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Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease

Melatonin, insulin, and Δ9-tetrahydrocannabinol (THC) have been shown to reverse cognitive deficits and attenuate neuropathologies in transgenic mouse models of Alzheimer’s disease (AD) when used individually. Here, we evaluated the therapeutic properties of long-term intranasal treatment with a nov...

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Autores principales: Fihurka, Oksana, Wang, Yanhong, Hong, Yuzhu, Lin, Xiaoyang, Shen, Ning, Yang, Haiqiang, Brown, Breanna, Mommer, Marcus, Zieneldien, Tarek, Li, Yitong, Kim, Janice, Li, Minghua, Cai, Jianfeng, Zhou, Qingyu, Cao, Chuanhai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9953380/
https://www.ncbi.nlm.nih.gov/pubmed/36830601
http://dx.doi.org/10.3390/biom13020232
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author Fihurka, Oksana
Wang, Yanhong
Hong, Yuzhu
Lin, Xiaoyang
Shen, Ning
Yang, Haiqiang
Brown, Breanna
Mommer, Marcus
Zieneldien, Tarek
Li, Yitong
Kim, Janice
Li, Minghua
Cai, Jianfeng
Zhou, Qingyu
Cao, Chuanhai
author_facet Fihurka, Oksana
Wang, Yanhong
Hong, Yuzhu
Lin, Xiaoyang
Shen, Ning
Yang, Haiqiang
Brown, Breanna
Mommer, Marcus
Zieneldien, Tarek
Li, Yitong
Kim, Janice
Li, Minghua
Cai, Jianfeng
Zhou, Qingyu
Cao, Chuanhai
author_sort Fihurka, Oksana
collection PubMed
description Melatonin, insulin, and Δ9-tetrahydrocannabinol (THC) have been shown to reverse cognitive deficits and attenuate neuropathologies in transgenic mouse models of Alzheimer’s disease (AD) when used individually. Here, we evaluated the therapeutic properties of long-term intranasal treatment with a novel nanoformulation containing melatonin, insulin, and THC in aged APPswe/PS1ΔE9 (APP/PS1) mice, a transgenic model of AD. Transgenic mice at the age of 12 months were intranasally administered with a new nanoformulation containing melatonin, insulin, and THC at doses of 0.04, 0.008, and 0.02 mg/kg, respectively, once daily for 3 months. The spatial memory of the mice was assessed using the radial arm water maze (RAWM) test before and after drug treatment. Brain tissues were collected at the end of the treatment period for the assessment of Aβ load, tauopathy state, and markers of mitochondrial function. The RAWM test revealed that the treatment with the melatonin–insulin–THC (MIT) nasal spray improved the spatial learning memory of APP/PS1 mice significantly. Results of protein analyses of brain homogenates indicated that MIT treatment significantly decreased the tau phosphorylation implicated in tau toxicity (p < 0.05) and the expression of CKMT1 associated with mitochondrial dysfunction. Moreover, MIT significantly decreased the expression of two mitochondrial fusion-related proteins, Mfn2 and Opa1 (p < 0.01 for both), while increasing the expression of a mitophagy regulator, Parkin, suggesting a compensatory enhancement of mitophagy due to MIT-promoted mitochondrial fusion. In conclusion, this study was the first to demonstrate the ability of an MIT nanoformulation to improve spatial memory in AD mice through its multi-targeting effects on Aβ production, tau phosphorylation, and mitochondrial dynamics. Thus, MIT may be a safe and effective therapeutic for AD.
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spelling pubmed-99533802023-02-25 Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease Fihurka, Oksana Wang, Yanhong Hong, Yuzhu Lin, Xiaoyang Shen, Ning Yang, Haiqiang Brown, Breanna Mommer, Marcus Zieneldien, Tarek Li, Yitong Kim, Janice Li, Minghua Cai, Jianfeng Zhou, Qingyu Cao, Chuanhai Biomolecules Article Melatonin, insulin, and Δ9-tetrahydrocannabinol (THC) have been shown to reverse cognitive deficits and attenuate neuropathologies in transgenic mouse models of Alzheimer’s disease (AD) when used individually. Here, we evaluated the therapeutic properties of long-term intranasal treatment with a novel nanoformulation containing melatonin, insulin, and THC in aged APPswe/PS1ΔE9 (APP/PS1) mice, a transgenic model of AD. Transgenic mice at the age of 12 months were intranasally administered with a new nanoformulation containing melatonin, insulin, and THC at doses of 0.04, 0.008, and 0.02 mg/kg, respectively, once daily for 3 months. The spatial memory of the mice was assessed using the radial arm water maze (RAWM) test before and after drug treatment. Brain tissues were collected at the end of the treatment period for the assessment of Aβ load, tauopathy state, and markers of mitochondrial function. The RAWM test revealed that the treatment with the melatonin–insulin–THC (MIT) nasal spray improved the spatial learning memory of APP/PS1 mice significantly. Results of protein analyses of brain homogenates indicated that MIT treatment significantly decreased the tau phosphorylation implicated in tau toxicity (p < 0.05) and the expression of CKMT1 associated with mitochondrial dysfunction. Moreover, MIT significantly decreased the expression of two mitochondrial fusion-related proteins, Mfn2 and Opa1 (p < 0.01 for both), while increasing the expression of a mitophagy regulator, Parkin, suggesting a compensatory enhancement of mitophagy due to MIT-promoted mitochondrial fusion. In conclusion, this study was the first to demonstrate the ability of an MIT nanoformulation to improve spatial memory in AD mice through its multi-targeting effects on Aβ production, tau phosphorylation, and mitochondrial dynamics. Thus, MIT may be a safe and effective therapeutic for AD. MDPI 2023-01-25 /pmc/articles/PMC9953380/ /pubmed/36830601 http://dx.doi.org/10.3390/biom13020232 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fihurka, Oksana
Wang, Yanhong
Hong, Yuzhu
Lin, Xiaoyang
Shen, Ning
Yang, Haiqiang
Brown, Breanna
Mommer, Marcus
Zieneldien, Tarek
Li, Yitong
Kim, Janice
Li, Minghua
Cai, Jianfeng
Zhou, Qingyu
Cao, Chuanhai
Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease
title Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease
title_full Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease
title_fullStr Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease
title_full_unstemmed Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease
title_short Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease
title_sort multi-targeting intranasal nanoformulation as a therapeutic for alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9953380/
https://www.ncbi.nlm.nih.gov/pubmed/36830601
http://dx.doi.org/10.3390/biom13020232
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