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Biomedical subjects

William A Banks

Publications and source records attributed to William A Banks.

At least 19 recordsLinked to original sources
PubMed2006

Aluminum complexing enhances amyloid beta protein penetration of blood-brain barrier.

A significant co-morbidity of Alzheimer's disease and cerebrovascular impairment suggests that cerebrovascular dysregulation is an important feature of dementia. Amyloid beta protein (Abeta), a relevant risk factor in Alzheimer's disease, has neurotoxic properties and is thought to play a critical role in the cognitive impairments. Previously, we demonstrated that the 42mer of Abeta (Abeta42) complexed with aluminum (Al-Abeta42) is much more cytotoxic than non-complexed Abeta42. The level of Abeta in the brain is a balance between synthesis, degradation, and fluxes across the blood-brain barrier (BBB). In the present paper, we determined whether complexing with aluminum affected the ability of radioactively iodinated Abeta to cross the in vivo BBB. We found that the rates of uptake of Al-Abeta42 and Abeta42 were similar, but that Al-Abeta42 was sequestered by brain endothelial cells much less than Abeta42 and so more readily entered the parenchymal space of the brain. Al-Abeta42 also had a longer half-life in blood and had increased permeation at the striatum and thalamus. Brain-to-blood transport was similar for Al-Abeta42 and Abeta42. In conclusion, complexing with aluminum affects some aspects of blood-to-brain permeability so that Al-Abeta42 would have more ready access to brain cells than Abeta42.

Algorithms↗
PubMed2006

The blood-brain barrier as a regulatory interface in the gut-brain axes.

The blood-brain barrier (BBB) prevents the unrestricted movement of peptides and proteins between the brain and blood. However, some peptides and regulatory proteins can cross the BBB by saturable and non-saturable mechanisms. Leptin and insulin each cross the BBB by their own transporters. Impaired transport of leptin occurs in obesity and accounts for peripheral resistance; that is, the condition wherein an obese animal loses weight when given leptin directly into the brain but not when given leptin peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. Since hypertriglyceridemia occurs in both starvation and obesity, we have postulated that the peripheral resistance induced by hypertriglyceridemia may have evolved as an adaptive mechanism in response to starvation. Insulin transport is also regulated. For example, treatment of mice with lipopolysaccharide (LPS) increases insulin transport across the BBB by about threefold. Since many of the actions of CNS insulin oppose those of peripheral insulin and since LPS releases proinflammatory cytokines, enhanced transport of insulin across the BBB could be a mechanism which promotes insulin resistance in sepsis. The brain endothelial cells which comprise the BBB secrete many substances including cytokines. Such secretion can be stimulated from one side of the BBB with release into the other side. For example, it appears that adiponectin can inhibit release of interleukin-6 from brain endothelial cells. Overall, the BBB represents an important interface in mediating gut-brain axes.

Adiponectin↗
PubMed2006

The effects of high fat diets on the blood-brain barrier transport of leptin: failure or adaptation?

Leptin is a pluripotent regulatory protein secreted by fat and exerts many effects through the CNS. Interpretation of the characteristics by which it crosses the blood-brain barrier (BBB) supports the view that leptin most potently signals the brain at serum levels well below those associated with the current definition of ideal body weight. This fits with the perspective that low serum levels of leptin are a signal to brain that a sufficient store of calories are available for the organism to expend energy for efforts unrelated to acquisition of calories. This would explain why low serum levels of leptin are permissive in many of the non-feeding actions of leptin, such as enhancing CNS-mediated immune function, memory, bone growth, reproduction, breathing, and neurogenesis. Triglycerides inhibit the transport of leptin across the BBB and so could be key in the onset of the peripheral leptin resistance, which is a hallmark of obesity. These results explain the paradox of why obesity should induce resistance to an anorectic: hypertriglyceridemia also occurs with starvation and we postulate that triglyceride-induced resistance to leptin transport across the BBB initially evolved to limit the signal of an anorectic to the brain during starvation.

Adaptation, Physiological↗
PubMed2006

Potentiation of lead-induced cell death in PC12 cells by glutamate: protection by N-acetylcysteine amide (NACA), a novel thiol antioxidant.

Oxidative stress has been implicated as an important factor in many neurological diseases. Oxidative toxicity in a number of these conditions is induced by excessive glutamate release and subsequent glutamatergic neuronal stimulation. This, in turn, causes increased generation of reactive oxygen species (ROS), oxidative stress, excitotoxicity, and neuronal damage. Recent studies indicate that the glutamatergic neurotransmitter system is involved in lead-induced neurotoxicity. Therefore, this study aimed to (1) investigate the potential effects of glutamate on lead-induced PC12 cell death and (2) elucidate whether the novel thiol antioxidant N-acetylcysteine amide (NACA) had any protective abilities against such cytotoxicity. Our results suggest that glutamate (1 mM) potentiates lead-induced cytotoxicity by increased generation of ROS, decreased proliferation (MTS), decreased glutathione (GSH) levels, and depletion of cellular adenosine-triphosphate (ATP). Consistent with its ability to decrease ATP levels and induce cell death, lead also increased caspase-3 activity, an effect potentiated by glutamate. Exposure to glutamate and lead elevated the cellular malondialdehyde (MDA) levels and phospholipase-A(2) (PLA(2)) activity and diminished the glutamine synthetase (GS) activity. NACA protected PC12 cells from the cytotoxic effects of glutamate plus lead, as evaluated by MTS assay. NACA reduced the decrease in the cellular ATP levels and restored the intracellular GSH levels. The increased levels of ROS and MDA in glutamate-lead treated cells were significantly decreased by NACA. In conclusion, our data showed that glutamate potentiated the effects of lead-induced PC12 cell death by a mechanism involving mitochondrial dysfunction (ATP depletion) and oxidative stress. NACA had a protective role against the combined toxic effects of glutamate and lead by inhibiting lipid peroxidation and scavenging ROS, thus preserving intracellular GSH.

Acetylcysteine↗
PubMed2006

A novel antioxidant N-acetylcysteine amide prevents gp120- and Tat-induced oxidative stress in brain endothelial cells.

Free radical production and, consequently, oxidative stress play an important role in the pathogenesis of AIDS and cause damage to lipids, proteins, and DNA. In our previous study, the HIV-1 envelope glycoprotein (gp120) and transregulatory protein (Tat) of HIV-1 have been found to induce oxidative stress in an immortalized endothelial cell line from rat brain capillaries, RBE4 (in vitro model of the blood-brain barrier). Here, we have determined the effects of a novel antioxidant, N-acetylcysteine amide (NACA), on gp120- and Tat-induced oxidative stress. Various oxidative stress parameters, including reduced glutathione (GSH), oxidized glutathione (GSSG), catalase (CAT) activity, and glutathione reductase (GR) activity, as well as malondialdehyde (MDA) levels, were used as measures of oxidative stress. NACA significantly increased the levels of intracellular GSH, CAT, and GR and decreased the levels of MDA in RBE4 cells, showing that oxidatively challenged cells were protected. Gp120- and Tat-induced increases in intracellular reactive oxygen species (ROS) were observed by using the 2',7'-DCF assay; the ROS scavenger, NACA, blocked ROS generation. A well-known apoptosis indicator, caspase-3 activity, was measured and was also found to have been returned to its control levels by NACA. Treatment of RBE4 cells with gp120 and Tat caused an increase in toxicity, as measured by lactate dehydrogenase (LDH) and tetrazolium reduction (MTS) assays. HIV-1 protein-induced toxicity in these cells was blocked by treatment with NACA. These studies show that NACA reverses gp120- and Tat-induced oxidative stress in immortalized endothelial cells.

Acetylcysteine↗
PubMed2006

Effects of chronic ethanol administration on brain interstitial fluid levels of Methionine-enkephalin as measured by microdialysis in vivo.

The level of Met-enkephalin in the brain is inversely correlated with ethanol consumption and is controlled partially through efflux activity of peptide transport system-1 (PTS-1) at the blood-brain barrier (BBB). Prolonged alcohol drinking can perturb aspects of this system, including a loss of control of Met-enkephalin levels at the transcriptional and translational levels, and impaired release of Met-enkephalin from tissue sources. Met-enkephalin levels in whole brain homogenates often first paradoxically increase after a few days of ethanol drinking and then decrease with the development of physical dependence. Which of those various changes drives the others is unclear. To clarify these interactions, we here determined the levels of Met-enkephalin in striatal interstitial fluid (ISF) by microdialysis, striatal tissue homogenates, and serum after chronic ethanol treatment and alcohol withdrawal. Mice received ethanol (5%) in liquid diet for 7 days (ethanol-treated) and others withdrawn for a day following 7-day treatment (withdrawal). There was a significant (P<0.05) difference in the levels of Met-enkephalin in striatal microdialysate between the control (79.1+/-5.9 pg/ml) and ethanol-treated group (94.9+/-4.3 pg/ml), which was lost by withdrawing ethanol (83.9+/-3.8 pg/ml). In contrast, ethanol treatment did not affect Met-enkephalin levels in the striatal tissue. In the ethanol-treated group, there was a significant (P<0.05) reduction of the levels of Met-enkephalin in serum to 70.5% of control levels. This decrease was restored to the level of control by withdrawing ethanol. These reversible changes in ISF and serum are readily explained by the known changes in the efflux activity of PTS-1 at the BBB.

Animals↗
PubMed2006

Ghrelin controls hippocampal spine synapse density and memory performance.

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Animals↗
PubMed2006

Leptin and adiponectin levels in middle-aged postmenopausal women: associations with lifestyle habits, hormones, and inflammatory markers--a cross-sectional study.

To investigate the relationships between blood levels of leptin or adiponectin and lifestyle habits, hormones, and inflammatory markers, we measured parameters of alcohol intake, smoking, physical activity, and blood levels of leptin, adiponectin, testosterone, estrone, estradiol, cortisol, dihydroepiandrostenedione, luteinizing hormone, thyroxin, C-reactive protein (CRP), and interleukin 6 and interleukin 2 receptor in 76 healthy middle-aged postmenopausal women. Anthropometric measures and body composition (evaluated by dual-energy x-ray absorptiometry) and lipid profiles were also assessed. By simple regression, leptin correlated positively with fat and lean masses, glucose, triglycerides, low-density lipoprotein cholesterol, and total cholesterol, and negatively with high-density lipoprotein cholesterol. Adioponectin correlated negatively with fat and lean masses and low-density lipoprotein cholesterol, and positively with high-density lipoprotein cholesterol. Leptin concentration was correlated inversely with adiponectin (r = -0.26, P < .05) and positively with CRP (r = 0.56, P < .01). Adiponectin concentration was negatively correlated with time since last alcoholic drink (r = -0.24, P < .05) and CRP (r = -0.27, P < .05) and positively with testosterone level (r = 0.23, P < .05). By multiple regression analysis, leptin concentration was predicted by age (P < .05), testosterone (P < .05), adiponectin (P < .05), CRP (P < .01), and interleukin 6 receptor (P < .01). Adiponectin concentration was predicted by the time since last alcoholic drink (P < .05), testosterone (P < .05), leptin (P < .05), and C-reactive protein (P = .05). Similar results were found when leptin or adiponectin concentration was adjusted for fat mass. These results suggested that levels of leptin and adiponectin in middle-aged postmenopausal women are partially determined by sexual hormones and inflammatory marker levels, and both predicted one another. Moreover, adiponectin level may be modulated by alcohol intake.

Adiponectin↗
PubMed2006

The blood-brain barrier in psychoneuroimmunology.

The very term "psychoneuroimmunology" connotes separate compartments that interact. The BBB is the physical and physiologic dividing line between the immune system and the CNS and is the locale for interaction. Interactions between the immune system and the CNS are mediated at the BBB through a variety of mechanisms. The BBB restricts unregulated mixing of the immune substances in the blood with those in the CNS, directly transports neuroimmune active substances between the blood and the CNS, and secretes neuroimmune substances. All these normal functions of the BBB can be altered in an adaptive or pathologic manner by neuroimmune events. As such, the BBB is an important conduit in the communication of the immune and the central nervous systems.

Blood-Brain Barrier↗
PubMed2006

Blood-brain barrier and energy balance.

The blood-brain barrier (BBB) plays a critical role in the transduction of signals between the central nervous system and peripheral tissues. It does so through several mechanisms, including the direct transport of peptides and regulatory proteins such as insulin and leptin. Another mechanism that may be important is the secretion by brain endothelial cells of substances that affect feeding, such as proinflammatory cytokines and NO. We have recently shown that the BBB is capable of receiving an input from one side and secreting a substance into the other. Additionally, BBB secretions can be modulated by substances that affect feeding, such as adiponectin and lipopolysaccharide.

Biological Transport↗
PubMed2006

The CNS as a target for peptides and peptide-based drugs.

Peptides hold great potential as CNS drugs, but their delivery to the CNS is problematic. However, actual roadblocks to peptide delivery are different from those often perceived. Many peptides cross the blood-brain barrier by saturable and non-saturable mechanisms, and accumulate in brain in amounts sufficient to produce physiological effects. Peripheral factors (e.g., short half-life in blood) can be dominant factors limiting therapeutic use. Production of therapeutics that are enzymatically resistant and have long circulation times, even when the blood-brain barrier penetration is low, can result in substances with significant CNS accumulation. Surprisingly low amounts of peptide in brain can result in CNS effects, and so the dose needed for brain delivery is generally much smaller than for peripheral tissues. Brain-to-blood transporters can greatly limit CNS accumulation of a potential therapeutic. Finally, intranasal and intrathecal routes may be especially useful for substances that are rapidly degraded in blood or are large and hydrophobic, respectively.

Administration, Intranasal↗
PubMed2006

Adiponectin does not cross the blood-brain barrier but modifies cytokine expression of brain endothelial cells.

Adiponectin has recently been reported to generate a negative energy balance by increasing energy expenditure. However, it is unclear whether such effects require the presence and direct action of the adiponectin protein in the central nervous system. In this study, neither radiolabeled nonglycosylated nor glycosylated globular adiponectin crossed the blood-brain barrier (BBB) in mice. In addition, adiponectin was not detectable in human cerebrospinal fluid using various established methods. Using murine cerebral microvessels, we demonstrated expression of adiponectin receptors, which are upregulated during fasting, in brain endothelium. Interestingly, treatment with adiponectin reduced secretion of the centrally active interleukin-6 from brain endothelial cells, a phenomenon that was paralleled by a similar trend of other proinflammatory cytokines. In summary, our data suggest that direct effects of endogenous adiponectin on central nervous system pathways are unlikely to exist. However, the identification of adiponectin receptors on brain endothelial cells and the finding of a modified secretion pattern of centrally active substances from BBB cells provides an alternate explanation as to how adiponectin may evoke effects on energy metabolism.

Adiponectin↗
PubMed2005

Release of cytokines by brain endothelial cells: A polarized response to lipopolysaccharide.

Brain endothelial cells (BECs) comprise the blood-brain barrier (BBB) and are an active part of the neuroimmune system, responding to and transporting cytokines. BECs also have the ability to secrete neuroimmune substances, including cytokines. A unique feature of the BEC is its polarization, with its luminal (blood-facing) and abluminal (brain-facing) cell membranes differing in their lipid, receptor, and transporter compositions. This polarization could have functional consequences for neuroimmune communication. We postulated (i) that cytokine secretion from the luminal or abluminal membranes could differ under baseline or stimulated conditions and (ii) that an immune challenge from one side of the BBB could result in cytokine release from the other. We used an in vitro BBB model of mouse BECs cultured as monolayers to investigate cytokine secretion into luminal and abluminal chambers. Our major findings in these studies were: (i) the first demonstration that interleukin (IL)-1alpha, IL-10, and granulocyte-macrophage colony-stimulating factor are secreted from BECs and confirmation of the secretions of IL-6 and tumor necrosis factor-alpha, (ii) that constitutive and lipopolysaccharide (LPS)-stimulated secretion of cytokines is polarized in favor of luminal secretion, and (iii) that response to neuroimmune stimulation is also polarized as exemplified by the finding that abluminal LPS more robustly induced secretion of IL-6 than did luminal LPS. Overall, these findings support the BBB as an important source of cytokines. Furthermore, the BBB can respond to immune challenges received from one side of the neuroimmune axis by releasing cytokines into the other.

Amyloid beta-Peptides↗
PubMed2005

Effects of leptin on memory processing.

Leptin is a peptide hormone secreted by adipose tissue. Studies have shown that leptin crosses the blood-brain barrier (BBB) by a saturable transport system where it acts within the hypothalamus to regulate food intake and energy expenditure. Leptin also acts in the hippocampus where it facilitates the induction of long-term potentiation and enhances NMDA receptor-mediated transmission. This suggests that leptin plays a role in learning and memory. Obese mice and rats, which have leptin receptor deficiency, have impaired spatial learning. In disease states such as diabetes, humans and animals develop leptin resistance at the BBB. This suggests that low leptin levels in the brain may be involved in cognitive deficits associated with diabetes. In the current study, the effects of leptin on post-training memory processing in CD-1 mice were examined. Mice were trained in T-maze footshock avoidance and step down inhibitory avoidance. Immediately after training, mice received bilateral injections of leptin into the hippocampus. Retention was tested 1 week later in the T-maze and 1 day later in step down inhibitory avoidance. Leptin administration improved retention of T-maze footshock avoidance and step down inhibitory avoidance. Leptin administered 24 h after T-maze training did not improve retention when tested 1 week after training. SAMP8 mice at 12 months of age have elevated amyloid-beta protein and impaired learning and memory. We examined the effect of leptin on memory processing in the hippocampus of 4 and 12 months old SAMP8 mice. Leptin improved retention in both 4 and 12 months old SAMP8 mice; 12 month SAMP8 mice required a lower dose to improve memory compared to 4 months SAMP8 mice. The current results indicate that leptin in the hippocampus is involved in memory processing and suggests that low levels of leptin may be involved in cognitive deficits seen in disease states where leptin transport into the CNS is compromised.

Animals↗