和厚朴酚(HO)在几种阿尔茨海默病(AD)动物模型中发挥神经保护作用,但不良的溶出度阻碍了其生物利用度和治疗效果。
在这项研究中开发了一种具有较小尺寸和出色稳定性的新型和厚朴酚纳米级药物递送系统(Nano-HO),以提高HO的溶解度和生物利用度。测定了Nano-HO的抗AD作用。
雄性TgCRND8小鼠每天口服相同剂量(20mg/kg)的Nano-HO或HO,连续17周,然后使用Morris水迷宫测试(MWMT)评估空间学习和记忆功能。
我们的药代动力学研究表明,Nano-HO大大提高了口服生物利用度。此外,Nano-HO通过抑制TNF-α水平显著改善认知缺陷和抑制神经炎症,IL-6和IL-1β在大脑中,防止小胶质细胞(IBA-1)和星形胶质细胞(GFAP)的激活,并减少TgCRND8小鼠皮质和海马中β-淀粉样蛋白(Aβ)的沉积。此外,Nano-HO在通过抑制β-分泌酶调节淀粉样前体蛋白(APP)加工方面比HO更有效,以及增强Aβ降解酶,如Neprilysin(NEP)。此外,Nano-HO通过降低p-Tau(Thr205)/tau的比例和调节tau相关的凋亡蛋白(caspase-3和Bcl-2),更明显地抑制tau过度磷酸化。此外,Nano-HO更明显地减弱了p-JNK/JNK和p-35/CDK5的比率,同时增强了p-GSK-3β(Ser9)/GSK-3β的比率。最后,Nano-HO以比游离HO更有效的方式预防TgCRND8小鼠的肠道菌群失调。
Nano-HO在通过抑制Aβ沉积改善TgCRND8小鼠的认知障碍方面比游离HO更有效,tau蛋白过度磷酸化通过抑制JNK/CDK5/GSK-3β信号通路的激活而引起神经炎症。Nano-HO还比游离HO更有效地调节肠道微生物群落以保护其稳定性。这些结果表明,Nano-HO具有进一步开发用于AD治疗的治疗剂的良好潜力。
Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer\'s disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy.
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.
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).
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.
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.