Cited by 57Barrier Structure and Function StudiesNitric Oxide and Endothelin EffectsDrug Transport and Resistance Mechanisms

Nitric oxide isoenzymes regulate lipopolysaccharide-enhanced insulin transport across the blood-brain barrier

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Banks, William A., Dohgu, Shinya, Lynch, Jessica L., Fleegal-DeMotta, Melissa A., Erickson, Michelle A., Nakaoke, Ryota, Vo, Than Q.·2008·Endocrinology

Abstract

Insulin transported across the blood-brain barrier (BBB) has many effects within the central nervous system. Insulin transport is not static but altered by obesity and inflammation. Lipopolysaccharide (LPS), derived from the cell walls of Gram-negative bacteria, enhances insulin transport across the BBB but also releases nitric oxide (NO), which opposes LPS-enhanced insulin transport. Here we determined the role of NO synthase (NOS) in mediating the effects of LPS on insulin BBB transport. The activity of all three NOS isoenzymes was stimulated in vivo by LPS. Endothelial NOS and inducible NOS together mediated the LPS-enhanced transport of insulin, whereas neuronal NOS (nNOS) opposed LPS-enhanced insulin transport. This dual pattern of NOS action was found in most brain regions with the exception of the striatum, which did not respond to LPS, and the parietal cortex, hippocampus, and pons medulla, which did not respond to nNOS inhibition. In vitro studies of a brain endothelial cell (BEC) monolayer BBB model showed that LPS did not directly affect insulin transport, whereas NO inhibited insulin transport. This suggests that the stimulatory effect of LPS and NOS on insulin transport is mediated through cells of the neurovascular unit other than BECs. Protein and mRNA levels of the isoenzymes indicated that the effects of LPS are mainly posttranslational. In conclusion, LPS affects insulin transport across the BBB by modulating NOS isoenzyme activity. NO released by endothelial NOS and inducible NOS acts indirectly to stimulate insulin transport, whereas NO released by nNOS acts directly on BECs to inhibit insulin transport.

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Crossref · 10.1210/en.2007-1091

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  • Gut-derived lipopolysaccharide can promote disruption of the blood brain barrier and thus facilitate neuroinflammation and injury in the substantia nigra triggered by environmental factors.

    “In addition, gut-derived LPS can promote the disruption of the blood brain barrier (Banks et al., 2008;Banks and Erickson, 2010) and thus facilitate neuroinflammation and injury in the SN that is triggered by the above stated environmental factors.”

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Authors
Banks, W. A., Dohgu, S., Lynch, J. L., Fleegal-DeMotta, M. A., Erickson, M. A., Nakaoke, R., & Vo, T. Q.
Affiliations
  • St. Louis VA Medical Center (US)
  • Division of Geriatrics, Department of Internal Medicine, Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, St. Louis, and Saint Louis University School of Medicine, St. Louis, Missouri 63106
Venue
Endocrinology
Published
2008-01-10
Volume
149
Issue
4
Pages
1514-1523
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
OpenAlex
W1976811593
Cited by
57
References
75
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 2 · 2013: 1 · 2012: 3
FWCI
2.63
Type
journal article
Language
en
Open access
Locations
  • Endocrinology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
nitric oxide, nitric oxide synthase, insulin transport, blood-brain barrier, lipopolysaccharide, endothelial nitric oxide synthase, inducible nitric oxide synthase, neuronal nitric oxide synthase, neurovascular unit, brain endothelial cells, inflammation, obesity
MeSH terms
Animals, Biological Transport, Blood-Brain Barrier, Cells, Cultured, Insulin, Isoenzymes, Lipopolysaccharides, Nitric Oxide, Ornithine, Electric Impedance, Nitric Oxide Synthase, Mice

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