TY - JOUR
T1 - Long-term intranasal insulin aspart
T2 - A profile of gene expression, memory, and insulin receptors in aged F344 rats
AU - Frazier, Hilaree N.
AU - Ghoweri, Adam O.
AU - Sudkamp, Emily
AU - Johnson, Eleanor S.
AU - Anderson, Katie L.
AU - Fox, Grant
AU - Vatthanaphone, Keomany
AU - Xia, Mengfan
AU - Lin, Ruei Lung
AU - Hargis-Staggs, Kendra E.
AU - Porter, Nada M.
AU - Pauly, James R.
AU - Blalock, Eric M.
AU - Thibault, Olivier
N1 - Funding Information:
This work is supported by the National Institutes of Health (R01AG033649 to O.T., T32DK007778 to H.N.F., and T32AG057461 to A.O.G.).
Publisher Copyright:
© The Author(s) 2019.
PY - 2020
Y1 - 2020
N2 - Intranasal insulin is a safe and effective method for ameliorating memory deficits associated with pathological brain aging. However, the impact of different formulations and the duration of treatment on insulin’s efficacy and the cellular processes targeted by the treatment remain unclear. Here, we tested whether intranasal insulin aspart, a short-acting insulin formulation, could alleviate memory decline associated with aging and whether long-term treatment affected regulation of insulin receptors and other potential targets. Outcome variables included measures of spatial learning and memory, autoradiography and immunohistochemistry of the insulin receptor, and hippocampal microarray analyses. Aged Fischer 344 rats receiving long-term (3 months) intranasal insulin did not show significant memory enhancement on the Morris water maze task. Autoradiography results showed that long-term treatment reduced insulin binding in the thalamus but not the hippocampus. Results from hippocampal immunofluorescence revealed age-related decreases in insulin immunoreactivity that were partially offset by intranasal administration. Microarray analyses highlighted numerous insulin-sensitive genes, suggesting insulin aspart was able to enter the brain and alter hippocampal RNA expression patterns including those associated with tumor suppression. Our work provides insights into potential mechanisms of intranasal insulin and insulin resistance, and highlights the importance of treatment duration and the brain regions targeted.
AB - Intranasal insulin is a safe and effective method for ameliorating memory deficits associated with pathological brain aging. However, the impact of different formulations and the duration of treatment on insulin’s efficacy and the cellular processes targeted by the treatment remain unclear. Here, we tested whether intranasal insulin aspart, a short-acting insulin formulation, could alleviate memory decline associated with aging and whether long-term treatment affected regulation of insulin receptors and other potential targets. Outcome variables included measures of spatial learning and memory, autoradiography and immunohistochemistry of the insulin receptor, and hippocampal microarray analyses. Aged Fischer 344 rats receiving long-term (3 months) intranasal insulin did not show significant memory enhancement on the Morris water maze task. Autoradiography results showed that long-term treatment reduced insulin binding in the thalamus but not the hippocampus. Results from hippocampal immunofluorescence revealed age-related decreases in insulin immunoreactivity that were partially offset by intranasal administration. Microarray analyses highlighted numerous insulin-sensitive genes, suggesting insulin aspart was able to enter the brain and alter hippocampal RNA expression patterns including those associated with tumor suppression. Our work provides insights into potential mechanisms of intranasal insulin and insulin resistance, and highlights the importance of treatment duration and the brain regions targeted.
KW - Animal model
KW - Antiaging
KW - Cognitive decline
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U2 - 10.1093/GERONA/GLZ105
DO - 10.1093/GERONA/GLZ105
M3 - Article
C2 - 31180116
AN - SCOPUS:85085263537
SN - 1079-5006
VL - 75
SP - 1021
EP - 1030
JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
IS - 6
ER -