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Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier

St-Amour, Isabelle; Paré, Isabelle; Alata, Wael; Coulombe, Katherine; Ringuette-Goulet, Cassandra; Drouin-Ouellet, Janelle LU ; Vandal, Milène; Soulet, Denis LU ; Bazin, Renée and Calon, Frédéric (2013) In Journal of Cerebral Blood Flow and Metabolism 33(12). p.92-1983
Abstract

Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood-brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009±0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low... (More)

Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood-brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009±0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053  per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Biological Availability, Blood-Brain Barrier, Brain, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulins, Intravenous, Mice, Mice, Inbred C57BL, Journal Article, Research Support, Non-U.S. Gov't
in
Journal of Cerebral Blood Flow and Metabolism
volume
33
issue
12
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:84889089629
ISSN
0271-678X
DOI
10.1038/jcbfm.2013.160
language
English
LU publication?
no
id
1c26d2b0-c02d-4234-b78b-b25250ea0898
date added to LUP
2016-11-22 09:03:26
date last changed
2018-10-03 11:02:15
@article{1c26d2b0-c02d-4234-b78b-b25250ea0898,
  abstract     = {<p>Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood-brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009±0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053  per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets.</p>},
  author       = {St-Amour, Isabelle and Paré, Isabelle and Alata, Wael and Coulombe, Katherine and Ringuette-Goulet, Cassandra and Drouin-Ouellet, Janelle and Vandal, Milène and Soulet, Denis and Bazin, Renée and Calon, Frédéric},
  issn         = {0271-678X},
  keyword      = {Animals,Biological Availability,Blood-Brain Barrier,Brain,Enzyme-Linked Immunosorbent Assay,Female,Humans,Immunoglobulins, Intravenous,Mice,Mice, Inbred C57BL,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {12},
  pages        = {92--1983},
  publisher    = {Nature Publishing Group},
  series       = {Journal of Cerebral Blood Flow and Metabolism},
  title        = {Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier},
  url          = {http://dx.doi.org/10.1038/jcbfm.2013.160},
  volume       = {33},
  year         = {2013},
}