Biomedical subjects

W A Banks

Publications and source records attributed to W A Banks.

At least 55 records · Page 3Linked to original sources

PubMed1999

The effect of cardiac arrest on the permeability of the mouse blood-brain and blood-spinal cord barrier to pituitary adenylate cyclase activating polypeptide (PACAP).

Time-dependent changes in peptide transport system (PTS-6), which transports the 38 amino acid pituitary adenylate cyclase activating polypeptide (PACAP) across the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), were studied in mice in a cardiac arrest model. The permeability of the BSCB to radioactivity labeled I131 showed a reversible increase on Day 2-(24 h) after cardiac arrest. The BBB showed no such increase. The increase in BSCB permeability was primarily located within the thoracic region of the spinal cord. We conclude that the ischemia occurring with cardiac arrest results in a transient increase in PTS-6 activity located primarily in the thoracic region of the spinal cord.

Animals↗

PubMed1999

Passage of leptin across the blood-testis barrier.

Leptin is a 17-kDa protein, secreted by fat, that controls adiposity and has been proposed to have numerous effects on reproduction in the mouse. To assess whether the effects of leptin on testicular function are direct, we determined whether leptin can cross the murine blood-testis barrier. Multiple time regression analysis showed that a small amount of blood-borne leptin is able to enter the testis but does so by a nonsaturable process. In addition, no significant expression of leptin receptors was found at the Leydig cells or Sertoli cells of the testis. This compares with the presence of a saturable transport system for leptin at the blood-brain barrier and abundant receptors for leptin at the leptomeninges, neurons, and choroid plexus of the central nervous system (CNS). These results support the hypothesis that the effects of leptin on reproductive function are not mediated at the level of the testis but indirectly, probably through the CNS.

Animals↗

PubMed1999

Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice.

We have investigated a potential role for tumor necrosis factor (TNF)-alpha and its two receptors (p55 and p75) in lung injury. We used several varieties of mice exposed endotracheally to two fibrogenic agents, silica (0.2 g/kg) and bleomycin (4 U/kg). The lungs were analyzed at 14 and 28 d after exposure to bleomycin or silica, respectively, for TNF and TNF receptor (TNFR) messenger RNA (mRNA), hydroxyproline content, and histopathology. Silica induced increased (over saline-treated animals) expression of TNF mRNA in double TNFR knockout (Ko), C57BL/6, BALB/c, and 129/J mice. In contrast, bleomycin increased expression in all but BALB/c mice, which are resistant to the fibrogenic effects of this drug. mRNA expression of both receptors was constitutively expressed in all of the normal murine strains. Silica upregulated expression of the p75 receptor, but not the p55 receptor, in the C57BL/6, BALB/c, and 129/J mice. In comparison, bleomycin had little effect on either receptor in the bleomycin-resistant BALB/c mice. Hydroxyproline content of the lungs after treatment followed this same pattern, with significant increases caused by silica in the C57BL/6, BALB/c, and 129/J mice, whereas bleomycin caused no apparent increases in the BALB/c mice. Even though silica and bleomycin induced increases in TNF in the TNFR Ko mice, the mice were protected from the fibrogenic effects of these agents. This study supports the concept that TNF is a central mediator of interstitial pulmonary fibrosis.

Animals↗

PubMed1999

Physiology and pathology of the blood-brain barrier: implications for microbial pathogenesis, drug delivery and neurodegenerative disorders.

The blood-brain barrier (BBB) regulates the passage of solutes between the CNS and the blood. The BBB not only restricts the entry of serum proteins into the CNS, but it also controls the passage of nutrients, electrolytes, vitamins, minerals, free fatty acids, peptides, and regulatory proteins in both the brain to blood and blood to brain direction. The BBB performs these functions through a number of saturable and non-saturable mechanisms. For example, efflux (CNS to blood) mechanisms regulate the levels of nutrients and minerals in the CSF, detoxify the CNS, reinforce the impermeability of the BBB against circulating toxins and many drugs, secrete CNS-originating substances into the blood, and drain substances directly into the cervical lymphatic nodes. Influx mechanisms control the homeostatic environment of the CNS, supply the brain with nutrients, and help to integrate CNS and peripheral functions. These mechanisms are altered in and can be the basis for disease and many of these systems are altered in neuroAIDS. We review here examples of several diseases in which the functions of the BBB are altered, and some conditions, such as alcoholism, multiple sclerosis, obesity, and a subtype of mental retardation, where those altered functions may underlie the pathophysiology. Finally, we consider some of the ways in which these aspects of the BBB could be active in neuroAIDS, including the efflux of anti-virals, the transport of virus by adsorptive endocytosis, egress routes for HIV-1 via brain lymphatics, and the release of neurotoxins from brain endothelial cells.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Differences in cadmium transport to the testis, epididymis, and brain in cadmium-sensitive and -resistant murine strains 129/J and A/J.

Although most animals with scrotal testes are susceptible to cadmium-induced testicular toxicity, strain-related differences are seen in mice. Resistant murine strains demonstrate a decreased cadmium concentration in the testis and also in the epididymis and seminal vesicle. In this study we analyzed cadmium transport into tissues with a vascular barrier, the testis, epididymis, and brain, in an attempt to characterize the mechanisms of strain resistance to cadmium-induced testicular toxicity. In the resistant murine strain A/J, 109Cd transport (administered as 109CdCl2) was significantly attenuated in the testis, epididymis, and brain, when compared to the sensitive murine strain 129/J. The unidirectional influx constant (Ki, in microliter g-1 min-1) for 109Cd was 0.01929 in the A/J testis as compared with 1.174 in the 129/J testis (P <.0001). The percentage of a 109Cd dose that reached the A/J testis by 60 min was over 10 times less than that which reached the 129/J testis. The transport system used by cadmium in the 129/J testis was saturable, with 20 microM unlabeled cadmium chloride inhibiting transport by over 60%. The transporter was competitively inhibited by zinc (P =. 00017), but not by calcium, indicating a specificity in ion transport. Studies with isolated tubules and analysis of testicular fluid compartments demonstrated no significant difference in cadmium uptake or efflux between the strains when corrected for the amount of 109Cd entering the testis. Therefore, murine strain differences in testicular sensitivity to cadmium appear to be related to the variable presence of a transport system for cadmium in the testicular vasculature.

Animals↗

PubMed1999

Characterization of interleukin-1alpha binding to mouse brain endothelial cells.

In vivo studies have shown that interleukin (IL)-1alpha binds to and is transported across brain endothelial cells, whereas in vitro studies have shown that brain endothelial cells respond to IL and contain mRNA for the IL-type 1 receptor. However, these binding sites have yet to be characterized. Herein, we used murine brain microvessels to characterize the binding of IL labeled with (125)I. Binding was temperature- and time-dependent with maximal binding after 4 h of incubation at 37 degrees C. The amount of radioactivity determined by HPLC to represent intact (125)I-labeled murine IL-1alpha at 4 h was approximately 100% in the incubation fluid and 80 to 90% for radioactive material recovered from the incubated cells. B(max) was 0.955 fmol and the K(d) was 292 pM for human (125)I-IL and binding was displaced by interleukin-1beta and interleukin-1 receptor antagonist but not by tumor necrosis factor alpha. Binding was dependent on magnesium and glucose. Incubation with antibodies showed that the binding site was not identical with the IL-type 1 receptor but closely resembled the blood-brain barrier transporter. These results show that murine brain endothelial cells have specific binding sites for IL and that these sites more closely resemble the transporter than the type 1 receptor.

Animals↗

PubMed1998

Characterization of lectin-mediated brain uptake of HIV-1 GP120.

The viral coat of the HIV-1 virus, gp120, has been shown to cross the blood-brain barrier (BBB) in lectin-like fashion by inducing adsorptive endocytosis (AE), a vesicular mechanism that could provide pathways into and across brain endothelial cells for virus and infected immune cells. Here, we extended those findings to show that gp120 slowly crossed the BBB with about 0.15% of an intravenously injected dose entering the brain after about 2 hr. The plant lectin glycoprotein wheat germ agglutinin (WGA) greatly enhanced gp120 crossing without disrupting the BBB. WGA enhanced the uptake of gp120 into all peripheral tissues studied, but the greatest percent increase occurred for brain, whereas another barrier tissue, the testis, had the least increase. Five other plant lectins tested had little or no effect on gp120 uptake by brain, suggesting a key role for sialic acid and N-acetyl-beta-D-glucosaminyl acid, the sugars to which WGA binds, in the uptake of gp120 by brain endothelial cells. WGA did not enhance the uptake of nonglycosylated gp120 and the uptake of gp120 was not self-inhibitable or altered by pretreatment of mice with aluminum. In conclusion, these studies show that gp120 crosses the BBB by a lectin-like mechanism resembling AE that is likely mediated by binding to specific sugar moieties and is rather selective for brain.

Animals↗

PubMed1998

Permeability of the blood-brain barrier to neurotrophins.

To evaluate the feasibility of applying blood-borne neurotrophins to promote normal function of the central nervous system (CNS) and to rescue neuronal degeneration, we characterized the permeability of the blood-brain barrier (BBB) to neurotrophins. We report here that some members of the neurotrophin family (NGF, betaNGF, NT3, and NT5) can cross the BBB of mice in vivo to arrive at the brain parenchyma. BBB permeability differed among individual neurotrophins in that NGF had the fastest influx rate (Ki) and NT3 the slowest, and that the entry rate of NGF was twice that of its smaller bioactive subunit betaNGF. BBB permeability also differed at various CNS regions in that the cervical spinal cord had the greatest rate of influx, whereas brain had the lowest. Saturability of influx was suggested by self-inhibition studies for NT3 in vivo, and for NGF in an in situ brain perfusion system, indicating the presence of saturable transport systems. The results suggest that peripheral administration of neurotrophins could have therapeutic effects within the CNS.

1-Octanol↗

PubMed1998

Regional differences in the metabolism of Tyr-MIF-1 and Tyr-W-MIF-1 by rat brain mitochondria.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) are endogenous neuropeptides with opiate modulating and other CNS effects. After incubation of the tritiated tetrapeptides with fractions of tissue from different areas of rat brain, formation of the metabolites was determined by HPLC. Marked regional differences in degradation were found for both peptides. The metabolism of Tyr-MIF-1, resulting in the formation of the biologically active MIF-1 (Pro-Leu-Gly-NH2), was greater in the mitochondrial than in the synaptosomal fractions. In the mitochondrial fraction, about twice as much MIF-1 was formed in brain cortex than in striatum, diencephalon, or midbrain/pons medulla. These results, showing differential metabolism in various areas of the brain, indicate another means for regulation of the concentrations of neuropeptides.

Animals↗

PubMed1998

Effect of spinal cord injury on the permeability of the blood-brain and blood-spinal cord barriers to the neurotropin PACAP.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to be a potent neurotropin. Because PACAP crosses the blood-brain barrier (BBB) by peptide transport system (PTS)-6, it can exert its neurotropic effects even when given peripherally. Recent studies have shown that the activity of BBB transporters of peptides and regulatory proteins can be affected by pathophysiological events, including spinal cord injury. We, therefore, determined whether PTS-6 is affected by spinal cord injury. We found that radioactively iodinated PACAP was taken up by brain and by all regions of the spinal cord. PTS-6 activity was demonstrable in the brain and the cervical and thoracic regions of the spinal cord. Spinal cord transection had widespread and long-lasting effects throughout the CNS on PTS-6 activity. The most dramatic effect was an anatomically descending decrease of PTS-6 activity that began in the brain immediately after injury. Later, beginning on day 7 after injury, PTS-6 activity was increased throughout the CNS. These effects on PTS-6 were unrelated to the negligible disruption of barrier function by the injury. We conclude that spinal cord injury results in responses that are regionally and temporally unique to PTS-6 and could affect the delivery of blood-borne PACAP to the CNS.

Animals↗

PubMed1998

Transport of brain-derived neurotrophic factor across the blood-brain barrier.

Brain-derived neurotrophic factor (BDNF) is a potential therapeutic agent for degenerative disorders of the central nervous system. In this report, we investigated the ability of BDNF to cross the blood-brain barrier (BBB). BDNF was stable in blood up to 60 min after i.v. injection, with evidence for aggregation, and had an early, rapid influx into brain. By 10 min, most of the BDNF sequestered by the cerebral cortex was associated with the parenchyma rather than with the endothelial cells, demonstrating complete passage across the BBB. A small dose of unlabeled BDNF enhanced the entry of 125I-BDNF from blood to brain after an i.v. bolus injection, whereas larger doses had no effect. In contrast, a large dose of unlabeled BDNF inhibited the influx of 125I-BDNF during in situ brain perfusion. After intracerebroventricular injection, the efflux of BDNF from brain to blood occurred at a rate similar to that for reabsorption of cerebrospinal fluid, and no evidence for self-inhibition was found. Therefore, we conclude that intact BDNF in the peripheral circulation crosses the BBB by a high-capacity, saturable transport system.

Animals↗

PubMed1998

Differential permeability of the blood-brain barrier to two pancreatic peptides: insulin and amylin.

Insulin and amylin are cosecreted by pancreatic B cells and have receptors within the central nervous system (CNS), where they exert multiple effects. Although these peptides are not produced in the CNS, their ability to cross the blood-brain barrier (BBB) explains their presence there. We used multiple-time regression analysis to measure, in mice, the unidirectional influx constant (Ki) of each of these peptides to compare their rates of transport with each other and in different regions of the brain. The uptake of amylin by whole brain and by the cerebellum, midbrain, frontal cortex, parietal cortex, and occipital cortex was greater than that for insulin. For amylin, the areas of highest uptake were the pons-medulla and the cerebellum, and the areas of lowest uptake were the thalamus and midbrain. For insulin, the areas of highest uptake were the pons-medulla and the hypothalamus, whereas three regions (midbrain, thalamus, and occipital cortex) did not have a measurable Ki. The peak percent of injected dose taken up by whole brain was 0.12% for amylin and 0.046% for insulin. These results show that the permeabilities of these two peptides across the BBB differed from each other and among brain regions, suggesting that differential permeability of the BBB for blood-borne peptides could provide a mechanism by which their effects on the CNS are regulated.

Amyloid↗

PubMed1998

Enkephalin, PPE mRNA, and PTS-1 in alcohol withdrawal seizure-prone and -resistant mice.

Inbred animal strains provide an opportunity to study genetic factors in alcoholism in the absence of environmental factors. Although the concentration of methionine enkephalin (Met-enkephalin) in whole brain has been implicated in the consumption of ethanol, it has not been studied in the brains of alcohol withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice. We compared these concentrations with the levels of preproenkephalin (PPE) mRNA and with the activity of peptide transport system-1 (PTS-1), a brain-to-blood transport system for Met-enkephalin that is affected by ethanol. The concentrations of Met-enkephalin were significantly greater in WSP mice than in WSR mice, whereas synthesis of Met-enkephalin, as reflected by PPE mRNA levels, and transport out of the brain by PTS-1 was not different. These results support a direct link between elevated concentrations of Met-enkephalin in whole brain and proneness to withdrawal-induced seizures. We suggest that the inverse relationship between the consumption of ethanol and proneness to seizures in inbred mice can be explained through their opposite relationships to Met-enkephalin.

Animals↗

PubMed1998

Relative contributions of a CVO and the microvascular bed to delivery of blood-borne IL-1alpha to the brain.

Diffusion from brain regions lacking a blood-brain barrier (BBB) and saturable transport across capillaries are possible pathways for the entry of blood-borne interleukin-1alpha into the central nervous system (CNS). To assess the involvement of these putative routes, mice received intravenous injections of radioiodinated interleukin-1alpha, and their brains were subjected to emulsion autoradiography. The resulting patterns of silver grain distribution showed that diffusion of interleukin-1alpha from the choroid plexus and the subfornical organ was greatly restricted. These restrictive properties were quantified by the determination of D1/2 values, the distances needed for the concentration of silver grains to decrease by one-half. Within several brain regions, a subset of the microvasculature indicated transport of interleukin-1alpha across the BBB. Individual microvessels showed different patterns of transport ranging from robust to absent. The high degree of containment of blood-borne interleukin-1alpha within the regions lacking a BBB indicates that these sites cannot account for total delivery of the cytokine into the brain and suggests instead that the microvascular network may serve as the major route of entry into the CNS.

Analysis of Variance↗

PubMed1998

Fate of leptin after intracerebroventricular injection into the mouse brain.

The fate of the metabolic regulatory protein leptin was studied after intracerebroventricular (i.c.v.) administration into the lateral ventricle of the brain. In the brain, a mean of 72% of the recovered radioiodinated leptin was intact. Efflux from the brain for leptin occurred with the reabsorption of the cerebrospinal fluid into the blood. Leptin appearing in the blood was 71% intact over the course of the study. The amount of leptin in the blood rose slowly, and 20 min after i.c.v. injection equaled or exceeded levels previously seen 20 min after i.v. administration. Autoradiography showed the slow disappearance of leptin from the ventricular system over time. The degree of periventricular penetration of radiolabeled leptin also was determined. By 30 min, leptin was detected 600 microm from the midline, but computer-assisted image analysis showed that the amount of radioactivity had fallen to half the midline value by 300 microm. The concentration of leptin within the arcuate nucleus, previously observed after i.v. administration, was not seen after i.c.v. injection. High concentrations of leptin were found at the choroid plexus, suggesting the presence of leptin receptors on the brain side of the blood-cerebrospinal fluid barrier and within the lumen of the middle cerebral arteries.

Animals↗

PubMed1998

Adsorptive endocytosis mediates the passage of HIV-1 across the blood-brain barrier: evidence for a post-internalization coreceptor.

HIV-1 induces the AIDS dementia complex and infects brain endothelial and glial cells. Because the endothelial cells comprising the blood-brain barrier (BBB) do not possess CD4 receptors or galactosylceramide binding sites, it is unclear how HIV-1 negotiates the BBB. Previous work has suggested that gp120, the glycoprotein viral coat of HIV-1, is capable of inducing adsorptive endocytosis. Glycoprotein lectins like wheatgerm agglutinin induce adsorptive endocytosis and greatly potentiate the uptake by and passage across mouse endothelial cells in vivo and in vitro. We show here that the wheatgerm agglutinin-induced binding of gp120 is dose-dependent and involves components of the cytoskeleton. The uptake is partially dependent on temperature and energy and is modestly enhanced by potassium depletion. Glycosylation of gp120 is critical for its uptake by adsorptive endocytosis since the non-glycosylated form of gp120 is unaffected by wheatgerm agglutinin. Evidence is presented for the existence of a coreceptor sensitive to protamine sulfate that is primarily involved in membrane fusion after 125I-gp120 has bound to the cell membrane and is probably activated after internalization. This coreceptor probably contains a negatively charged heparin sulfate group and could be a member of the chemokine receptor family.

Adsorption↗

PubMed1997

Interactions of beta-amyloids with the blood-brain barrier.

Blood-borne beta-amyloids (A beta s) could affect brain function by (1) crossing the BBB to directly interact with brain tissues or (2) altering BBB function by interacting with the brain capillaries that make up the BBB. Several radioactively labeled A beta s have been examined for such interactions. Blood-borne A beta 1-28 is hindered from accumulating in brain by a slow rate of passage across the BBB and by robust enzymatic degradation. A beta 1-40, but not A beta 40-1 or A beta 1-42, is sequestered by brain capillaries, raising the possibility that it could affect BBB function. Small amounts of circulating A beta 1-40 are recovered intact from CSF and brain. A beta 1-40 is degraded by aluminum-sensitive, calcium-dependent intracellular enzymes. Apo-J, which can bind A beta, has been shown with an in situ method to be transported by a saturable system across the BBB. However, our recent work has shown that this system is not operable in vivo, probably because the transporter is saturated at physiological blood levels. In conclusion, A beta s have been shown to interact with and to cross the BBB.

Amyloid beta-Peptides↗

PubMed1997

Ethanol alters the concentration of Met-enkephalin in brain by affecting peptide transport system-1 independent of preproenkephalin mRNA.

Alcohol-related events have been proposed to be under neurochemical control. For example, the concentration of methionine enkephalin (Met-enkephalin) in brain has been inversely correlated with ethanol consumption in alcohol-preferring and alcohol-nonpreferring mice. The concentrations of Met-enkephalin are controlled in part by peptide transport system-1 (PTS-1), a brain-to-blood transport system for Met-enkephalin located at the blood-brain barrier. We examined the relationships among concentrations of Met-enkephalin, preproenkephalin (PPE) mRNA, and PTS-1 activity in mice exposed to ethanol. PTS-1 activity decreased progressively during the process of addiction and then partially recovered within hours after withdrawal of ethanol. Serotonin lost its ability to modulate PTS-1 activity in exposed mice, indicating that regulation of PTS-1 activity was affected by ethanol. Concentrations of Met-enkephalin tended to move in the opposite direction from PTS-1 activity, increasing significantly with addiction. In naive mice, PPE mRNA levels correlated with the concentrations of Met-enkephalin. However, levels of PPE mRNA remained unchanged during addiction, withdrawal, and recovery, no longer correlating with concentrations of Met-enkephalin. These results suggest that ethanol affects concentrations of Met-enkephalin in brain through post-transcriptional mechanisms and that PTS-1 activity is one of those mechanisms.

Animals↗