Nitric oxide isoenzymes regulate lipopolysaccharide-enhanced insulin transport across the blood-brain barrier
Open accessAbstract
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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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.”
From The Gut-Brain Axis in Parkinson’s Disease: Possibilities for Food-Based Therapies (2017) · cites this paper as Banks et al., 2008
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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
- Publisher
- The Endocrine Society
- Published
- 2008-01-10
- Volume
- 149
- Issue
- 4
- Pages
- 1514-1523
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2276709
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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