Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota
| Autor: | Chang Qu, Siu-Po Ip, Qiao-Ping Li, Qiuju Yuan, Yan-Feng Huang, Zi-Ren Su, You-Liang Xie, Zhi-Xiu Lin, Qing-Qing Xu, Yan-Fang Xian, Wen Yang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Honokiol Male WT wild type Medicine (General) Science (General) Aβ β-amyloid Morris water navigation task Pharmaceutical Science MWMT Morris Water Maze test PDI poly-dispersity index PS-1 presenilin-1 Pharmacology NEP neprilysin NFTs neurofibrillary tangles chemistry.chemical_compound Q1-390 Mice IL-1β interleukin 1β 0302 clinical medicine Cognition Neuroinflammation Amyloid precursor protein Neprilysin GSK-3β glycogen synthase kinase 3β Multidisciplinary Microglia biology Cognitive deficits TEM transmission electron microscope IL-6 interleukin 6 medicine.anatomical_structure Tau protein hyperphosphorylation HPLC high performance liquid chromatography 030220 oncology & carcinogenesis JNK c-Jun N-terminal kinase Bcl-2 B cell lymphoma-2 CMC-Na sodium carboxymethylcellulose PBS phosphate-buffered saline Honokiol nanoscale drug delivery system Gut microbiota AD Alzheimer’s disease Neuroprotection Lignans 03 medical and health sciences MCT Medium-chain triglycerides R5-920 HO Honokiol ROS reactive oxygen species Alzheimer Disease APP amyloid precursor protein medicine Animals IDE insulin degrading enzyme Cognitive Dysfunction ZP zeta potential ComputingMethodologies_COMPUTERGRAPHICS Glycogen Synthase Kinase 3 beta Biphenyl Compounds CDK5 cyclin-dependent kinase 5 Nano-HO honokiol nanoscale drug delivery system TgCRND8 mice Bioavailability Gastrointestinal Microbiome APH-1 anterior pharynx-defective-1 TNF-α tumor necrosis factor 030104 developmental biology chemistry BACE-1 β-site APP cleaving enzyme-1 Neuroinflammatory Diseases biology.protein |
| Zdroj: | Journal of Advanced Research Journal of Advanced Research, Vol 35, Iss, Pp 231-243 (2022) |
| ISSN: | 2090-1224 |
| Popis: | Graphical abstract Highlights • In the same content, Nano-HO could effectively enhance the bioactivity of HO remarkably and prolonged its circulation time in rats. • Nano-HO improved cognitive deficits in TgCRND8 mice. • Nano-HO suppressed neuroinflammatory response (TNF-α, IL-Iβ, IL-6) inhibited the activation of microglia, astrocyte and A-β plaque burdens in TgCRND8 mice. • Nano-HO ameliorated AD through regulating APP processing, preventing tau hyperphosphorylation and modulating JNK/CDK5/GSK-3β pathway. • Nano-HO regulated the composition and structure of gut microbiota to protect the gut microflora and its stability. 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. |
| Databáze: | OpenAIRE |
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