular, gastrointestinal, immune, reproductive, and nervous systems. In rats, high glucocorticoid levels have been reported to cause neuronal death and injury as well as enhance susceptibility to neurotoxic agents and attenuate repair mechanisms; however, the impact of high dosages of CORT in mice has not been fully evaluated. We investigated the ability of supraphysiological levels of CORT to cause hippocampal neuronal death, and to modulate the neurotoxicity of kainic acid (KA) in male C57BL/6J mice. Timed-release CORT pellets (10, 35, 100 mg/21 d) were implanted subcutaneously in the back of mice, and the sustained release of glucocorticoid caused involution of the thymus and decreased the weight of the spleen. Kainic acid caused stage 1 seizures that were unaffected by CORT; however, steroid treatment decreased KA-associated mortality. Little neuronal damage was detected by the cupric-silver neurodegeneration stain. Neurotoxicity caused by an intraperitoneal injection of 25 mg/kg KA was attenuated by seven days of CORT pre-treatment. The KA-induced increase in cupric-silver staining, reactive gliosis, microglial activation, and blood–brain barrier disruption was attenuated indicating neuroprotection. Our data indicate supraphysiological levels of CORT do not cause neuronal death or injury in hippocampus of C57BL/6J mice and provide neuroprotection against KA-induced neural damage.
Transport activity of d-pipecolic acid and of l-pipecolic acid in mouse brain and peripheral tissues were tested, and the effect of immobilization stress was described, along with the method for preparative, enantiomeric resolution and purification of d,l-pipecolic acid using high performance liquid chromatography equipped with a chiral column. It was found that l-isomer, an endogenous substance, was more rapidly transported to brain and liver than the d-isomer, non-endogenous one, which was more rapidly eliminated into the kidney. Immobilization stress caused acceleration of transport of l-pipecolic acid into the brain region, liver and heart, but not that of d-pipecolic acid. From these results it was suggested that the elevation of pipecolic acid concentration caused by stress might be exerted through its stimulatory effect on the transport of l-pipecolic acid into the tissues.
Bielefeld, Univ., Diss., 2002. Computerdatei im Fernzugriff.
There is a large number of interactions at molecular and cellular levels between the nervous system and the immune system. It has been demonstrated that the opioid neuropentapeptide methionine-enkephalin (Met-Enk) is involved in humoral and cell-mediated immune reactions. Met-Enk injected peripherally produces a dual and dose-dependent immunomodulatory effect: high doses suppress, whereas low doses potentiate the immune reactivity. The present mini-review concerns the immunological activity of Met-Enk after its administration into the lateral ventricles of the rat brain, and describes the extraordinary capacity of centrally applied Met-Enk to regulate/modulate the immune function. This survey is composed of sections dealing with (a) the role of opioid peptides in the central nervous system (CNS); (b) the activity of opioid peptides in the immune system; (c) the application of Met-Enk into the cerebral cavity; (d) the influence of centrally administered Met-Enk on nonspecific local inflammatory reaction; (e) the effect of Met-Enk injected intracerebroventricularly (i.c.v.) on specific delayed hypersensitivity skin reaction, experimental allergic encephalomyelitis, anaphylactic shock, plaque-forming cell response, and hemagglutinin production; (f) the central antagonizing action of quaternary naltrexone, an opioid antagonist that does not cross the brain-blood barrier, on Met-Enk-induced immunomodulation; (g) the alteration of immune responsiveness by i.c.v. injection of enkephalinase-degrading enzymes; (h) the participation of the brain-blood/blood-brain barrier in the CNS-immune system interaction; and (i) the role of opioid receptors in immunological activity of Met-Enk. A hypothesis has been advanced for the reaction of Met-Enk and opioid receptor sitting on the cell membrane. This concept suggests that the constellation of chemical residues of enkephalin and receptor in the microenvironment determines the binding between the opioid partners. The plurality of conformational structures of enkephalins and receptors makes possible their involvement in a variety of processes which occur in different physiological systems, including the nervous system and the immune system, and intercommunications between the two systems.
Adrenal gland metabolism is markedly altered in heroin addicts. During daytime hours, the addict may suffer corticoid deficiency of the addisonian type, and in the evening, an excess of the cushingoid type. The high plasma levels of cortisol that are found in the evening in addicts antagonize endogenous opioids in a manner similar to naloxone. In the present study, 72% of the heroin addicts who sought treatment demonstrated reduced adrenal cortisol reserve. Effective immune and stress responses are dependent on adrenal cortisol reserve. This finding provides an explanation for the heroin addict's vulnerability to AIDS and other infectious diseases. One of methadone's greatest attributes is that it helps normalize adrenal metabolism. Clinical methods to at least partially correct adrenal metabolism may enhance current opioid addiction treatment modalities.
The personal and maternal characteristics of 27 babies with early‐onset germinal matrix hemorrhage (EGMH) were compared with those of 280 babies with normal cranial ultrasonograms, studied in a separate clinical trial. None of the mothers of the babies with EGMH had high blood pressure or pre‐eclampsia during pregnancy. Gestational age <30 weeks and initial pH <7·2 indicated increased risks of EGMH, and maternal receipt of steroids indicated reduced risk of EGMH. Thus prenatal and immediately perinatal factors appear to convey much of the information about the risk of EGMH.
RÉSUMÉ
Epidémiologie des hémorragies manifestes de la couche germinative durant la première demi‐journée de vie
Les caractéristiques personnelles et maternelles de 27 nourrissons présentant une hémorragie précoce de la couche germinative (EGMH) ont été comparées à celles de 280 nourrissons avec échographies craniennes normales, observés dans un service clinique séparé. Aucune des mères n'avait présenté d'hypertension artérielle ou d'éclampsie durant la grossesse. Un âge conceptuel de moins de 30 semaines et un pH initial inférieur à 7,2 traduisaient un risque accru et l'administration de corticoïdes stéroïdiens a la mère, un risque diminué d'EGMH. Ainsi, les facteurs prénataux et périnataux précoces paraissent fournir l'essentiel de l'information sur le risque d'EGMH.
ZUSAMMENFASSUNG
Die Epidemiologie von Keimschichtblutungen in den ersten Lebensstunden
Von 27 Babies mit früh auftretender Keimschichtblutung (EGMH) wurden die kindlichen und mütterlichen Befunde mit denen von 280 Babies mit normalen cranialen Ultraschallbefunden, die gesondert untersucht wurden, verglichen. Keine der Mütter hatte einen hohen Blutdruck oder eine Praeeklampsie in der Schwangerschaft. Ein Gestationsalter <30 Wochen und ein initialer pH Wert <7·2 bedeutete ein erhöhtes Risiko und eine Steroidtherapie der Mutter ein vermindertes Risiko für EGMH. So scheinen pränatale und perinatale Faktoren viel über das Risiko der EGMH auszusagen.
RESUMEN
Epidemiologie de la hemorragia de la martiz ferminal evidente durante el primer medio año de vida
Se compararon las caractersticas personales y maternas de veintisiete lactantes con hemorragia precoz de la matriz germinal (HPMG), con las de 280 lactantes con ultrasonografia craneal normal, estudiados em dos grupos clinicos separados. Ninguna de las madres habia tenido hipertensión o preeclamsia durante el embarazo. Una edad de gestacion de menos de 30 semanas y un pH inicial inferior a 7,2 indicaban un aumento de riesgo y la recepción materna de esteroides indicaba un riesgo reducido de HPMG. Asi pues, los factores prenatales e inmediatamente perinatales se muestran como indicadores de una gran parte de la información acerca del riesgo de HPMG.
Effects of adrenalectomy (ADX) on analgesic potency and morphine (MOR) content after SC administration of 3.5 or 7 mg/kg of MOR, and effects of prednisolone (PRED) on the ADX-induced effects were studied. ADX significantly potentiated MOR analgesia at both MOR doses, and PRED reversed the ADX-induced potentiation of MOR analgesia, ADX did not affect MOR content in brain and plasma after 3.5 mg/kg MOR, but significantly increased MOR content in brain and plasma after 7 mg/kg MOR, and PRED reversed the ADX-induced increase in the MOR content. Although the analgesic potency of 3.5 mg/kg MOR in ADX group was equipotent with those of 7 mg/kg MOR in sham-operated and PRED-treated ADX groups, MOR content in the former group was significantly lower than those in the latter two groups. These results suggest that ADX potentiates MOR analgesia through both mechanisms of the increased MOR content and the increased sensitivity to MOR, and that the lack of glucocorticoids participates in both of these ADX-induced effects.
The hypothesis that blood-borne beta-endorphin modulates nociception was examined with corticotropin-releasing factor (CRF) as a potent and selective agent to stimulate its release from the pituitary gland. Intravenously administered CRF produced a dose-related antinociception in rats as determined by measuring paw-lick latencies on a 50 degrees C hot plate. A dose of 25 nmol/kg of CRF was comparable in both magnitude and duration of antinociception to a 7,500 nmol/kg (= 2.5 mg/kg) dose of morphine sulfate. The antinociceptive effect of CRF was blocked by both hypophysectomy and dexamethasone pretreatment, suggesting that it was mediated by hormone release from the anterior pituitary corticotrophs. Furthermore, the effect of CRF was antagonized by 1) naltrexone, 2) naltrexone methyl bromide, and 3) passive immunization with anti-beta-endorphin antiserum. Together, these data support the hypothesis that opiate-active, beta-endorphin, released by pituitary corticotrophs, participates in the physiological modulation of nociception in rats.
Neuroendocrine regulatory processes have been intensively studied, and a considerable amount of data has accumulated on the central regulatory mechanisms involved in the control of pituitary hormone release. Special attention has been given to monoamines and peptides of central origin that act as neurotransmitters and neuromodulators, and there are several reviews summarizing the large amount of information on this important topic (1–5). Nevertheless, many results dealing with the effects of various neuroactive substances on the secretion of individual pituitary hormones are controversial and need further elucidation.
Corticosteroids reportedly decrease blood-brain barrier (BBB) permeability and/or IgG synthesis in patients with multiple sclerosis or brain tumors. However, these effects have not been studied in healthy humans. We investigated the effects of prednisone, 80 mg/day for five days, on the ratio of cerebrospinal fluid (CSF) albumin/serum albumin, a measure of blood-brain barrier (BBB) permeability, and on CSF and serum IgG levels in six healthy, normal volunteers. We found significant steroid-induced decreases in serum and CSF albumin levels and in serum IgG levels. However, we found only a nonsignificant decrease in BBB permeability and no significant change in CNS IgG synthesis. These findings, based on a small number of volunteers, suggest that it may be difficult to further decrease BBB permeability and CNS IgG synthesis in medically healthy subjects.
An early increase in ornithine decarboxylase (ODC) activity and polyamine levels in rat cerebral capillaries was previously implicated in the mediation of blood-brain barrier (BBB) breakdown in cold-injured brain. A time course study in rat cerebrum indicated that cold injury evokes a biphasic increase in ODC activity and polyamine levels in perilesional cortex. ODC activity rose sharply (fourfold) within 1 min, remained elevated for 5 min, and then returned to the basal level by 10 min. A transient rise in polyamine concentration followed in the rank order of putrescine greater than spermidine greater than spermine. A secondary rise in ODC activity commenced in perilesional tissue at 2-6 h and peaked (8.8-fold) at 48 h. Major increases in the content of putrescine (330%), spermidine (103%), and spermine (50%) developed at 48-72 h. alpha-Difluoromethylornithine (DFMO), a specific irreversible inhibitor of ODC, suppressed the evoked increase in ODC activity and abolished the associated increase in content of polyamines, findings indicating that the accumulation of polyamines in cryoinjured brain reflects enhanced synthesis resulting from an ODC-mediated increase in putrescine content. Cycloheximide and actinomycin D were without effect on the early increase in ODC activity but inhibited the delayed increase in ODC activity, an observation suggesting that the initial increase in activity reflects an activation of a cryptic ODC via a posttranslational process, whereas the delayed increase in activity results from ODC synthesis mainly under transcriptional control.(ABSTRACT TRUNCATED AT 250 WORDS)
It is known that various experimental, pathological and even physiological situations may be accompanied by transient increases in blood-brain barrier (BBB) permeability. The hypothesis that under such conditions the blood-borne substances can reach the active sites in the brain in concentrations high enough to influence central control of hormone release was verified in these studies. A suitable experimental model of BBB opening by protamine sulfate administration in conscious rats was introduced. Using this model it was shown that the dopaminergic blocker domperidone inhibited apomorphine-induced ACTH release if permeability of the BBB was increased, but not under normal conditions. It is suggested that the changes in BBB function can modify the neuroendocrine response also to other circulating substances and this may be an important, until now unconsidered phenomenon in neuroendocrine research.
This study was designed to assess effects of exercise on plasma and cerebrospinal fluid (CSF) levels of immunoreactive (ir) beta-endorphin, ACTH, cortisol, norepinephrine, and glucose in the conscious dog. Dogs were exercised on a treadmill at low or high intensity (4.2 miles/h and a 6% or 20% incline) for 90 min, and were allowed to recover for 90 additional min. Neither intensity of exercise changed plasma glucose levels, but dose-related changes in glucose kinetics did occur. CSF glucose declined in both groups. During low intensity exercise, plasma levels of ir-beta-endorphin, ACTH, and cortisol increased with duration of exercise. During high intensity exercise, ACTH, ir-beta-endorphin and cortisol increased faster, and the integrated plasma response of these hormones was greater. Thus, peripheral release of ir-beta-endorphin, ACTH, and cortisol during exercise is dose-related with respect to time and intensity. CSF ir-beta-endorphin and ACTH both increased during low- but not high-intensity exercise. CSF cortisol rose markedly in both exercise groups. During high-intensity exercise there was a 50% increase in CSF norepinephrine, indicating that exercise induces alterations in central noradrenergic turnover. We conclude that exercise is a physiologic regulator of both peripheral and central neuroendocrine systems.
The unit impulse response theory has been adapted to characterize the transport profile of drugs into the central nervous system (CNS). From the obtained input function, the cumulative plasma volume (V) cleared by transport into the CNS in time can be calculated. Simulation studies demonstrated that transport governed by passive diffusion resulted in a linear relationship between V and time, while the slope of the line, the blood-brain barrier (BBB) clearance, proved to be an adequate and model independent parameter to characterize drug transport into the CNS. The error in the result of the numerical procedure could be limited to less than 10% of the theoretically predicted value. Superposition of 5 or 10% random noise on simulated data did not result in significant differences between the calculated and theoretically predicted clearance values. Simulations of carrier-mediated transport resulted in nonlinear transport curves; the degree of nonlinearity, and thus the detectability, was dependent on the initial degree of saturation of the system, the rate of desaturation, as caused by drug elimination processes and the noise level on the data. In vivo experiments in the rat were performed, using atenolol, acetaminophen, and antipyrine as model drugs. Linear transport relationships were obtained for all drugs, indicating that transport was dependent on passive diffusion or a low affinity carrier system. BBB-clearance values were 7 +/- 1 microliters/min for atenolol, 63 +/- 7 microliters/min for acetaminophen and 316 +/- 25 microliters/min for antipyrine. These experiments validate the applicability of the presented technique in in vivo studies.
Horseradish peroxidase was administered to mice by intravenous injection, and its distribution in cerebral cortex studied with a recently available technique for localizing peroxidase with the electron microscope. Brains were fixed by either immersion or vascular perfusion 10-60 min after administration of various doses of peroxidase. Exogenous peroxidase was localized in the lumina of blood vessels and in some micropinocytotic vesicles within endothelial cells; none was found beyond the vascular endothelium. Micropinocytotic vesicles were few in number and did not appear to transport peroxidase while tight junctions between endothelial cells were probably responsible for preventing its intercellular passage. Our findings therefore localize, at a fine structural level, a "barrier" to the passage of peroxidase at the endothelium of vessels in the cerebral cortex. The significance of these findings is discussed, particularly with reference to a recent study in which similar techniques were applied to capillaries in heart and skeletal muscle.
The effect of adrenal cortical steroids and osmotic blood-brain barrier modification on methotrexate delivery to normal and glioma-bearing rats was studied. In animals with the avian sarcoma virus-induced glioma, osmotic blood-brain barrier modification resulted in significantly increased delivery of methotrexate to the tumor-bearing hemisphere (including the tumor, the brain around the tumor, and the brain distant to the tumor), compared to the nonmodified hemisphere or to control animals. The administration of adrenal steroids, followed by intracarotid methotrexate, resulted in slightly decreased chemotherapeutic agent (methotrexate) delivery to the tumor, the brain around the tumor, and the brain distant to the tumor. When adrenal steroids were given prior to barrier modification and methotrexate therapy, the level of methotrexate was significantly less in the tumor. These studies provide evidence that the blood-brain barrier exists in tumors and is a factor in drug delivery to tumors. Steroid administration greatly interferes with the enhancement of drug delivery to tumors that can be achieved with osmotic blood-brain barrier modification.
Peculiar to most of the central nervous system is the phenomenon of the blood-brain barrier. In this article Michael Bradbury considers why such a barrier should have developed during evolution, and its value in homeostatic maintenance of the neuronal environment.
Amphetamine administration to rats anaesthetized with nitrous oxide resulted in protein extravasation in the brain, particularly in the frontoparietal cortex. The drug is known to increase the cerebral blood flow in the same areas, indicating a vasodilatory action on the cerebral vessels. Protein leakage could be prevented by lowering the blood pressure and, to a large extent, also by hyperventilation. This suggests that the permeability disturbance is caused by the mechanical stress which results from high intraluminal pressure in combination with vasodilatation.
The pharmacological effect of amphetamine is caused by a catecholamine release in the central nervous system and in the periphery. The vasodilatory effect of amphetamine could be either a direct effect on the cerebral vessels or could be secondary to an increased cerebral metabolism. The vasodilatory betaadrenergic receptors in the cerebral vessels are of beta1 type. Practolol, a selective beta1-receptor antagonist which can prevent the vasodilatory effect of isoprenaline on cerebral vessels, did not influence the amphetamine induced protein leakage. In contrast, propranolol, a non-selective beta-receptor blocking drug which earlier has been shown to prevent catecholamine induced increase of CBF and oxygen consumption, diminished or prevented the protein leakage. It is likely that the cerebral vasodilatation caused by amphetamine, at least in part, is secondary to an increased cerebral metabolism induced by a catecholamine release.
The possible effects of dibutyryl cyclic GMP (db-cGMP), the lipid-soluble derivative of cyclic GMP, on brain microvessels were studied by light microscopic detection of albumin and quantitative electron microscopy. Different concentrations (25, 50, 100 and 200 μg) of db-cGMP were given to adult rats by intracarotid infusion, while in the controls, the animals were infused either with Krebs-Ringer solution or with the same solution containing butyrate or cyclic GMP. In contrast to the controls, db-cGMP was found to be able to increase the permeability of brain microvessels to albumin in a dose-dependent manner. At the same time, the number of transport vesicles being indicative of the pinocytotic activity of the endothelial cells was also increased. These results indicate that, similarly to the cyclic AMP whose effects have been revealed earlier, the cyclic GMP-system may also be involved in the regulation of opening mechanisms of the blood-brain barrier.
The blood-brain barrier to the protein horseradish peroxidase (HRP, tool. wt. 40 000) is the consequence of both an obstruction to passive extracellular movement and the absence of an active transcellular migration. Although the endothelium of some cerebral arterioles can transfer protein from blood to perivascular basement membrane by means of vesicles, the endothelium of cerebral capillaries cannot. The barrier may be passed when the junctions between endothelial cells become patent as in some brain tumors and in vitally- induced choroid plexus papillomas. The vessels in the latter tumors also have fenestrae and numerous endothelial pits and vesicles, features that may also account for the increased permeability of the tumor vessels.
The barrier is also opened by infusing hyperosmotic non-electrolytes into the internal carotid artery. Within 60 sec after the infusion of 1.4 M-arabinose into one carotid artery of adult rats that had received HRP intravenously, the vessels on the infused side of the brain extravasate peroxidase. The escape of HRP is probably through junctions or actively formed channels and not by means of vesicular transport. When hyperosmotic arabinose is injected first, the brain fixed and then, 1 hr after fixation, HRP is infused into the aorta, perivascular exudates appear primarily on the saccharide-infused side of the brain. Since vesicular transfer requires energy and is halted by chemical fixation, the protein must have crossed the endothelium through pre-existing channels. Comparable to the effects of hyperosmotic urea on the vessels of the rabbit brain, only a few endothelial junctions were obviously patent. It is likely, therefore, that most of the passage is by way of channels formed, perhaps, by confluent vesicles. The channels, once formed, do not close im- mediately but remain patent long enough to be fixed in the open position.
Neurons deep within the brain stem are inaccessible to protein circulating within capillaries immediately adjacent to them. The same neurons, however, can pinocytose HRP at their axon terminals which innervate peripheral organs such as muscle and mucous membrane. The blood vessels of these tissues are permeable to protein which, upon crossing the vessels, are incorporated by the axon terminals and transported within the axons back to lysosomes within the neuronal soma. In this way, large molecules circulating in the systemic blood may enter certain neurons even though the same molecules are barred from crossing the cerebral capillaries supplying these neurons.
In contrast to hydrophilic molecules, there is no appreciable restriction to the passage of lipids from blood to brain. Fatty acids (FA) injected into blood are directly incorporated into cerebral lipids. When large concentrations of the polyunsaturated FA linolenic acid, wbich is strongly osmiophilic, is infused into one carotid artery, the soap droplets formed fuse with endothelial cell membranes. The osmiophilic droplets enter the endothelium and penetrate cytomembranes as well as cell membranes except, perhaps, for the inner nuclear membrane; droplets readily enter the perinuclear cistern but are never found within the nucleus of any cell, be it endothelial, smooth muscle, epithelial or neuronal. Some of the FA enters endothelial pits and vesicles and may represent that fraction of the FA which normally circulates as a complex with serum albumin. Mitochondria are infiltrated by droplets as are synaptic vesicles and axoplasm of perivascular and intracerebral neurons.
A human choriocarcinoma was successfully adapted to grow in the brain of monkeys (Macaca mulatta), thus providing a model of tumor-induced brain edema. Four animals were given dexamethasone (3 mg/kg/day) during 3 to 5 days after the onset of clinical signs, and the other five received no treatment for the same period. Tissue water and electrolyte content of treated and untreated animals were compared in cortex and white matter at various distances from the edge of the tumor. In untreated animals, 67.9% and 23.6% swelling was detected in adjacent and remote white matter, respectively, but only 11.8% swelling was noted in adjacent cortex. In animals treated with dexamethasone these percentages of swelling were improved to 32.4% and 11.9% in the corresponding white matter, and to 4.9% in adjacent cortex. The electrolyte changes shown in edematous brain of control animals also demonstrated significant improvement in the dexamethasone-treated group. Tissue radioactivity of 3H-dexamethasone at 60 minutes after intravenous injection was high in the periphery of tumor, adjacent cortex, and white matter, but low in the center of tumor, remote cortex, and white matter. The sites with high concentrations of dexamethasone also showed significant improvement of brain edema after dexamethasone treatment, suggesting that dexamethasone may act directly at these loci.
The endothelial and periendothelial parts of the blood-brain barrier in the rat have been studied by electron microscopy. Extravasation of horseradish peroxidase (HRP) occurred after Aramine-induced acute hypertension. It was exclusively due to a local vesicular transport. This was most prominent in arterioles, but also occurred in segments of capillaries and venules. The tight junctions between adjacent endothelial cells were never penetrated by HRP. Following extravasation, HRP reached the endothelial basement membrane, from where it often spread into the extracellular space of the neuropil. A phagocytic pericyte was observed, exhibiting a well-developed vacuolar apparatus and a pronounced uptake of HRP. It is suggested that the phagocytic pericytes in the rat brain represent “microglial” cells, and that they play an important role in the periendothelial part of the blood-brain barrier.
A previous study showed intracisternal injection of melanotropic peptides caused a 3-5 times increase in concentration of protein in cerebrospinal fluid (CSF) within 15 min. This finding suggested that the peptides modify permeability of the plasma/CSF barrier. The present study examined the effect of four melanotropic peptides (adrenocorticotropin (ACTH), α- and β-melanocyte-stimulating hormones (MSH), and choroid plexus peptide IIF) ('agonists') on permeability of the plasma/CSF barrier to a series of radioactive substances, which are transported across this barrier by diverse mechanisms: albumin, mannitol, sucrose, insulin, glucose, α-aminoisobutyric acid, and valine ('circulants'). In anesthetized rabbits, 6-10 μCi of circulant was injected intravenously and 1-1,000 μg of agonist intracisternally. At 15-min intervals during the next 75 min, radioactivity in CSF and in plasma was measured. Intracisternal injection of 1,000 μg of the melanotropic peptides did not influence the rate of removal of any circulant from the plasma. In contrast, injection of the peptides increased the rate of appearance of albumin, mannitol, inulin, and sucrose in the CSF 2-4 times over control. The effects was proportional to dose. Minimal effective dose (MED) was generally 1 μg for α-MSH and β-MSH, 10 μg for ACTH, and 100 μg for IIF. Trypsinized peptides were inactive. MED was 100 times higher by the intravenous route. The melanotropic peptides did not accelerate appearance of radioactivity in CSF after injection of labeled glucose, α-aminoisobutyric acid, or valine. Intracisternally injected arginine vasopressin (100μg), norepinephrine (100 μg), histamine (100 μg), and serotonin (100 μg) had no effect on rate of entry of any circulant from plasma to CSF.
This review paper deals with the transport of the protein tracer horseradish peroxidase across cerebral vessels under normal and various experimental conditions.
Electronmicroscopical investigations have revealed that, under normal conditions, a minor vesicular transfer of intravenously injected peroxidase occurs across the endothelium in segments of arterioles, capillaries and venules, especially in arterioles with a diameter about 15–30 μ. This normally occurring vesicular transport is susceptible to various experimental conditions. Thus the transfer of tracer increases when a hypertonic solution is injected into the internal carotid artery presumably due to vesicular transport.
Extensive acute hypertension of short duration also increases the vesicular transfer of peroxidase from blood to brain. Identical observations are obtained when the hypertension is evoked by intravenous injection of phentolamine and by electrically induced seizures.
During the postischemic period, one hour after release of the occlusion of an internal carotid artery in the Mongolian gerbil the vesicular transport of peroxidase is increased across the endothelium of cerebral vessels. The explanation may be release of serotonin from blood platelets during the occlusion. The serotonin could then increase the blood pressure locally in the brain resulting in an enhanced permeability.
Serotonin, after perfusion through the cerebral ventricular system, is also able to increase the normally occurring vesicular transfer. The most likely mechanism behind this phenomenon seems at the moment to be local hypertension evoked by serotonin-induced vasoconstriction of arterioles.
Finally, the enhanced vesicular transport across cerebral endothelium caused by porto-caval anastomosis is mentioned and the possible role of disturbances in the metabolism of amines as responsible for the extravasation is discussed.
IT is known that the cardiovascular system is extremely sensitive to the effects of both exogenous1,2 and endogenous3 opiates. In rats, less than 1% of the morphine dose necessary to produce antinociception results in significant hypotension and brady-cardia4. The endogenous opiate beta-endorphin is stored along with pituitary adrenocorticotrophin (ACTH)5,6, and the action of stressors seems to result in the release of both peptides5,6. Therefore, it seemed likely that beta-endorphin is released during shock states and that it might contribute to the hypotension. To test this hypothesis we used an endotoxin shock model7,8. If endotoxin-induced hypotension were mediated through endorphin release, then blockade of endorphins should reverse such hypotension. Using the specific opiate antagonist, naloxone, we not only rapidly reversed endotoxin-induced hypotension, but also prophylactically blocked its occurrence. These findings suggest that endorphins may have a role in the patho-physiology of shock and that narcotic antagonists should be evaluated for their potential therapeutic value in the treatment of shock.
Sixty-eight Arab patients suffering from psychogenic sexual inadequacy were compared with 54 non-psychiatric patients. The patients showed a greater preponderance of negative feelings towards their fathers and the opposite towards their mothers. Parental loss and disharmony were not significant contributory factors. More control subjects slept alone between the ages of 7 and 12 years. More patients slept with their brothers and sisters during the same interval. The rank distribution showed that the eldest first males figured prominently among the patients.
The sexually inadequate patients showed a higher incidence of neurotic symptoms during childhood. A positive family history of mental illness did not differentiate patients from control subjects. The relevance of these findings in relation to cultural factors is discussed.
A simple double‐isotope assay for phospholipase A 2 activity of perfused organs is described.
Guinea‐pig lungs perfused through the pulmonary circulation exhibit a low background enzyme activity. This activity is blocked by dexamethasone, betamethasone and hydrocortisone, mepacrine, procaine or chlorpromazine. Aspirin and indomethacin are without effect.
Mechanical trauma, antigen challenge or injections of bradykinin, rabbit aorta contracting substance‐releasing factor (RCS‐RF) or histamine increase ‘basal’ phospholipase activity. The effect of these agents, except that of bradykinin, is blocked by dexamethasone or mepacrine.
The blocking effect of steroids is cumulative and dose‐dependent. They do not work in cell‐free systems. Inhibition by mepacrine is rapid and is effective in cell‐free lung homogenates.
It is suggested that agents which liberate prostaglandin endoperoxides and thromboxane A 2 from perfused lungs do so by activating phospholipase A 2 .
Under normal conditions a slight vesicular transfer of intravenously injected horseradish peroxidase (HRP) occurs across the endothelium of cerebral vessels, especially short segments of arterioles. The vesicular transport can be notably increased by chemically induced acute hypertension. In the present investigation 4 groups of animals received HRP, and the permeability of the cerebral endothelium was studied semimacroscopically, light microscopically and electron microscopically. The rats in group 1 were given 10 electroshocks. This caused a significant rise in the blood pressure (BP). Furthermore, a noticeable extravasation of HRP was observed, especially across the endothelium in cerebral arterioles. From the basement membranes of the vessels reaction product could be followed into the extracellular spaces of the neighbouring neuropil. Group 2 comprises rats that were given 10 electroshocks preceded by transection of the cervical part of the spinal cord. The BP remained at normal level and the permeability was unaltered. The animals in group 3 received only 1 electroshock. Usually, the BP was markedly increased and this was accompanied by enhanced permeability across the vessels of the brain. Group 4 consists of control animals, injected with HRP and treated as groups 1 and 3 with the difference that electrical stimulation was not performed. A general feature was that no endothelial damage was observed and that reaction product was not found between neighbouring endothelial cells from the first luminal to the first abluminal tight junction. Based on the observations it seems reasonable to assume that the increased permeability of tracer that occurs after 10 electroshocks or only one is caused by the acute hypertension evoked by the electrical stimulation; furthermore, the transfer is concluded to be vesicular transport.
A chronic, indwelling, tail arterial cannula was implated in conscious undisturbed rats for measurement of blood pressure and heart rate and for obtaining blood samples. As an index of sympathetic activity, plasma levels of catecholamines in arterial blood of conscious animals were assayed by a radioenzymatic, paper-chromatographic procedure. Blood pressures of unrestrained spontaneously hypertensive (SHR) rats in their home cages (161 +/- 3/141 +/- 4 mmHg) were not different from those of pentobarbitol-anesthetized, hypertensive animals but were about 25 mmHg lower than awake animals during the restraint required for the tail-cuff procedure. Basal levels of plasma catecholamines in awake, undisturbed or in pentobarbital-anesthetized animals were similar in age-matched SHR and normotensive Wistar-Kyoto (WKY) rats. SHR rats were shown to have greater increase in plasma catecholamines than WKY rats during forced immobilization or restraint for indirect measurement of blood pressure.
Anatomical studies employing the immunofluorescence localization of dopamine-beta-hydroxylase [= dopamine beta-monooxygenase; 3,4-dihydroxyphenylethylamine, ascorbate:oxygen oxidoreductase (beta-hydroxylating); EC 1.14.17.1] have demonstrated in brain central noradrenergic nerve fibers on small intraparenchymal blood vessels, including capillaries. This system is distinct from the peripheral noradrenergic system inervating the large extraparenchymal blood vessels. From these anatomical findings evolved the working hypothesis that the central noradrenergic system is analogous to the peripheral sympathetic system except that it is specialized for performing specific functions related to the brain microvasculature. To test this hypothesis cerebral blood flow and the brain vascular permeability of water (H215O) were measured in four adult rhesus monkeys (three with bilateral superior cervical ganglionectomies) with stereotaxically placed cannulae permanently located in the lateral ventricles and the locus coeruleus for the injection of drugs. Our data demonstrate that stimulation of the noradrenergic cell bodies in the locus coeruleus with carbachol (8 mug) produces a prompt reduction in hemispheric cerebral blood flow and an increase in brain vascular permeability of water. The intraventricular administration of the alpha-adrenergic blocker phentolamine (25--50 mug) has the opposite effect. These preliminary data support the hypothesis that the central noradrenergic system is analogous to the peripheral sympathetic system with the special function of regulating brain vascular permeability as well as blood flow.
Acute hypertension in rats was produced by intravenous infusion of metaraminol bitartrate (Aramine). The permeability to intravenously injected horseradish peroxidase (HRP) was increased across the cerebral arterioles, capillaries and venules. From the basement membranes of the vessel walls the protein tracer moved into the extracellular spaces of the adjacent neuropil. No endothelial cell damage was observed. The tight junctions between endothelial cells were intact and prevented intercellular movement of peroxidase. Many HRP-labeled vesicles within the endothelial cells or connected with the luminal or abluminal surface, occurred in segments of the microvasculature. Otherwise the endothelium was unchanged. Diffuse uptake of HRP into the cytoplasm of neurons and glial cells was not observed. The alphablocker phentolamine (Regitin) was given to a group of rats simultaneously to Aramine. The increase in blood pressure was thus prevented; furthermore, the permeability remained as under normal conditions. The Aramine, Regitin and HRP did not significantly influence the pH,pO2 andpCO2 of the arterial blood.
It is concluded that acute hypertension increases the vesicular transport of HRP across the endothelium of cerebral arterioles, venules and capillaries that normally occurs to a small extent only after intravenous injection of the tracer.
During experimental seizures, the blood-brain barrier (BBB) is broken; tracer substances such as I131-albumin, Evans blue and horseradish peroxidase (HRP) geographically locate the barrier breakdown primarily in the diencephalon. Using rats, we have induced seizures with electroshocks and demonstrated the breakdown of the BBB with Evans blue and HRP. We have shown that (1) the BBB breakdown is proportional to the number of electroconvulsant shocks (ES) given; (2) the mechanism of increased barrier permeability is primarily by micropinocytosis in the cerebral capillaries, arterioles, and, to a lesser extent, venules; and (3) the stimulus for micropinocytosis and hence BBB breakdown is associated with the abrupt rise in systemic blood pressure and cerebral vasodilatation that accompanies each ES. If the systolic hypertension is abolished via cervical cordotomy, there is little to no breakdown in the BBB.
Fluorescence-and electron-microscopic studies were performed on nerve terminals close to intracerebral blood vessels in the rat. For the electron microscope subdural perfusion fixation with potassium permanganate was used. In the rat cerebral cortex deprived of the bilateral superior cervical ganglion some aminergic terminal boutons containing large and small core vesicles were observed contiguous to blood vessels. These terminals abutted on the capillary basement membrane. Since these terminals are found in the rat after bilateral superior cervical ganglion exision, they probably originate from central catecholaminergic neurons in the brain stem. These findings suggest that central aminergic neurons might play some role in cerebral blood flow regulation. In addition to aminergic terminal boutons, non-aminergic nerve terminals containing non-core vesicles also ended in the capillaries. Cerebral capillaries also have central dual innervation, aminergic and cholinergic, and dual peripheral innervation by sympathetic and parasympathetic fibers.
Zusammenfassung Die Anzahl der pinocytotischen und stachligen Vesicula wurde unter normalen Bedingungen mit Bezug auf einheitliche Gebiete der pinocytotischen Aktivität der Kapillaren von Mäusegehirnen quantitativ charakterisiert. Die Pinocytose der Gehirnkapillaren war durch das substitutielle cyclische N6O2-Dibutyrylderivat des 3′,5′-Adenosinmonophosphats signifikant gesteigert.
Dexamethasone was administered to mice bearing intracerebral ependymoblastomas. Maximum increased survival of 24% over nontreated animals required a dose of 40 mg/kg daily beginning the day following tumor implantation. Water and sodium content of brain adjacent to and distant from the tumors were also reduced by lesser doses of dexamethasone. The tumors in the treated mice were substantially smaller than those in nontreated controls, and the drug retarded the incorporation of 3H thymidine into tumor DNA. The mechanisms by which corticosteroid hormones reduce edema surrounding brain tumors and inhibit tumor growth remain unknown.
SEVERAL studies have demonstrated the ability of experimentally induced seizures to increase the penetration of a variety of blood borne solutes into brain.1-5 In general, this increase has been attributed to an alteration in the permeability of the blood-brain barrier, as indicated by the increased passage of albumin from blood to central nervous system (CNS).2,3,6 Under normal conditions, little, if any, blood protein gains access to the CNS.7 A recent report from this laboratory has shown that the increase in brain permeability to albumin labeled with iodine 131, associated with prolonged pentylentetrazol seizures, was predominantly restricted to the thalamus, reversible within minutes after arrest of the seizure, and accompanied by an appreciable increase in the total water content of the thalamus.8 These features provided a useful model to assess the effectiveness of glucosteroids on altered brain permeability, since the alteration (1) has a specific localization
ALTHOUGH clinically the beneficial effect of steroid therapy in patients with cerebral edema is well established,1,2 only recently has experimental evidence indicated that dexamethasone treatment may diminish cerebral edema associated with traumatic lesions. Poor parameters for assessing the extent of edema, insufficient experimental time interval, and lack of control regarding the biological activity of the drugs in the species used are some of the reasons why the studies reported to date have been contradictory or inconclusive.³⁻¹¹ Thus, previously we could not demonstrate any effect of cortisone on water and electrolyte content of edematous cerebral tissues of the cat.³ These earlier experiments, however, did not rule out the possibility that the volume of the tissue which became edematous was diminished in treated animals nor was there any assurance that the cat responds to cortisone in the same way as the human.
The present study was designed
Muscarinic cholinergic receptor sites were detected with [3H]quinuclidinylbenzilate (QNB) binding techniques in two fractions of bovine intracerebral vessels; one of the fractions contained primarily small arteries and veins with some attached capillaries, and the other one was highly enriched in capillaries. The amounts of binding were similar in equivalent vascular fractions isolated from cerebral cortex, caudate nucleus and cerebellar cortex in spite of large differences among the 3 regions in [3H]QNB binding to brain tissue. The different distribution of muscarinic receptors in brain tissue and blood vessels argues against the possibility that the receptors represent a contamination of the vascular fractions by brain parenchyma. Cerebral endothelial cells, which were isolated by treating capillaries with collagenase, bound [3H]QNB to the same extent as did cerebral capillaries. This is consistent with an endothelial localization of capillary muscarinic receptors. Choline acetyltransferase (ChAT) activity, a marker for cholinergic neurons, also was present in the vascular preparations. Within each brain region, ChAT activities in capillaries and larger vessels were similar, but significant regional differences were found for vascular ChAT activity, with the highest values in the caudate. Isolated endothelial cells contained significantly lower levels of ChAT activity than intact capillaries, suggesting a periendothelial location of the enzyme, as would also be the case for attached nerve terminals. The presence of [3H]QNB binding sites and ChAT activity in intracerebral blood vessels is consistent with an innervation of the cerebral vasculature by a cholinergic system that may regulate cerebral blood flow and capillary permeability.
The neuroendocrine and neurochemical responses of rats to 5 min of cold exposure versus 5 min of forced immobilization were determined and compared. We found that plasma hormones and brain neurochemical systems responded differently to the two different stressors. Plasma prolactin levels were elevated over 10-fold in the immolilized group, while rising only 2-fold in the cold stress group. Levels of corticosterone were significantly increased and growth hormone levels were decreased in both stressed groups as compared to controls. Levels of cyclic GMP were markedly elevated in 11 brain regions following cold exposure. Surprisingly, no elevation of cyclic GMP was found after forced immobilization. Cyclic AMP, norepinephrine, and dopamine levels throughout the 17 regions of brain examined showed no significant response to 5 min of either stressor. Lesions of the ventral medial tegmental area did not affect the cyclic GMP or neuroendocrine responses to cold stress. Lesion of the nucleus locus ceruleus did not affect the cyclic GMP response but significantly reduced growth hormone levels in the cold-stressed rats.
The endothelium of the cerebral microvasculature is, under normal conditions, tight to proteins and peptides, or conceivably, a very limited blood-to-brain (and brain-to-blood) transport by means of endothelial vesicles takes place in segments of the microvasculature. This barrier to lipid-insoluble macromolecules can be ascribed to the tight junctions among the endothelial cells. Uncertainties exist, however, with respect to the permeability properties of the cerebral endothelial junctions to ions and small lipid-insoluble molecules. Many experimental or pathological situations, for example, acute hypertension, cause an opening of the blood–brain barrier. One possible pathway across the cerebral endothelium for larger hydrophilic molecules appears to be vesicular transport comparable with that occurring in normal noncerebral tissue. This may be indicative of the presence of a labile pore system in the cerebral microvasculature, which can be reversibly opened, but normally is closed. Transendothelial channels may also be responsible for the extravasation. Additionally, intravenous administration of hypertonic solutions and long-term hypertension cause an opening of the tight junctions between the endothelial cells.
Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats were given saline, histamine (1.25, 2.5 or 5.0 micrograms/kg) or acetylcholine (1.0 or 2.0 micrograms/kg). Both agents caused a dose-dependent decrease in blood pressure which was greater in the spontaneously hypertensive animals. The permeability of the blood brain-barrier was measured with 131I-labelled serum albumin (RISA) or with 99mTc-sodium pertechnetate (TcO4-). The lowest dose of histamine caused a decrease in permeability of the blood-brain barrier to serum albumin in normotensive rats and acetylcholine caused an increase. Only the largest dose of histamine increased the permeability of the blood-brain barrier to serum albumin in spontaneously hypertensive rats. All doses of histamine and acetylcholine increased the permeability of the blood-brain barrier to sodium per technetate in nomotensive rats and the two lower doses of histamine increased the permeability in spontaneously hypertensive animals. This provides another example of the dissociation of change in the systemic blood pressure and change in the permeability of the blood-brain barrier.
Evidence from anatomic and physiologic studies has led to the development of a central adrenergic neurohumoral hypothesis. This hypothesis proposes that the central adrenergic system is part of an intra-axial autonomic system distinct from the peripheral sympathetic system, but having analogous functions. One specific function predicted by this concept is modulation of cerebral microvascular permeability and flow.
One of the early observations made using dopamine-β-hydroxylase (DBH) immunohistochemistry was a close association of centrally derived varicose adrenergic nerve fibers with small blood vessels, deep within the brain parenchyma (1,2). The central origin of these DBH-positive fibers was established by demonstrating their persistence after bilateral superior cervical ganglionectomy (3). On the basis of this anatomic association, it was hypothesized that one function of the central adrenergic system was regulation of the cerebral microvasculature (1–3). This association of central DBH-containing fibers with small blood vessels, including capillaries, was first demonstrated in rat brain, but subsequently has been demonstrated in the brain of superior cervical ganglionectomized monkeys (4) and human brain (3). A similar association had been observed using catecholamine histofluorescence (5) and a central origin also confirmed in ganglionectomized animals. The central innervation hypothesis has, however, been questioned because of a lack of physiologic and electron microscopic evidence (6).
We examined the effects of dexamethasone administration and withdrawal on regional cerebral blood flow (CBF) and the permeability surface area (PS) product for water in the central nervous system of conscious rats. There were no significant changes in CBF. Dexamethasone treatment produced a significant decrease in the PS product for water in the cerebral cortex, while withdrawal of dexamethasone resulted in a significant increase. Water content of the cerebral cortex was also increased in rats from which dexamethasone had been withdrawn. These findings may help in understanding the pathogenesis of brain swelling in some patients.
Brain edema accompanies a wide variety of pathologic processes and contributes to the morbidity and mortality of many neurologic diseases. It has a major role in head injury, ischemic and hemorrhagic stroke, and brain tumor. Edema also accompanies cerebral infections, including brain abscess, encephalitis and meningitis, lead encephalopathy, liver failure, hypoxia, hypo-osmolality, the disequilibrium syndromes associated with dialysis and diabetic ketoacidosis, demyelinating diseases, and the various forms of obstructive hydrocephalus. The clinical assessment of brain edema has been greatly facilitated by computed tomography, which allows visualization of the extent of edema with an accuracy not previously possible. Laboratory studies of . . .
The effects of amitriptyline, lithium, and electroconvulsive shock on cerebral permeability and blood flow were tested. These
three treatments share in common (i) the ability to influence the functional activity of central adrenergic neurons by way
of effects on the release, reuptake, or metabolism of norepinephrine and (ii) therapeutic efficacy in mood disturbances. Under
control conditions, cerebral permeability increases linealy with increasing arterial partial pressure of carbon dioxide and
hence cerebral blood flow. All three treatments altered this relationship in a manner consistent with their adrenergic effects.
Amitriptyline potentiated this increase in cerebral permeability whereas lithium and electroconvulsive shock blunted this
phenomenon. These results support the hypothesis that one function of central adrenergic neurons is regulation of the blood-brain
barrier and raise the possibility that a related effect may underlie the clinical usefulness of such treatment.
RECENT procedures for the immunological assay of protein hormones in human plasma1-3 require the routine preparation of hormones labelled with iodine-131 of high specific activity.
Ion Homeostasis of the Brain
- C Crone
- S Nag
- Quantitative Estimate
- Pinocytosis
- Experimental
- Hypertension
Frontiers of Catecholamine Research
- B K Hartman
Blood-Brain Barrier in
- S I Rapoport
Neuroregulation of Autonomic Endocrine and Immune Systems
- D J Reis