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Article

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

1
Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
2
Department of Neurology, College of Medicine, University of South Florida, Tampa, FL 33612, USA
3
Department of Chemistry, College of Arts & Sciences, University of South Florida, Tampa, FL 33612, USA
4
USF-health Byrd Alzheimer Institute, Tampa, FL 33612, USA
*
Authors to whom correspondence should be addressed.
Biomolecules 2023, 13(2), 232; https://doi.org/10.3390/biom13020232
Received: 28 October 2022 / Revised: 5 January 2023 / Accepted: 20 January 2023 / Published: 25 January 2023
(This article belongs to the Special Issue Effective Strategies for the Treatment of Alzheimer’s Disease)

Abstract

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.
Keywords: melatonin; insulin; THC; intranasal treatment; APP/PS1 mice; Alzheimer’s disease melatonin; insulin; THC; intranasal treatment; APP/PS1 mice; Alzheimer’s disease

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MDPI and ACS Style

Fihurka, O.; Wang, Y.; Hong, Y.; Lin, X.; Shen, N.; Yang, H.; Brown, B.; Mommer, M.; Zieneldien, T.; Li, Y.; Kim, J.; Li, M.; Cai, J.; Zhou, Q.; Cao, C. Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease. Biomolecules 2023, 13, 232. https://doi.org/10.3390/biom13020232

AMA Style

Fihurka O, Wang Y, Hong Y, Lin X, Shen N, Yang H, Brown B, Mommer M, Zieneldien T, Li Y, Kim J, Li M, Cai J, Zhou Q, Cao C. Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease. Biomolecules. 2023; 13(2):232. https://doi.org/10.3390/biom13020232

Chicago/Turabian Style

Fihurka, Oksana, Yanhong Wang, Yuzhu Hong, Xiaoyang Lin, Ning Shen, Haiqiang Yang, Breanna Brown, Marcus Mommer, Tarek Zieneldien, Yitong Li, Janice Kim, Minghua Li, Jianfeng Cai, Qingyu Zhou, and Chuanhai Cao. 2023. "Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer’s Disease" Biomolecules 13, no. 2: 232. https://doi.org/10.3390/biom13020232

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