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Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota.
J Adv Res. 2022 01; 35:231-243.JA

Abstract

Introduction

Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy.

Objectives

A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined.

Methods

Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT).

Results

Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO.

Conclusion

Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.

Authors+Show Affiliations

School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Brain Research Centre, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Brain Research Centre, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Brain Research Centre, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Brain Research Centre, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35024199

Citation

Qu, Chang, et al. "Nano-Honokiol Ameliorates the Cognitive Deficits in TgCRND8 Mice of Alzheimer's Disease Via Inhibiting Neuropathology and Modulating Gut Microbiota." Journal of Advanced Research, vol. 35, 2022, pp. 231-243.
Qu C, Li QP, Su ZR, et al. Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota. J Adv Res. 2022;35:231-243.
Qu, C., Li, Q. P., Su, Z. R., Ip, S. P., Yuan, Q. J., Xie, Y. L., Xu, Q. Q., Yang, W., Huang, Y. F., Xian, Y. F., & Lin, Z. X. (2022). Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota. Journal of Advanced Research, 35, 231-243. https://doi.org/10.1016/j.jare.2021.03.012
Qu C, et al. Nano-Honokiol Ameliorates the Cognitive Deficits in TgCRND8 Mice of Alzheimer's Disease Via Inhibiting Neuropathology and Modulating Gut Microbiota. J Adv Res. 2022;35:231-243. PubMed PMID: 35024199.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota. AU - Qu,Chang, AU - Li,Qiao-Ping, AU - Su,Zi-Ren, AU - Ip,Siu-Po, AU - Yuan,Qiu-Ju, AU - Xie,You-Liang, AU - Xu,Qing-Qing, AU - Yang,Wen, AU - Huang,Yan-Feng, AU - Xian,Yan-Fang, AU - Lin,Zhi-Xiu, Y1 - 2021/03/31/ PY - 2020/10/25/received PY - 2021/03/08/revised PY - 2021/03/28/accepted PY - 2022/1/13/entrez PY - 2022/1/14/pubmed PY - 2022/1/27/medline KW - AD, Alzheimer’s disease KW - APH-1, anterior pharynx-defective-1 KW - APP, amyloid precursor protein KW - Aβ, β-amyloid KW - BACE-1, β-site APP cleaving enzyme-1 KW - Bcl-2, B cell lymphoma-2 KW - CDK5, cyclin-dependent kinase 5 KW - CMC-Na, sodium carboxymethylcellulose KW - Cognitive deficits KW - GSK-3β, glycogen synthase kinase 3β KW - Gut microbiota KW - HO, Honokiol KW - HPLC, high performance liquid chromatography KW - Honokiol nanoscale drug delivery system KW - IDE, insulin degrading enzyme KW - IL-1β, interleukin 1β KW - IL-6, interleukin 6 KW - JNK, c-Jun N-terminal kinase KW - MCT, Medium-chain triglycerides KW - MWMT, Morris Water Maze test KW - NEP, neprilysin KW - NFTs, neurofibrillary tangles KW - Nano-HO, honokiol nanoscale drug delivery system KW - Neuroinflammation KW - PBS, phosphate-buffered saline KW - PDI, poly-dispersity index KW - PS-1, presenilin-1 KW - ROS, reactive oxygen species KW - TEM, transmission electron microscope KW - TNF-α, tumor necrosis factor KW - Tau protein hyperphosphorylation KW - TgCRND8 mice KW - WT, wild type KW - ZP, zeta potential SP - 231 EP - 243 JF - Journal of advanced research JO - J Adv Res VL - 35 N2 - Introduction: Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy. Objectives: A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined. Methods: Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT). Results: Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO. Conclusion: Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment. SN - 2090-1224 UR - https://www.unboundmedicine.com/medline/citation/35024199/Nano_Honokiol_ameliorates_the_cognitive_deficits_in_TgCRND8_mice_of_Alzheimer's_disease_via_inhibiting_neuropathology_and_modulating_gut_microbiota_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2090-1232(21)00061-8 DB - PRIME DP - Unbound Medicine ER -