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Rapid transport of insulin to the brain following intranasal administration in rats
We previously reported that intranasal insulin protects substantia nigra dopaminergic neurons against 6-hydroxydopamine neurotoxicity in rats. This study aimed to assess insulin pharmacokinetics in the rat brain following intranasal application. Recombinant human insulin (rh-Ins) or phosphate buffer...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Medknow Publications & Media Pvt Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404510/ https://www.ncbi.nlm.nih.gov/pubmed/30762017 http://dx.doi.org/10.4103/1673-5374.250624 |
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author | Fan, Lir-Wan Carter, Kathleen Bhatt, Abhay Pang, Yi |
author_facet | Fan, Lir-Wan Carter, Kathleen Bhatt, Abhay Pang, Yi |
author_sort | Fan, Lir-Wan |
collection | PubMed |
description | We previously reported that intranasal insulin protects substantia nigra dopaminergic neurons against 6-hydroxydopamine neurotoxicity in rats. This study aimed to assess insulin pharmacokinetics in the rat brain following intranasal application. Recombinant human insulin (rh-Ins) or phosphate buffer solution was administered to both nostrils of rats. Animals were sacrificed at 15 minutes, 1, 2, and 6 hours to determine insulin levels in different brain regions by an ultrasensitive, human-specific enzyme-linked immunosorbent assay kit. For fluorescence tracing study, rats were administered with intranasal florescence-tagged insulin (Alex546-Ins), and brains were fixed at 10 and 30 minutes to prepare sagittal sections. rh-Ins was detected in all brain regions examined except the cerebral cortex. The highest levels were detected in the brainstem, followed by the cerebellum, substantia nigra/ventral tegmental area, olfactory bulb, striatum, hippocampus, and thalamus/hypothalamus. Insulin levels reached a peak at 15 minutes and then declined gradually overtime, but remained significantly higher than baseline levels at 6 hours in most regions. Consistently, widespread Alex546-Ins-binding cells were detected in the brain at 10 and 30 minutes, with the olfactory bulb and brainstem showing the highest while the cerebral cortex showing lowest fluorescence signals. Double-immunostaining showed that Alex546-Ins-bindings were primarily co-localized with neuronal nuclei-positive neurons. In the subtantia nigra, phospho-Akt was found to be activated in a subset of Alex546-Ins and tyrosine hydroxylase double-labeled cells, suggesting activation of the Akt/PI3K pathway in these dopaminergic neurons. Data from this study suggest that intranasal insulin could effectively reach deep brain structures including the nigrostriatal pathways, where it binds to dopaminergic neurons and activates intracellular cell survival signaling. This study was approved by the Institutional Animal Care Committee at the University of Mississippi Medical Center (protocol 1333A) on June 29, 2015. |
format | Online Article Text |
id | pubmed-6404510 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Medknow Publications & Media Pvt Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-64045102019-06-01 Rapid transport of insulin to the brain following intranasal administration in rats Fan, Lir-Wan Carter, Kathleen Bhatt, Abhay Pang, Yi Neural Regen Res Research Article We previously reported that intranasal insulin protects substantia nigra dopaminergic neurons against 6-hydroxydopamine neurotoxicity in rats. This study aimed to assess insulin pharmacokinetics in the rat brain following intranasal application. Recombinant human insulin (rh-Ins) or phosphate buffer solution was administered to both nostrils of rats. Animals were sacrificed at 15 minutes, 1, 2, and 6 hours to determine insulin levels in different brain regions by an ultrasensitive, human-specific enzyme-linked immunosorbent assay kit. For fluorescence tracing study, rats were administered with intranasal florescence-tagged insulin (Alex546-Ins), and brains were fixed at 10 and 30 minutes to prepare sagittal sections. rh-Ins was detected in all brain regions examined except the cerebral cortex. The highest levels were detected in the brainstem, followed by the cerebellum, substantia nigra/ventral tegmental area, olfactory bulb, striatum, hippocampus, and thalamus/hypothalamus. Insulin levels reached a peak at 15 minutes and then declined gradually overtime, but remained significantly higher than baseline levels at 6 hours in most regions. Consistently, widespread Alex546-Ins-binding cells were detected in the brain at 10 and 30 minutes, with the olfactory bulb and brainstem showing the highest while the cerebral cortex showing lowest fluorescence signals. Double-immunostaining showed that Alex546-Ins-bindings were primarily co-localized with neuronal nuclei-positive neurons. In the subtantia nigra, phospho-Akt was found to be activated in a subset of Alex546-Ins and tyrosine hydroxylase double-labeled cells, suggesting activation of the Akt/PI3K pathway in these dopaminergic neurons. Data from this study suggest that intranasal insulin could effectively reach deep brain structures including the nigrostriatal pathways, where it binds to dopaminergic neurons and activates intracellular cell survival signaling. This study was approved by the Institutional Animal Care Committee at the University of Mississippi Medical Center (protocol 1333A) on June 29, 2015. Medknow Publications & Media Pvt Ltd 2019-06 /pmc/articles/PMC6404510/ /pubmed/30762017 http://dx.doi.org/10.4103/1673-5374.250624 Text en Copyright: © Neural Regeneration Research http://creativecommons.org/licenses/by-nc-sa/4.0 This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. |
spellingShingle | Research Article Fan, Lir-Wan Carter, Kathleen Bhatt, Abhay Pang, Yi Rapid transport of insulin to the brain following intranasal administration in rats |
title | Rapid transport of insulin to the brain following intranasal administration in rats |
title_full | Rapid transport of insulin to the brain following intranasal administration in rats |
title_fullStr | Rapid transport of insulin to the brain following intranasal administration in rats |
title_full_unstemmed | Rapid transport of insulin to the brain following intranasal administration in rats |
title_short | Rapid transport of insulin to the brain following intranasal administration in rats |
title_sort | rapid transport of insulin to the brain following intranasal administration in rats |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404510/ https://www.ncbi.nlm.nih.gov/pubmed/30762017 http://dx.doi.org/10.4103/1673-5374.250624 |
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