Biomedical subjects

Victoria Akerstrom

Publications and source records attributed to Victoria Akerstrom.

9 recordsLinked to original sources

PubMed2004

Neuregulin-1-beta1 enters brain and spinal cord by receptor-mediated transport.

Proteins of the neuregulin (NRG) family play important regulatory roles in neuronal survival and synaptic activity. NRG-1-beta1 has particular potential as a therapeutic agent because it enhances myelination of neurites in spinal cord explants. In this study, we determined the permeation of NRG-1-beta1 across the blood-brain and blood-spinal cord barriers (BBB and BSCB respectively). Intact radioactively labeled NRG-1-beta1 had a saturable and relatively rapid influx rate from blood to the CNS in mice. Capillary depletion studies showed that NRG-1-beta1 entered the parenchyma of the brain and spinal cord rather than being trapped in the capillaries that compose the BBB. The possible mechanism of receptor-mediated transport was shown by the ability of antibodies to erbB3 and erbB4 receptors to inhibit the influx. Lipophilicity, less important for such saturable transport mechanisms, was measured by the octanol : buffer partition coefficient and found to be low. The results indicate that NRG-1-beta1 enters spinal cord and brain by a saturable receptor-mediated mechanism, which provides the opportunity for possible therapeutic manipulation at the BBB level.

Animals↗

PubMed2004

Modulation of feeding-related peptide/protein signals by the blood-brain barrier.

The peptide urocortin is a member of the corticotropin-releasing factor (CRF) family and a potent satiety signal to the brain. Urocortin in blood does not reach the brain significantly by itself, but its permeation across the blood-brain barrier (BBB) can be enhanced by leptin. How leptin facilitates the influx of urocortin has not been elucidated. In this study, we tested the hypothesis that leptin activates receptor-mediated endocytosis of urocortin. We measured the kinetics of permeation of radioactively labeled urocortin across the mouse BBB and determined the specific effects of leptin and receptor antibodies. The results show that the influx transfer constant of urocortin was enhanced in the presence of leptin and mediated by CRF-2beta, the specific receptor for urocortin. To determine the specificity of this modulation, the effect of leptin was compared with that of TNFalpha. Both TNFalpha and leptin independently facilitated receptor-mediated transport of urocortin across the BBB. Even though TNFalpha and leptin have similar effects on urocortin transport, leptin did not significantly affect the influx of TNFalpha across the BBB. The results indicate that permeation of ingestive peptides and cytokines across the BBB can be acutely modulated, consistent with a role of BBB in regulating feeding behavior. Thus, sites of action of leptin, urocortin, and TNFalpha exist not only in the brain but also at the BBB where they each control the flow of other ingestive signals to CNS targets.

Animals↗

PubMed2003

Interleukin-10 as a CNS therapeutic: the obstacle of the blood-brain/blood-spinal cord barrier.

Interleukin (IL)-10 exerts beneficial effects on the central nervous system (CNS) after peripheral administration, but its penetration across the blood-brain barrier (BBB) has not been quantified. We show that 125I-IL-10 is stable in circulating blood but does not cross the intact BBB after intravenous delivery. Thus, peripheral IL-10 probably can serve as a CNS therapeutic only when the BBB is disrupted.

Albumins↗

PubMed2003

Glial cell line-derived neurotrophic factor does not enter normal mouse brain.

Glial cell line-derived neurotrophic factor (GDNF) is produced both in the central nervous system (CNS) and the periphery. Effective in ameliorating neurodegeneration in several animal models of CNS disease, its promise as a therapeutic agent would be greatly enhanced if it readily crossed the blood-brain barrier (BBB) in unmodified form. Here, we used the sensitive techniques of multiple-time regression analysis and ex-vivo perfusion in blood-free buffer to examine the entry of (125)I-GDNF into mouse brain. The integrity of GDNF in blood and brain was examined by high performance liquid chromatography and the physicochemical properties determining permeability were measured by octanol/buffer partition coefficient and hydrogen bonding. The efflux of (125)I-GDNF was determined to test for the presence of a bidirectional transport system. The results show that (125)I-GDNF differs from other peptides and polypeptides in that it does not enter brain any faster than (99m)Tc-albumin, an effect that cannot be explained by degradation, rapid efflux, protein binding, or inadequate lipophilicity. Thus, GDNF shows a different type of interaction with the BBB. In normal mice, the BBB functions as a substantial physical barrier; in pathological or traumatic situations when the barrier is partially disrupted, the lack of restriction by a saturable transport system could make GDNF a suitable candidate for peripheral delivery in promoting neuroregeneration.

Animals↗

PubMed2003

Different mechanisms influencing permeation of PDGF-AA and PDGF-BB across the blood-brain barrier.

Platelet-derived growth factor (PDGF) exerts neurotrophic and neuromodulatory effects on the CNS. To determine the permeability of the blood-brain barrier (BBB) to PDGF, we examined the blood-to-brain influx of radioactively labeled PDGF isoforms (PDGF-AA and PDGF-BB) by multiple-time regression analysis after intravenous (i.v.) injection and by in-situ perfusion, and also determined the physicochemical characteristics which affect their permeation across the BBB, including lipophilicity (measured by octanol:buffer partition coefficient), hydrogen bonding (measured by differences in octanol : buffer and isooctane : buffer partition coefficients), serum protein binding (measured by capillary electrophoresis), and stability of PDGF in blood 10 min after i.v. injection (measured by HPLC). After i.v. bolus injection, neither 125I-PDGF-AA nor 125I-PDGF-BB crossed the BBB, their influx rates being similar to that of the vascular marker 99mTc-albumin. 125I-PDGF-AA degraded significantly faster in blood than 125I-PDGF-BB. PDGF-BB, however, was completely bound to a large protein in serum whereas PDGF-AA showed no binding. Thus, degradation might explain the poor blood-to-brain influx of PDGF-AA, whereas protein binding could explain the poor influx of circulating PDGF-BB. Despite their lack of permeation in the intact mouse, both 125I-PDGF-AA and 125I-PDGF-BB entered the brain by perfusion in blood-free buffer, and the significantly faster rate of 125I-PDGF-AA than 125I-PDGF-BB may be explained by the lower hydrogen bonding potential of 125I-PDGF-AA. Thus, the lack of significant distribution of PDGF from blood to brain is not because of the intrinsic barrier function of the BBB but probably because of degradation and protein binding. Information from these studies could be useful in the design of analogues for delivery of PDGF as a therapeutic agent.

Animals↗

PubMed2003

Circulating TGF-beta1 does not cross the intact blood-brain barrier.

Transforming growth factor-beta (TGF-beta) from the periphery can cross the disrupted blood-brain barrier (BBB) to exert neuroprotective effects on the brain. Here, we quantify its permeation across the normal mouse BBB. By high-performance liquid chromatography, we show that TGF-beta1 is stable in circulating blood but does not cross the intact BBB after intravenous injection any faster than the vascular marker 99mTc-albumin. This poor rate of influx cannot be explained by rapid efflux out of the brain or lack of lipophilicity as measured by the octanol/buffer partition coefficient, although the hydrogen bonding potential was relatively high, consistent with poor penetration. Thus, the therapeutic potential of TGF-beta1 administered in blood is probably limited to situations in which the BBB has been disrupted.

Animals↗

PubMed2002

Novel peptide-peptide cooperation may transform feeding behavior.

There is need for a new approach to the suppression of feeding. Here, we show that two of the most potent endogenous satiety peptides interact in a novel way to cross the blood-brain barrier (BBB) and to suppress food intake. Combined peripheral administration of leptin and urocortin (UCN) significantly decreased food intake, whereas neither one showed an effect when given alone in the same doses. We further provide a mechanism whereby this novel cooperativity can occur by demonstrating that UCN, which by itself does not cross the BBB, can readily enter the brain by associating with leptin. Such a novel interaction between two peptides at the BBB opens new approaches for general study of the dynamic regulatory role of the BBB in brain-body communication as well as the specific study of obesity.

Animals↗

PubMed2002

Differential interactions of urocortin/corticotropin-releasing hormone peptides with the blood-brain barrier.

The two newest members of the urocortin (UCN)/corticotropin-releasing hormone (CRH) family of peptides - UCN II and UCN III - bind to the CRH-2 receptor, suppress feeding, and are expressed in the periphery as well as the brain. We used several sensitive techniques to examine their interactions with the blood-brain barrier (BBB). Of the four known peptides in this family, each interacts with the BBB differently. UCN I barely enters the brain from blood unless its latent saturable influx system is activated by leptin or pretreatment with glucose. However, neither leptin nor glucose affected the entry of intact UCN II. UCN II reached brain paranchyma at a moderate rate that was not self-inhibited or cross-inhibited by UCN/CRH peptides. The apparent, but misleading, rapid influx of UCN III (stresscopin) could be explained by degradation at the BBB itself. Influx of CRH into brain was slower than UCN II but faster than UCN I; it was inhibited by excess CRH but not by excess UCN I, II, III, or leptin. CRH is the only member of this family to have a saturable efflux system out of the brain. Determination of hydrogen bonding, newly applied here to ingestive peptides, was not helpful in explaining these differential interactions of the UCN peptides with the BBB.

Animals↗

PubMedDate not supplied

Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier.

Glucagon-like peptide-1 (GLP-1) reduces insulin requirement in diabetes mellitus and promotes satiety. GLP-1 in the periphery (outside the CNS) has been shown to act on the brain to reduce food ingestion. As GLP-1 is readily degraded in blood, we focused on the interactions of [Ser8]GLP-1, an analog with similar biological effects and greater stability, with the blood-brain barrier (BBB). The influx of radiolabeled [Ser8]GLP-1 into brain has several distinctive characteristics: 1. A rapid influx rate of 8.867 +/- 0.798 x 10(4) mL/g-min as measured by multiple-time regression analysis after iv injection in mice. 2. Lack of self-inhibition by excess doses of the unlabeled [Ser8]GLP-1 either iv or by in situ brain perfusion, indicating the absence of a saturable transport system at the BBB. 3. Lack of modulation by short-term fasting and some other ingestive peptides that may interact with GLP-1, including leptin, glucagon, insulin, neuropeptide Y, and melanin-concentrating hormone. 4. No inhibition of influx by the selective GLP-1 receptor antagonist exendin(9-39), suggesting that the GLP-1 receptor is not involved in the rapid entry into brain. Similarly, there was no efflux system for [Ser8]GLP-1 to exit the brain other than following the reabsorption of cerebrospinal fluid (CSF). The fast influx was not associated with high lipid solubility. Upon reaching the brain compartment, substantial amounts of [Ser8]GLP-1 entered the brain parenchyma, but a large proportion was loosely associated with the vasculature at the BBB. Finally, the influx rate of [Ser8]GLP-1 was compared with that of GLP-1 in a blood-free brain perfusion system; radiolabeled GLP-1 had a more rapid influx than its analog and neither peptide showed the self-inhibition indicative of a saturable transport system. Therefore, we conclude that [Ser8]GLP-1 and the endogenous peptide GLP-1 can gain access to the brain from the periphery by simple diffusion and thus contribute to the regulation of feeding.

Animals↗