Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimer's disease via inhibiting neuropathology and modulating gut microbiota

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-alpha, IL-6 and IL-1 beta in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing beta-amyloid (A beta) 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 beta-secretase, as well as enhancing A beta-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-3 beta (Ser9)/GSK-3 beta. 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 A beta deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3 beta 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. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.

Automated summary

The novel honokiol nanoscale drug delivery system greatly improved the oral bioavailability of honokiol and effectively inhibited amyloid deposition, improved cognitive deficits, and attenuated neuroinflammation in Alzheimer's disease model mice. Honokiol nanoscale drug delivery system showed great potential for further development as a therapeutic agent for Alzheimer's disease treatment.