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.
Keywords: AD, Alzheimer’s disease; APH-1, anterior pharynx-defective-1; APP, amyloid precursor protein; Aβ, β-amyloid; BACE-1, β-site APP cleaving enzyme-1; Bcl-2, B cell lymphoma-2; CDK5, cyclin-dependent kinase 5; CMC-Na, sodium carboxymethylcellulose; Cognitive deficits; GSK-3β, glycogen synthase kinase 3β; Gut microbiota; HO, Honokiol; HPLC, high performance liquid chromatography; Honokiol nanoscale drug delivery system; IDE, insulin degrading enzyme; IL-1β, interleukin 1β; IL-6, interleukin 6; JNK, c-Jun N-terminal kinase; MCT, Medium-chain triglycerides; MWMT, Morris Water Maze test; NEP, neprilysin; NFTs, neurofibrillary tangles; Nano-HO, honokiol nanoscale drug delivery system; Neuroinflammation; PBS, phosphate-buffered saline; PDI, poly-dispersity index; PS-1, presenilin-1; ROS, reactive oxygen species; TEM, transmission electron microscope; TNF-α, tumor necrosis factor; Tau protein hyperphosphorylation; TgCRND8 mice; WT, wild type; ZP, zeta potential.
© 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.