Studies of the slow bidirectional transport of iron and transferrin across the blood-brain barrier

Banks, William A.; Kastin, Abba J.; Fasold, Melita B.; Barrera, Carlos M.; Augereau, Genevieve

doi:10.1016/0361-9230(88)90021-4

Cited by 89 publications

(38 citation statements)

References 18 publications

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“…This indicates that the brain/serum ratio does not vary with time, and suggests that no net transport from blood to brain occurs. The best estimate for Ki derived from the regression equation is lower than the one already defined for BSA with a similar methodology [35], This shows that CRH is not effectively transported from the blood to the brain. Since in this model no blood-borne CRH-BP are present, the possible interfering effects of these proteins need not be considered.…”

Section: Discussionmentioning

confidence: 87%

“…These studies were performed with methods described previously [34][35][36][37]. Briefly, mice anesthetized by an intraperitoneal injection of 40% urethane (4 g/kg) had their right carotid artery and left jugular vein exposed; 0.2 ml of the stock solution containing 500,000 cpm of either l25I-hCRH or l25I-oCRH was injected intravenously at time 0.…”

Section: Brain and Peripheral Tissue Uptakementioning

confidence: 99%

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Unidirectional Specific and Modulated Brain to Blood Transport of Corticotropin-Releasing Hormone

Martins

Kastin

Banks³

1996

Neuroendocrinology

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103

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Corticotropin-releasing hormone (CRH) is produced and acts both within the central nervous system and at several peripheral sites. However, it is not known whether CRH is able to cross the blood-brain barrier (BBB) in either direction, or whether the central and peripheral compartments are independent. We studied the transport across the BBB of both human/rat CRH (hCRH) and ovine CRH (oCRH) using the native peptides labeled with ¹²⁵I at the histidine residue, thereby avoiding the use of other synthetic modifications. No apparent transport of either hCRH or oCRH into the brain from blood was found, as measured by multiple-time regression analysis after intravenous injection of the labeled peptides. There were no significant differences between the two forms of the CRH peptide. However, both hCRH and oCRH were rapidly transported out of the brain after intracerebroventricular injection, with half-time (t½) disappearances of 11.1 (hCRH) and 15.1 min (oCRH); the transport rate was significantly different for the human and ovine forms. The transport of hCRH could be specifically inhibited by 5 nmol of unlabeled hCRH (t½ = 17.7 min) but not by the same dose of the synthetic analog αCRH_12–41. The process could also be inhibited by pretreatment with aluminum chloride (t½ = 18.8 min). An indirect influence of the endogenous opiate modulating peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH₂ 5 nmol) was apparent by a change in the initial distribution within the brain. In conclusion, there is a specific unidirectional brain to blood transport system for CRH. This transport system in the mouse has a greater affinity for the human/rat than for the ovine form of the peptide, is inhibited by hCRH itself, and can be disrupted by pretreatment with aluminum. By facilitating the rapid clearance of central CRH, this transport system could be involved in the regulation of central CRH levels and could allow central CRH to reach the general circulation and act at peripheral sites.

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Section: Discussionmentioning

confidence: 87%

Section: Brain and Peripheral Tissue Uptakementioning

confidence: 99%

Unidirectional Specific and Modulated Brain to Blood Transport of Corticotropin-Releasing Hormone

Martins

Kastin

Banks³

1996

Neuroendocrinology

Self Cite

103

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“…Tf-Fe3+ normally enters tissues throughout the body by receptormediated endocytosis of the TfR-(Tf)2 complex (1, 2, 9, 10). Tf receptors have been identified on the endothelial cells of brain vasculature (11)(12)(13) and a bidirectional transport of iron and Tf into and out of the brain has also been demonstrated (14). Histochemical, immunohistochemical, and autoradiographic studies have outlined a differential distribution of iron, Tf, and its receptor throughout the CNS (15)(16)(17)(18).…”

mentioning

confidence: 97%

Aluminum access to the brain: a role for transferrin and its receptor.

Roskams

Connor

1990

Proc. Natl. Acad. Sci. U.S.A.

207

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The toxicity of aluminum in plant and animal cell biology is well established, although poorly understood. Several recent studies have identified aluminum as a potential, although highly controversial, contributory factor in the pathology of Alzheimer disease, amyotrophic lateral sclerosis, and dialysis dementia. For example, aluminum has been found in high concentrations in senile plaques and neurofibrillary tangles, which occur in the brains of subjects with Alzheimer disease. However, a mechanism for the entry of aluminum (Al3+) into the cells of the central nervous system (CNS) has yet to be found. Here we describe a possible route of entry for aluminum into the cells of the CNS via the same high-affmnity receptor-ligand system that has been postulated for iron (Fe3 ) delivery to neurons and glial cells. These results suggest that aluminum is able to gain access to the central nervous system under normal physiological conditions. Furthermore, these data suggest that the interaction between transferrin and its receptor may function as a general metal ion regulatory system in the CNS, extending beyond its postulated role in iron regulation.

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“…The correlation between til2 from the brain and entry rate into the brain also suggests that these two parameters may be interrelated for these three somatostatin analogs. Such a relationship does not generally exist among unrelated compounds (30).…”

mentioning

confidence: 99%

“…insensitive methods. The much more sensitive graphical Fraction method used here has been used to measure entry rates for several peptides and centrally active proteins (29)(30)(31).…”

mentioning

confidence: 99%

Permeability of the murine blood-brain barrier to some octapeptide analogs of somatostatin.

Banks

Barrera

Fasold³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Analogs of somatostatin are being investigated clinically for the treatment of various malignancies, including brain tumors. We studied the ability of three therapeutically promising radioactively labeled somatostatin octapeptide analogs, RC-160, RC-121, and RC-161, to cross the blood-brain barrier (BBB) after peripheral or central injection. After i.v. injection, intact RC-160 was recovered from the blood and the brain. The entry rates were different for each compound but were generally low. By contrast, entry across the intact BBB increased 220 times when RC-160 was given in a serum-free perfusate. This suggests that some serum-related factor, probably the previously described protein binding or an aggregation-promoting factor, is the main determinant in limiting the blood-to-brain passage of somatostatin analogs. Entry into the brain was not inhibited by the addition of unlabeled analog to the perfusate, showing that passage was probably by diffusion across the membranes that comprise the BBB rather than by saturable transport. By contrast, a saturable system was found to transport peptide out of the central nervous system (CNS). The clearance from the CNS of RC-160 and RC-121, but not RC-161, was faster than could be accounted for by reabsorption of cerebrospinal fluid. Transport of radioactively labeled RC-160 out of the CNS was inhibited by unlabeled RC-160 or somatostatin but was not affected by some other peptides known to cross the BBB by their own transport systems. More than 80% of the radioactivity recovered from the blood after intracerebroventricular injection of RC-160 was eluted by HPLC at the position of the labeled analog, showing that the peptide had crossed the BBB in intact form. Our results indicate the presence of a saturable transport system in one direction across the BBB for some superactive analogs of somatostatin. Several problems impede the therapeutic use of naturally occurring peptides, including poor absorption by the gastrointestinal tract, a short half-life in the circulation, and multiple actions. For use in the central nervous system (CNS), limited passage across the blood-brain barrier (BBB) may also be a factor. Most of these problems have been solved in the case of somatostatin by the development of analogs. Circulating half-life has been increased by the development of enzymatically resistant analogs. In addition, the administration of the analogs in sustained-delivery systems (microcapsules) permits the maintenance of high therapeutic blood levels (6, 10, 17). Many analogs show selectivity in their activities. For example, RC-121 is about 100 times more potent than somatostatin-(1-14) tetradecapeptide in the inhibition of growth hormone release but <5 times more potent in the inhibition of gastric acid release (17,18).In contrast, essentially no work has been done to investigate the ability of somatostatin analogs to cross the BBB, although it is known that radioactively iodinated Tyrsomatostatin-(1-14) pentadecapeptide can cross (19). This relationship to the BBB...

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Studies of the slow bidirectional transport of iron and transferrin across the blood-brain barrier

Cited by 89 publications

References 18 publications

Unidirectional Specific and Modulated Brain to Blood Transport of Corticotropin-Releasing Hormone

Unidirectional Specific and Modulated Brain to Blood Transport of Corticotropin-Releasing Hormone

Aluminum access to the brain: a role for transferrin and its receptor.

Permeability of the murine blood-brain barrier to some octapeptide analogs of somatostatin.

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