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Distribution of insulin in trigeminal nerve and brain after intranasal administration

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Lochhead, Jeffrey J., Kellohen, Kathryn L., Ronaldson, Patrick T., Davis, Thomas P.·2019·Scientific Reports
DOI 10.1038/s41598-019-39191-5PMC PMC6385374
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Abstract

In the brain, insulin acts as a growth factor, regulates energy homeostasis, and is involved in learning and memory acquisition. Many central nervous system (CNS) diseases are characterized by deficits in insulin signaling. Pre-clinical studies have shown that intranasal insulin is neuroprotective in models of Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. Clinical trials have also shown that intranasal insulin elicits beneficial cognitive effects in patients with Alzheimer’s disease. It is known that insulin can be detected in the CNS within minutes following intranasal administration. Despite these advances, the anatomical pathways that insulin utilizes to reach the CNS and the cellular CNS targets after intranasal administration are not fully understood. Here, we intranasally administered fluorescently labeled insulin and imaged its localization within the brain and trigeminal nerves. Our data indicates that intranasal insulin can reach cellular CNS targets along extracellular components of the trigeminal nerve. Upon CNS entry, we found insulin significantly increased levels of an activated form of the insulin receptor. These findings suggest that the intranasal route of administration is able to effectively deliver insulin to CNS targets in a biologically active form.

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Crossref · 10.1038/s41598-019-39191-5

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Figures

Figure 1 FITC-insulin was intranasally administered and imaged in the trigeminal nerve 30 min later (B,E,H). Axons in the trigeminal nerve were labeled with the pan-neuronal marker Neuro-Chrom (A,D,G). The merged images (C,F,I) show FITC-insulin in the perineural spaces of the trigeminal nerve. These data suggest FITC-insulin reaches the CNS along perineural spaces of the trigeminal nerve. Scale bar = 10 μm.
Figure 1 FITC-insulin was intranasally administered and imaged in the trigeminal nerve 30 min later (B,E,H). Axons in the trigeminal nerve were labeled with the pan-neuronal marker Neuro-Chrom (A,D,G). The merged images (C,F,I) show FITC-insulin in the perineural spaces of the trigeminal nerve. These data suggest FITC-insulin reaches the CNS along perineural spaces of the trigeminal nerve. Scale bar = 10 μm.CC BY · PubMed Central
Figure 2 FITC-insulin can be detected with an anti-insulin antibody and shows widespread association with blood vessels in the cortex of rats after IN administration (A). Little staining is observed in rats administered IN saline (B). FITC-insulin is observed in the perivascular space (C) of cortical blood vessels (D) 30 min after intranasal administration. Merged image + DAPI is shown in (E). Scale bar = 100 μm for (A,B); 20 μmm for (C–E).
Figure 2 FITC-insulin can be detected with an anti-insulin antibody and shows widespread association with blood vessels in the cortex of rats after IN administration (A). Little staining is observed in rats administered IN saline (B). FITC-insulin is observed in the perivascular space (C) of cortical blood vessels (D) 30 min after intranasal administration. Merged image + DAPI is shown in (E). Scale bar = 100 μm for (A,B); 20 μmm for (C–E).CC BY · PubMed Central
Figure 3 Intranasally administered FITC-insulin can be detected with an anti-insulin antibody in brain regions with high expression of insulin receptors such as the cortex (A), cerebellum (C), hippocampus (E), and hypothalamus (G). Detection of insulin in rats administered intranasal saline is reduced in the cortex (B) cerebellum (D), hippocampus (F), and hypothalamus (H). Scale bar (A,B) = 50 µm; (C–H) = 100 µm.
Figure 3 Intranasally administered FITC-insulin can be detected with an anti-insulin antibody in brain regions with high expression of insulin receptors such as the cortex (A), cerebellum (C), hippocampus (E), and hypothalamus (G). Detection of insulin in rats administered intranasal saline is reduced in the cortex (B) cerebellum (D), hippocampus (F), and hypothalamus (H). Scale bar (A,B) = 50 µm; (C–H) = 100 µm.CC BY · PubMed Central
Figure 4 IN administration of insulin increases levels of phospho(Y1185)-insulin receptor in brain. One hour after IN administration of insulin or saline, Western blot analysis with an antibody specific for phospho(Y1185) insulin receptor was performed on whole brain homogenates. Rats administered IN insulin had significantly higher levels of phospho(Y1185)-insulin receptor in brain compared to rats administered IN saline. Relative expression levels are presented as percentage vs. control. *P < 0.02 (n = 4). The full-length blot is presented in Supplementary Fig. 2.
Figure 4 IN administration of insulin increases levels of phospho(Y1185)-insulin receptor in brain. One hour after IN administration of insulin or saline, Western blot analysis with an antibody specific for phospho(Y1185) insulin receptor was performed on whole brain homogenates. Rats administered IN insulin had significantly higher levels of phospho(Y1185)-insulin receptor in brain compared to rats administered IN saline. Relative expression levels are presented as percentage vs. control. *P < 0.02 (n = 4). The full-length blot is presented in Supplementary Fig. 2.CC BY · PubMed Central
Figure 5 FITC-insulin (~6 kDa) was subjected to SDS-PAGE on a 4–15% Criterion TGX gel (BioRad) and imaged on a ChemiDoc Touch Imaging System (BioRad) to confirm the FITC-insulin used in the study is primarily monomeric. The full-length gel is presented in Supplementary Fig. 1.
Figure 5 FITC-insulin (~6 kDa) was subjected to SDS-PAGE on a 4–15% Criterion TGX gel (BioRad) and imaged on a ChemiDoc Touch Imaging System (BioRad) to confirm the FITC-insulin used in the study is primarily monomeric. The full-length gel is presented in Supplementary Fig. 1.CC BY · PubMed Central

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Metadata

Authors
Lochhead, J. J., Kellohen, K. L., Ronaldson, P. T., & Davis, T. P.
Affiliations
University of Arizona (US)
Corresponding author
Lochhead, Jeffrey J.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-02-22
Volume
9
Issue
1
Pages
2621-2621
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-019-39191-5
PMC
PMC6385374
OpenAlex
W2917482585
Cited by
146
References
52
Citations by year
2026: 17 · 2025: 24 · 2024: 19 · 2023: 18 · 2022: 21 · 2021: 20 · 2020: 21 · 2019: 6
FWCI
7.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • American Heart Association (18CDA34110454)
  • U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (042652)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
intranasal insulin, trigeminal nerve, insulin receptor activation, insulin receptor tyrosine kinase, neuroprotection, Alzheimer's disease, Parkinson's disease, traumatic brain injury, insulin signaling
MeSH terms
Administration, Intranasal, Animals, Brain, Female, Humans, Insulin, Receptor, Insulin, Tissue Distribution, Trigeminal Nerve, Fluorescein-5-isothiocyanate, Rats, Sprague-Dawley, Phosphotyrosine

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