Biomedical subjects

W A Banks

Publications and source records attributed to W A Banks.

At least 37 records · Page 2Linked to original sources

PubMed2000

Persistence of blood-to-brain transport of leptin in obese leptin-deficient and leptin receptor-deficient mice.

In lean CD-1 mice, leptin is delivered into the brain by a saturable transport mechanism. Previous work has shown that obesity is associated with decreased leptin transport. Here, we investigated the transport of leptin across the blood-brain barrier (BBB) in two murine models of obesity. Radioiodinated leptin was intravenously injected into ob/ob (no leptin production) and db/db (high leptin levels, but no long-form leptin receptor) mutant mice and their lean controls. In all groups, the labeled polypeptide was transported across the BBB by a saturable mechanism. The rates of transport were not significantly different between the mutant strains and their lean controls. The results demonstrate that leptin transport persists in the absence of production of the endogenous polypeptide or its signal-transducing receptor and suggest that the impaired transport previously seen is not directly explained by only obesity or alterations in serum plasma levels.

Animals↗

PubMed2000

Permanent and temporary inactivation of the hippocampus impairs T-maze footshock avoidance acquisition and retention.

The hippocampus is widely recognized as playing an important role in learning and memory. Lesions of the hippocampus can disrupt spatial navigational learning and memory and injection of drugs into the hippocampus can affect both spatial navigational and nonspatial tasks. In the current studies we tested the effects of bilateral of electrolytic lesions and reversible inactivation of the hippocampus on acquisition and retention of T-maze footshock avoidance conditioning. Electrolytic lesions, which destroyed 31+/-0.04% of the hippocampus, significantly impaired acquisition and retention for T-maze footshock avoidance. No differences were found in motivation to avoid shock, open field activity, or foot shock sensitivity between lesion and control groups. Temporary inactivation of the hippocampus with lidocaine administered immediately before training disrupted acquisition and retention for T-maze footshock avoidance. Temporary hippocampal inactivation performed just prior to retention testing and post-training inactivation in mice trained to first avoidance had no effect on retention. However, temporary post-training inactivation in 'undertrained' (enough trials to remember 1 week later if treated with saline, but not allowed to make the avoidance response) mice impaired retention. The current findings indicate that the hippocampus plays an important role in learning and memory processing in the aversive T-maze paradigm.

Animals↗

PubMed2000

Estradiol potentiates acetylcholine and glutamate-mediated post-trial memory processing in the hippocampus.

There is increasing evidence that estrogen is involved in CNS activity, particularly memory. Several studies have suggested that estrogen improves memory by enhancing cholinergic and glutamatergic activity. In the present studies, we examined the effects of administration into the hippocampus of 17 beta-estradiol and estrone on retention of T-maze footshock avoidance in female ovariectomized mice. Both 17 beta-estradiol and estrone improved retention on an equimolar basis in a dose-dependent fashion. We then used the T-maze footshock paradigm to test whether a dose of 17 beta-estradiol ineffective as a single injection (subthreshold) could potentiate the effects of arecoline, a cholinergic agonist, or L-glutamate, a glutamatergic agonist, on retention. The dose of either arecoline or L-glutamate needed to improve retention was reduced at least ten-fold by the low dose of 17 beta-estradiol. These findings support the concept that estrogen improves memory by potentiating the activity of the cholinergic and glutamatergic systems.

Acetylcholine↗

PubMed2000

Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice.

beta amyloid protein (Abeta) is a 40-43 amino acid peptide derived from amyloid precursor protein (APP). Abeta has been implicated as a cause of Alzheimer's disease (AD). Mice with spontaneous or transgenic overexpression of APP show the histologic hallmarks of AD and have impairments in learning and memory. We tested whether antisense phosphorothiolated oligonucleotides (AO) directed at the Abeta region of the APP gene given with or without antibody directed at Abeta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontaneously overexpresses APP. We found that intracerebroventricular (ICV) administration of antibody with either of two AOs directed at the midregion of Abeta improved acquisition and retention in a footshock avoidance paradigm, whereas two AOs directed more toward the C-terminal, a random AO, and vehicle were without effect. Three injections of the more potent AO given without antibody reduced APP protein levels by 43-68% in the amygdala, septum, and hippocampus. These results show that AO directed at the Abeta region of APP can reduce APP levels in the brain and reverse deficits in learning and memory.

Age Factors↗

PubMed2000

Permeability of the blood-brain barrier to albumin and insulin in the young and aged SAMP8 mouse.

The decrease in the insulin cerebrospinal fluid/serum ratio seen in Alzheimer's disease has been suggested as a mechanism by which brain glucose utilization could be perturbed. Insulin is transported across the blood-brain barrier (BBB) by a system that is altered by pathophysiological events. We used SAMP8 mice, a strain that by 8-12 months of age develops severe deficits in learning and memory, to determine whether the insulin transporter or BBB integrity was altered with aging. BBB integrity was measured by injecting radioactive albumin intravenously, washing out the vascular space up to 17 hours later, and measuring brain/serum ratios. This very sensitive method found no increase in the permeability of the BBB to albumin in young and aged SAMP8 mice. This compares with previous studies in humans with Alzheimer's disease and in other colonies of SAMP8 mice that have found evidence for BBB disruption. For radioactively labeled insulin, we used multiple-time regression analysis to measure both the unidirectional influx rate (Ki) and the reversible binding to brain endothelium (Vi). A non-significant decrease in the transport rate for whole brain occurred in aged SAMP8 mice. Ki and Vi values significantly varied among brain regions and the Ki for the thalamus and the Vi for the cerebellum and thalamus were higher in aged mice. We conclude that alterations in BBB integrity or the activity of the BBB insulin transporter do not underlie the deficits in learning and memory seen in the aged SAMP8 mouse.

Aging↗

PubMed2000

Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice.

Impaired blood-brain barrier transport of leptin into the arcuate nucleus has been suggested to underlie obesity in humans and outbred aging mice. Here, we used a brain perfusion method in mice to measure transport rates and kinetic parameters for leptin at vascular concentrations between 0.15 and 130 ng/ml. Transport into whole brain was partially saturated at all concentrations, not only those seen in obesity. Leptin entered all regions of the brain, not only the hypothalamus, with entry and saturation rates differing among the brain regions. The value of the Michaelis-Menten constant of the transporter approximates normal serum levels and the maximum velocity value varies significantly among brain regions. These results suggest an important role for low serum levels signaling starvation status to the brain and show that the levels of leptin seen in obesity greatly saturate the transporter. Differences in regional uptake and saturation provide a mechanism by which leptin can control events mediated at the arcuate nucleus and other regions of the central nervous system with different regional thresholds for optimal function.

Animals↗

PubMed2000

Regional variations in the transport of interleukin-1alpha across the blood-brain barrier in ICR and aging SAMP8 mice.

OBJECTIVES: The blood-brain barrier (BBB) transports blood-borne interleukin-1alpha (IL-1) into the brain by a saturable process. Here, we determined whether all regions of the brain could transport IL-1 and whether transport differed between ICR and SAMP8 mice, a strain which overexpresses amyloid beta protein (Abeta) with aging. METHODS: We used multiple-time regression analysis to measure the unidirectional influx rate (transport rate) of radioactively labeled IL-1 for 10 brain regions in young (2 months old) ICR mice and in young and aged (17 months old) SAMP8 mice. We also used radioactively labeled sucrose and albumin to determine whether the BBB was disrupted in aged SAMP8 mice. RESULTS: In young ICR mice, eight of the 10 brain regions transported IL-1, with the pons-medulla having the fastest transport rate (0.584 +/- 0.163 microl/g x min), but no statistically significant differences occurred among regions. In SAMP8 mice, only four regions transported IL-1. In young SAMP8 mice, the pons-medulla transported IL-1 faster than any other region (0.642 +/- 0.197 microl/g x min), a rate that was significantly different (p < 0.01) from each of the other regions. Aged SAMP8 mice had a similar regional transport pattern to young SAMP8 mice, but there were no statistically significant differences among the four transporting regions. Sucrose and albumin spaces were not increased in aged SAMP8 mice, demonstrating an intact BBB. CONCLUSIONS: The smaller number of regions transporting IL-1 in SAMP8 mice as compared to ICR mice demonstrates a genetic influence on transport which could alter the ability of blood-borne IL-1 to directly affect brain functions. No evidence of BBB disruption was found in the aged SAMP8 mice from this colony.

Aging↗

PubMed2000

Designing stable blood-brain barrier-permeable prosaptide peptides for treatment of central nervous system neurodegeneration.

Prosaposin-derived peptides have been proposed as potential therapeutics for neurodegenerative diseases. Previously, we reported that the minimal length for bioactivity was 12 amino acids, and key amino acids were described based on interspecies conservation. In this article, we have further investigated the sequence requirements for bioactive Prosaptide (Myelos Corporation) peptides in terms of length and amino acid identity. The use of Prosaptide peptides for treatment of central nervous system (CNS) disorders requires that they are stable in vivo. Although robust effects of our prototypical peptide Prosaptide TX14(A) have been shown in the peripheral nervous system, minimal success has been achieved when treating the CNS in rats and this may be due to instability of Prosaptide TX14(A) in brain. Herein, we demonstrate that, indeed, Prosaptide TX14(A) is rapidly degraded in the brain and we have attempted to design prosaptides with increased CNS stability. One peptide, Prosaptide TX15-2, shows increased stability in brain and may be of use in the treatment of CNS disorders. With the aim of designing Prosaptide peptides that may be systemically administered for CNS treatment, we have investigated the blood-brain barrier permeability of Prosaptide TX14(A) and TX15-2. Both of these peptides cross the blood-brain barrier via a nonspecific mechanism.

Animals↗

PubMed2000

Retro-inverso prosaptide peptides retain bioactivity, are stable In vivo, and are blood-brain barrier permeable.

Prosaptide (trademark of Myelos Corporation, San Diego, CA) peptides are based on the 14-amino-acid neurotrophic sequence of human prosaposin and, like the parent protein, have potent neurotrophic and neuroprotective properties. We previously examined the in vivo stability of a series of bioactive Prosaptide peptides and designed peptides with increased enzymatic stability in the central and peripheral nervous systems. In this article, we examined the stability, biological activity, and permeability of the blood-brain barrier to retro-inverso Prosaptide peptidomimetics. Retro-inversion both reverses the primary sequence and replaces L-amino acids with D-amino acids. We examined the bioactivity of five peptidomimetics, Prosaptides D1-D5. Prosaptide D1, a peptide containing all D-amino acids with the primary sequence intact, was inactive. However, four retro-inverso peptidomimetics, Prosaptides D2-D5 retained bioactivity in neurite outgrowth and [(35)S]GTPgammaS binding assays. We focused on Prosaptide D4 as a prototypical retro-inverso Prosaptide peptidomimetic for further study. (125)I-Prosaptide D4 remained intact in brain or serum for 60 min after i.v. administration and was transported across the blood-brain barrier with a unidirectional influx constant of 2.5 x 10(-4) ml. g(-1). min(-1). We conclude that retro-inverso Prosaptide peptidomimetics are excellent candidates for development as therapeutics for central nervous system neurodegeneration.

Amino Acid Sequence↗

PubMed1999

Peptides crossing the blood-brain barrier: some unusual observations.

An interactive blood-brain barrier (BBB) helps regulate the passage of peptides from the periphery to the CNS and from the CNS to the periphery. Many peptides cross the BBB by simple diffusion, mainly explained by their lipophilicity and other physicochemical properties. Other peptides cross by saturable transport systems. The systems that transport peptides into or out of the CNS can be highly specific, transporting MIF-1 but not Tyr-MIF-1, PACAP38 but not PACAP27, IL-1 but not IL-2, and leptin but not the smaller ingestive peptides NPY, orexin A, orexin B, CART (55-102[Met(O)(67)]), MCH, or AgRP(83-132). Although the peptides EGF and TGF-alpha bind to the same receptor, only EGF enters by a rapid saturable transport system, suggesting that receptors and transporters can represent different proteins. Even the polypeptide NGF enters faster than its much smaller subunit beta-NGF. The saturable transport of some compounds can be upregulated, like TNF-alpha in EAE (an animal model of multiple sclerosis) and after spinal cord injury, emphasizing the regulatory role of the BBB. As has been shown for CRH, saturable transport from brain to blood can exert effects in the periphery. Thus, the BBB plays a dynamic role in the communication of peptides between the periphery and the CNS.

Animals↗

PubMed1999

Peptide transport system-1 (PTS-1) for Tyr-MIF-1 and Met-enkephalin differs from the receptors for either.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and Met-enkephalin share a saturable transport system (peptide transport system-1, PTS-1) across the blood-brain barrier but do not readily bind to each other's receptors. This information allows the unique opportunity to differentiate the transport protein(s) from the receptors for either peptide in brain endothelial cells. PTS-1 was studied in vitro by allowing radiolabeled Tyr-MIF-1 (125I-Tyr-MIF-1) to bind to the solubilized proteins of isolated murine brain microvessels in the presence or absence of potential inhibitors. Sephadex chromatography separated bound from free labeled peptide. The binding was saturable as shown by inhibition with increasing concentrations of unlabeled Tyr-MIF-1. 125I-Tyr-MIF-1 binding was not inhibited by an unrelated peptide or iodo-tyrosine. D-Tyr-MIF-1 had no effect, demonstrating the stereospecificity of the system. Met-enkephalin decreased the binding of 125I-Tyr-MIF-1 to 84.4% of total, whereas Leu-enkephalin was without effect. Agonists for the mu, delta, and kappa opiate receptors did not change the binding, indicating that the proteins which bound to 125I-Tyr-MIF-1 were not endogenous opiate receptors. The results indicate that, in vitro, Tyr-MIF-1 binds to brain microvessel proteins with characteristics similar to PTS-1.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Transmission routes of HIV-1 gp120 from brain to lymphoid tissues.

The blood-brain barrier (BBB) restricts the entry of antiviral agents into the CNS thereby facilitating the creation of a reservoir of HIV that could potentially reinfect peripheral tissues. We characterized the efflux from brain of radioactively labeled viral coat HIV-1 gp120 (I-gp120) after intracerebroventricular (i.c.v.) injection. The half-time disappearance rate of I-gp120 from brain was 12.6 min, which was faster than could be explained by the reabsorption of cerebrospinal fluid into blood but could not be explained by a saturable transporter. After i.c.v. injection, I-gp120 appeared in the serum and was sequestered by spleen and the cervical nodes, demonstrating a potential for virus within the CNS to reinfect peripheral tissues. However, the amount of I-gp120 appearing in serum was less than that expected based on the efflux rate, whereas uptake by the cervical nodes was much greater after i. c.v. than after i.v. injection of I-gp120. These findings were explained by drainage from the brain directly to the cervical lymph nodes through the brain's primitive lymphatic system. These lymphatics potentially provide a pathway through which CNS reservoirs of HIV-1 could directly reinfect lymphoid tissue without being exposed to circulating antiviral agents.

Acids↗

PubMed1999

Adsorptive endocytosis of HIV-1gp120 by blood-brain barrier is enhanced by lipopolysaccharide.

Previous work suggests that gp120 mediates the passage of HIV-1 and infected immune cells across the blood-brain barrier (BBB) by induction of adsorptive endocytosis (AE) in brain endothelial cells. Other work has suggested that cytokines may increase the permeability of the BBB to free virus or infected immune cells. Here, we investigated the ability of lipopolysaccharide (LPS), a bacterial wall toxin that stimulates the release of cytokines, to increase gp120 passage across the BBB by enhancement of AE and/or induction of BBB disruption. We found that LPS enhanced the passage of gp120 radioactively labeled with 125I (I-gp120) in a reversible, time-dependent, prostaglandin-independent manner that was not completely explained by disruption of the BBB. LPS also enhanced wheatgerm agglutinin mediated uptake of I-gp120 almost exclusively through the potentiation of AE. These results show that LPS or cytokines released by LPS can have a major effect on the permeability of the BBB to HIV-1gp120 both by stimulating AE and by inducing a disruption of the BBB. This suggests that bacterial infection or other inflammatory states could facilitate invasion of the CNS by HIV-1.

Animals↗

PubMed1999

Effects of wheatgerm agglutinin and aging on the regional brain uptake of HIV-1GP120.

HIV-1 is associated with infection and altered functions of the CNS, especially in the elderly. Most studies indicate that HIV-1 is not evenly distributed throughout the CNS but is concentrated in deep brain nuclei. This study examined whether regional or age-related differences in the permeability of the blood-brain barrier to gp120, the viral coat of HIV-1, exist. The initial concentration of gp120 in 10 brain regions correlated with vascular content in young and old mice. Susceptibility to wheatgerm agglutinin (WGA)-induced uptake of gp120, which relates to endothelial cell internalization, varied regionally, with no induction of uptake into the striatum or hypothalamus but with large increases in the cerebellum, cortex, and midbrain. Transport across the BBB, as measured by the unidirectional influx rate (Ki), also varied regionally with the hypothalamus, hippocampus, and pons-medulla showing the highest values for Ki and the striatum the lowest. These regional variations in the permeability of the BBB to gp120 could contribute to the inhomogeneous distribution of HIV-1 within the CNS whereas the failure to see differences with aging suggests other causes underlie the susceptibility of the elderly to the CNS manifestations of AIDS.

Aging↗

PubMed1999

Effect of cardiac arrest on brain weight and the permeability of the blood-brain and blood-spinal cord barrier to albumin and tumor necrosis factor-alpha.

Time-dependent changes in brain and spinal cord were studied in mice in a cardiac arrest model. A transient decrease in body weight and a prolonged decrease in brain weight occurred after arrest whereas spinal cord weight was unchanged. The permeability of the blood-brain barrier (BBB) to I131-albumin and I131 tumor necrosis factor-alpha (TNF) showed maximal, non-significant increases on day 5 after cardiac arrest, but the permeability of the blood-spinal cord barrier (BSCB) to both materials was unchanged with time. We conclude that selective weight loss occurs in the brain after cardiac arrest with the integrity of the BBB and BSCB remaining intact to serum proteins and minimal alteration in the blood to CNS transport of TNF.

Albumins↗

PubMed1999

Uptake and degradation of blood-borne insulin by the olfactory bulb.

Insulin found within the brain is derived from the blood and can affect various central nervous system (CNS) functions. The olfactory bulb contains one of the highest concentrations of insulin and insulin receptors within the CNS. To determine the mechanism underlying this high concentration of insulin, we used radioactively iodinated insulin to compare the blood to tissue transport rates and tissue degradation rates for the olfactory bulb, whole brain and spinal cord. We found that the olfactory bulb had both the highest transport rate across the blood-brain barrier (BBB) and the highest rate of degradation. Because a higher degradation rate would decrease, not increase, tissue concentrations of insulin, BBB transport may be the primary mechanism by which high concentrations of insulin are maintained within the olfactory bulb. This illustrates an adaptive aspect of the BBB in its regulation of the exchange of information molecules between the blood and the CNS.

Animals↗

PubMed1999

Effects of peptides: a cross-listing of peptides and their central actions published in the journal Peptides from 1994 through 1998.

Effects of peptides on the central nervous system are presented in two ways so as to provide a cross-listing. In the first table, the peptides are listed alphabetically. In the second table, the central nervous system effects are arranged alphabetically. No longer can there be any doubt that peptides affect the central nervous system, sometimes in several ways.

Peptides↗

PubMed1999

Impaired transport of leptin across the blood-brain barrier in obesity.

Leptin is a 17-kDa protein secreted by fat cells that regulates body adiposity by crossing the blood-brain barrier (BBB) to affect feeding and thermogenesis. Obese human and rodent models of dietary obesity have shown decreased sensitivity to blood-borne leptin, postulated to be due to impaired transport of leptin across the BBB. We show here that the transport rate of leptin across the BBB is reduced about 2/3 in 12-month-old obese CD-1 mice. In a follow-up study, a perfusion method was used that replaced the blood with a buffer containing low concentrations of radioactive leptin. Obese mice still had lower rates of transport into the brain than lean mice, which shows that the reduction in transport rate associated with obesity is not due simply to saturation of transporter secondary to higher serum leptin levels as has been thought, but to a decreased capacity of the BBB to transport leptin. This suggests a new model for obesity in which a defect in the BBB transport of leptin into the CNS underlies the insensitivity to leptin and leads to obesity.

Animals↗