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Biomedical subjects

W A Banks

Publications and source records attributed to W A Banks.

At least 73 records · Page 4Linked to original sources
PubMed1997

Blood-brain barrier permeability to ebiratide and TNF in acute spinal cord injury.

Spinal cord injury (SCI) in mammals has a poor outcome because of a lack of regeneration. Alteration of the local environment after injury may induce regeneration. However, the passage of blood-borne or exogenous neurotrophic substances through the blood-brain barrier (BBB) is not well characterized in either normal or injured states. We investigated the permeability of the BBB in normal and injured states to two markers of permeability (albumin and sucrose), to a peptide (ebiratide), and to a cytokine [tumor necrosis factor-alpha(TNF)]. We found that in normal mice the cervical and lumbar areas of the spinal cord were more permeable than the thoracic area and the brain to all four substances. The penetration of the alpha-MSH/ACTH analogue ebiratide and of TNF, substances that have saturable transport systems across the BBB and may be involved in regenerative processes in the CNS, followed a regional pattern of differential permeability comparable to that of albumin and sucrose. Complete transection at the lumbar level induced a temporal change in the permeability of the BBB. The increased permeability, as measured by the radioactively labeled tracers albumin and sucrose, was most apparent in the lumbar region proximal to the transection. After SCI, the permeability to ebiratide remained unchanged, suggesting that disruption of the BBB did not affect the transport system for ebiratide. By contrast, the increase of permeability to TNF exceeded that detected by the markers albumin and sucrose. This enhanced permeability was inhibited by excess unlabeled TNF in the blood, showing saturability. This suggests that the transport system for TNF may be activated in SCI.

Acute Disease↗
PubMed1997

The putative blood-brain barrier transporter for the beta-amyloid binding protein apolipoprotein j is saturated at physiological concentrations.

beta-amyloid (A beta), the major component of the amyloid deposited in the brains of patients with Alzheimer's disease, is found in blood and can cross the blood-brain barrier (BBB). This suggests that the circulation could be a source of A beta in brain. The passage of unbound A beta across the BBB is slow. Most of the A beta in blood, however, is likely to be bound to apolipoprotein J (ApoJ). ApoJ and A beta bound to ApoJ have been shown to rapidly cross the BBB of the guinea pig when studied in situ with a blood-free brain perfusion model. ApoJ in blood, however, is found in a concentration 28 times higher than that needed to saturate the ApoJ transporter in situ. This suggests that the putative ApoJ transporter may not be functional in vivo. We found here that when measured in a murine in situ brain perfusion model, 125I-ApoJ crossed the BBB with a unidirectional influx rate constant (Ki) of 3.75 x 10(-3) ml/g-min, which is similar to that found in the guinea pig. After intravenous injection, however, no penetration of ApoJ across the BBB was measured in either the mouse or guinea pig. These results suggest that ApoJ is unlikely to provide a significant route for the transport of A beta across the BBB in vivo.

Animals↗
PubMed1997

HIV-1 protein gp120 crosses the blood-brain barrier: role of adsorptive endocytosis.

HIV-1 infects the brain and leads to AIDS dementia complex. The viral coat glycoprotein, gp120, may facilitate the passage of HIV-1 and HIV-infected immune cells across the blood-brain barrier (BBB). Since the endothelial cells of the BBB do not possess the CD4 or galactosylceramide binding sites used by gp120 to induce HIV-1 uptake into other cell types, how gp120 mediates entry into brain is unknown. We postulate that gp120 crosses the BBB and does so by acting as a weak lectin to induce adsorptive endocytosis (AE) in a fashion similar to other glycoproteins like wheatgerm agglutinin (WGA). We found in vivo that gp120 crosses the BBB and its passage is enhanced 18.7-fold by WGA. In vitro studies confirm that WGA enhances uptake of gp120 by brain endothelia; most of the uptake is membrane-associated, as expected in AE. Uptake is not dependent on clatharin, caveolae, calcium channels, or endosomal acidification. Our results suggest that gp120 crosses the BBB and does so by acting as a lectin to induce AE.

Adsorption↗
PubMed1997

Tumor necrosis factor-alpha: a neuromodulator in the CNS.

In the central nervous system (CNS), the cytokine tumor necrosis factor-alpha (TNF alpha) is produced by both neurons and glial cells, participates in developmental modeling, and is involved in many pathophysiological conditions. There are activity-dependent expressions of TNF alpha as well as low levels of secretion in the resting state. In contrast to the conventional view of a cytotoxic effect of TNF alpha, accumulating evidence suggests a beneficial effect when TNF alpha is applied at optimal doses and at specific periods of time. The bimodal effect is related to subtypes of receptors, activation of different signal transduction pathways, and the presence of other molecules that alter the intracellular response elements such as immediate-early genes. TNF alpha may be an important neuromodulator in development of the CNS, diseases of demyelination and degeneration, and in the process of regeneration. It could induce growth-promoting cytokines and neurotrophins, or it could increase the production of antiproliferative cytokines, nitric oxide, and free radicals, thereby contributing to apoptosis.

Animals↗
PubMed1997

Permeability of the blood-brain and blood-spinal cord barriers to interferons.

Interferons (IFNs) are cytokines that produce effects in the CNS even though their production occurs mainly in the periphery. Direct passage of IFNs from blood to CNS could be an important route by which circulating IFNs exert their central effects. In this report, we characterize the pharmacokinetics of the passage of IFNs through the blood-brain and blood-spinal cord barriers in four separate regions: whole brain and the cervical, thoracic and lumbosacral segments of the spinal cord. We found that the spinal cord had greater permeability to IFNs than did the brain. For each corresponding region, the permeability to IFN alpha was higher than that to IFN gamma. Capillary depletion after cardiac perfusion showed that most of the injected IFN was not entrapped by the vasculature but entered the parenchyma of the brain. HPLC showed that most of the IFN gamma entered in intact form. The passage of radioactively labeled IFN gamma into the brain and cervical spinal cord was saturated by a low dose of unlabeled IFN gamma, while passage into the thoracic and lumbosacral spinal cord was not saturated. In contrast, for another cytokine, tumor necrosis factor alpha (TNF alpha), a saturable transport system was present in distal spinal cord as well as the brain. The results show that IFNs and TNF alpha can enter the CNS from the periphery but with regional differences.

Animals↗
PubMed1997

Relative contributions of peripheral and central sources to levels of IL-1 alpha in the cerebral cortex of mice: assessment with species-specific enzyme immunoassays.

The peripheral administration or release of cytokines is associated with central nervous system (CNS) effects that are often due to the actions of cytokines behind the blood-brain barrier (BBB). It is not known whether the majority of cytokine behind the BBB is derived from blood or is released from the CNS in response to peripheral signals. We addressed this question for interleukin-1 alpha (IL-1 alpha) by infusing human IL-1 alpha (humIL-1 alpha) into mice and measuring humIL-1 alpha and murine IL-1 alpha (murIL-1 alpha) in cerebral cortex and serum with specific, sensitive enzyme immunoassays. In adult mice receiving 50 micrograms/kg-24 h of humIL-1 alpha subcutaneously for 48 h, brain and blood samples contained humIL-1 alpha but no murIL-1 alpha. This shows that in our study blood-borne IL-1 alpha did not self-stimulate its release in blood or brain. The presence of humIL-1 alpha in brain could only have originated from blood, where it was administered; the brain/blood ratio of 0.126 ml/g indicates that at steady state, brain levels reach about 12% of blood levels. In neonatal mice, both murIL-1 alpha and humIL-1 alpha were detected in brain and blood after the acute subcutaneous injection of humIL-1 alpha. However, the vast majority of immunoactivity in blood and brain was humIL-1 alpha. These results show that most of the IL-1 alpha appearing in response to circulating IL-1 alpha in areas of the CNS behind the BBB is due to passage across the BBB and not to release from stores endogenous to the CNS.

Aging↗
PubMed1997

Selective, physiological transport of insulin across the blood-brain barrier: novel demonstration by species-specific radioimmunoassays.

Insulin in blood is thought to cross the blood-brain barrier (BBB) to act within the brain to help control appetite. We examined the ability of blood-borne insulin to cross the BBB. Human insulin was infused for 48 h subcutaneously at several doses into mice and the amount of human and murine insulin in serum and brain measured with species-specific radioimmunoassays. For the exogenous human insulin, both brain and blood concentrations increased with increasing doses of infused insulin, whereas for the endogenous murine insulin, brain and blood concentrations decreased. Since the mouse cannot make human insulin, blood was the only source for the human insulin in brain, demonstrating that insulin does indeed cross the BBB. The relationship between the concentrations of human insulin in brain and blood was nonlinear, showing that passage is by a saturable mechanism. Partial saturation of the transporter occurred at euglycemic concentrations of serum insulin. Thus, insulin enters the brain by a saturable transport system that is operational primarily at physiological levels of serum insulin.

Animals↗
PubMed1997

Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin.

Blood-borne insulin is known to cross the blood-brain barrier (BBB) where it can act as a satiety peptide. We examined in mice the pharmacokinetics and characteristics of such passage by multiple-time regression analysis. The unidirectional influx constant (Ki) of human insulin radioactively labeled with iodine (I-Ins) ranged from 0.87 to 1.7 microliters/g-min. The transport of I-Ins was inhibited almost 50% by 0.1 micrograms/mouse of unlabeled human insulin, a dose that had no effect on serum glucose. Similar results were found with rat insulin. The results with self-inhibition suggest that any hemoencephalic signal transmitted by the blood to brain transport of insulin is independent of the effects of insulin on glucose. The transport of I-Ins was altered by aluminum but not by administration of tyrosine, verapamil, or leptin, indicating independence from amino acid transport, the p-glycoprotein system, a slow calcium channel, or leptin transport. By contrast with insulin, enzyme degradation limited the uptake and accumulation by brain of intravenously injected, radioactively labeled glucagon and glucagon-like peptide. In conclusion, these results are consistent with the view that insulin can affect satiety and related behaviors independently of its peripheral effects by crossing the BBB to act within the brain.

Aluminum↗
PubMed1997

Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin.

Insulin derived from the peripheral circulation has been shown to exert various effects on the brain due to its ability to cross the blood-brain barrier (BBB). The relation between diabetes mellitus and insulin has been extensively studied for peripheral tissues but not for central nervous system tissues. We examined the effects that streptozotocin- or alloxan-induced diabetes have on the transport of insulin across the murine BBB. We used multiple-time regression analysis to measure the unidirectional influx rate constant (Ki) and vascular association (Vi) of intravenously injected, radioactively labeled human insulin (I-Ins). Treatment with streptozotocin induced an enhancement of both the Ki and Vi of I-Ins that correlated with the onset of diabetes. Brain perfusion showed that the enhanced uptake was not due to altered vascular space or levels of insulin in the serum. Alloxan enhanced Ki and Vi after 5 days but the early phase of diabetes was associated with a decreased Ki. Hyperglycemia induced by the intraperitoneal injection of glucose elevated the Vi but abolished the Ki. Furthermore, altered I-Ins uptake by brain was not associated with changes in brain or body weight. These results show that there is an increased uptake of I-Ins by the brain in the diabetic state that is not due to acute changes in the serum levels of glucose or insulin, altered vascular space, or catabolic events. Chronic changes in levels of glucose, insulin or other hormone or neuroendocrine agents are likely to underlie the altered rate of transport of insulin across the BBB of diabetic mice.

Alloxan↗
PubMed1997

Granulocyte-macrophage colony-stimulating factor crosses the blood--brain and blood--spinal cord barriers.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycoprotein with hormonal properties, is produced by several cell types, most of which exist outside the CNS. GM-CSF, however, affects the CNS. If capable of crossing from blood to CNS, GM-CSF might be an important signalling molecule between the CNS and periphery. We used an established in vivo method in mice and rats to study passage of radioactively labelled GM-CSF from blood to CNS. We found that GM-CSF crossed the blood-brain barrier and blood-spinal cord barrier significantly faster than the control substance, albumin. Labelled GM-CSF was recovered in intact form by high performance liquid chromatography from brain after peripheral injection, and passage was not significantly reduced by simultaneous injection of unlabelled L-tryptophan. Both findings indicate that the observed passage of radioactivity was intact protein. Capillary depletion experiments showed that most of the GM-CSF was deposited in brain parenchyma rather than cerebral capillary endothelium. Co-injection of unlabelled GM-CSF significantly reduced the passage rate of labelled cytokine across the blood-brain and blood-spinal cord barriers, demonstrating that passage was mediated by a saturable system. In summary, a saturable mechanism transports GM-CSF intact from blood to CNS.

Albumins↗
PubMed1997

Granulocyte macrophage-colony stimulating factor crosses the blood-testis barrier in mice.

Granulocyte macrophage-colony stimulating factor (GM-CSF) has hormone-like effects on female reproductive systems. Recent evidence has suggested that GM-CSF also might be important to male testicular function. It is possible, however, that most sources of GM-CSF might not be able to reach the testis, since testes are shielded from contact with the general circulation by vascular and Sertoli cell barriers, which together comprise the blood-testis barrier (BTB). We used a sensitive in vivo method to determine whether blood-borne GM-CSF crossed the BTB in mice. 125I-GM-CSF was found to cross the BTB, showing a unidirectional influx constant (Ki) of 1.45 x 10(-3) ml/g-min, nine times faster than the influx rate of the control substance, 99mTc-albumin. HPLC analysis confirmed the presence of intact 125I-GM-CSF in the testis after peripheral injection. More 125I-GMCSF than 99mTc-albumin crossed both the vascular barrier, to enter the testicular interstitial fluid, and the Sertoli cell barrier, to enter the seminiferous tubule fluid. Coinjection of unlabeled GM-CSF significantly reduced the passage rate of labeled cytokine across the BTB, demonstrating that passage was mediated by a saturable system and suggesting the presence of a transport or facilitated diffusion system for GM-CSF. In summary, GM-CSF passes intact from blood to testis by means of a saturable mechanism.

Albumins↗
PubMed1997

Acute modulation of active carrier-mediated brain-to-blood transport of corticotropin-releasing hormone.

The unidirectional brain-to-blood transport system for corticotropin-releasing hormone (CRH) across the blood-brain barrier could be instrumental in the homeostasis of central CRH. To characterize this system, the intracerebroventricular injection of 125I-CRH was used in mice. CRH was rapidly transported out of the brain with a half-time disappearance (t1/2) of 15 min, much faster than albumin (t1/2 = 50 min). Kinetic analysis revealed a saturable component with a low maximum velocity (apaproximately 0.020 nmol x min(-1) x brain(-1)) and low capacity (Michaelis constant approximately 1.4 nmol/brain). Transport was inhibited by verapamil, ouabain, and colchicine but not by cyclosporin. Transport was increased by corticosterone and inhibited by tumor necrosis factor-alpha and beta-endorphin. These results suggest that the specific unidirectional brain-to-blood transport system for CRH is dependent on energy and calcium channels, involves microtubules, is independent of the P-glycoprotein transporter, and is acutely modulated by adrenal steroids, cytokines, and endogenous opiates. This suggests its participation in the control of the stress response.

Adrenal Cortex Hormones↗
PubMed1997

Transport of CRH from mouse brain directly affects peripheral production of beta-endorphin by the spleen.

The blood-brain barrier (BBB) regulates the passage of substances between the brain and the periphery. It has not been shown that the secretion from the brain of a small amount of a substance can directly affect the periphery by transport across the BBB. We found that central injection of radioactively labeled corticotropin-releasing hormone (CRH) resulted in the accumulation of intact CRH in the spleen. CRH also increased splenic beta-endorphin, an effect not blocked by pretreatment with dexamethasone. Inhibition of the secretion of CRH from the brain by colchicine resulted in decreased accumulation of CRH in the spleen and also decreased splenic beta-endorphin. Similar findings occurred in the pituitary gland. The results show that the passage of labeled CRH from the brain can directly affect a peripheral organ, thus emphasizing the regulatory function of the BBB.

Animals↗
PubMed1996

Transport of pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier and the prevention of ischemia-induced death of hippocampal neurons.

PACAP is a member of the secretin/glucagon/VIP family of peptides and demonstrates neurotrophic and neuroprotective effects at very low concentrations. We have previously shown that PACAP crosses the BBB to a modest degree by way of a saturable transport system. PACAP is transported across the BBB as an intact peptide to enter the parenchymal space of the brain. We tested the possibility that this modest rate of transport would be sufficient to produce the low levels of PACAP needed in the brain to exert a neuroprotective effect against ischemia. We found that PACAP given intravenously could indeed prevent the death of CA1 hippocampal neurons, even if the administration of PACAP was delayed for 24 h after the ischemic event. We suggest that iv PACAP could be neuroprotective after stroke, cardiac arrest, and hypotensive episodes.

Animals↗
PubMed1996

Prevention of ischemia-induced death of hippocampal neurons by pituitary adenylate cyclase activating polypeptide.

Because neurons in the CA1 region of the hippocampus are vulnerable to forebrain ischemia, this model has been used for evaluating neuroprotective agents. We evaluated the 38-amino-acid variant of pituitary adenylate cyclase activating polypeptide (PACAP38), which had been previously shown to be neuroprotective in vitro against gp120-induced hippocampal neuronal death at concentrations as low as 0.1 pM. Ischemic death of rat CA1 neurons was prevented by infusing PACAP38 either intracerebroventricularly (1 pmol/h) or intravenously (16-160 pmol/h). Intravenous PACAP38 was effective even if the infusion was begun 24 h after ischemia. The results suggest that a concentration of PACAP38 in the brain which prevents the ischemic death of CA1 neurons can be reached by the systemic administration of a low dose of the peptide. The results are compatible with the previous reports that PACAP38 is transported from the circulation to the brain. Although the exact mechanisms remain to be determined, astrocytes in the CA1 subfield activated by ischemia appear to mediate the neuroprotection with PACAP38. These results are in contrast to those with other neuroprotective compounds and should be clinically important.

Animals↗
PubMed1996

Reversible association of the cytokines MIP-1 alpha and MIP-1 beta with the endothelia of the blood-brain barrier.

Macrophage inflammatory proteins (MIP)-1 alpha and -1 beta have been postulated to exert their pyrogenic effects by acting directly at sites within the brain. Such activity would require circulating MIP-1s to cross the blood-brain barrier (BBB). We examined the ability of the monomer and polymer of MIP-1 alpha and the polymer of MIP-1 beta radioactively labeled with 125iodine (I-MIP-1) to cross the BBB. These I-MIP-1s behaved very similarly to each other but in a manner not previously seen for other cytokines. The I-MIP-1s immediately associated to a high degree and in a reversible manner with the vascular space of the brain. This association did not increase over time nor was it self-inhibitable. These results make it unlikely that the MIP-1s are transported into the brain by saturable transport systems in the manner found for some of the other cytokines. Other mechanisms, such as interactions with brain endothelia, leakage into brain through extracellular pathways, and binding at circumventricular organs, are more likely to provide the mechanisms through which blood-borne MIP-1s affect the central nervous system.

Animals↗