College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, 130117, People's Republic of China.
School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, People's Republic of China.
Neurochem Res. 2024 Jul;49(7):1720-1734. doi: 10.1007/s11064-024-04129-5. Epub 2024 Mar 23.
Vascular dementia (VaD) has a serious impact on the patients' quality of life. Icariin (Ica) possesses neuroprotective potential for treating VaD, yet its oral bioavailability and blood-brain barrier (BBB) permeability remain challenges. This research introduced a PEG-PLGA-loaded chitosan hydrogel-based binary formulation tailored for intranasal delivery, enhancing the intracerebral delivery efficacy of neuroprotective agents. The formulation underwent optimization to facilitate BBB crossing, with examinations conducted on its particle size, morphology, drug-loading capacity, in vitro release, and biodistribution. Using the bilateral common carotid artery occlusion (BCCAO) rat model, the therapeutic efficacy of this binary formulation was assessed against chitosan hydrogel and PEG-PLGA nanoparticles loaded with Ica. Post-intranasal administration, enhanced cognitive function was evident in chronic cerebral hypoperfusion (CCH) rats. Further mechanistic evaluations, utilizing immunohistochemistry (IHC), RT-PCR, and ELISA, revealed augmented transcription of synaptic plasticity-associated proteins like SYP and PSD-95, and a marked reduction in hippocampal inflammatory markers such as IL-1β and TNF-α, highlighting the formulation's promise in alleviating cognitive impairment. The brain-derived neurotrophic factor (BDNF)/tropomyosin related kinase B (TrkB) pathway was activated significantly in the binary formulation compared with the other two. Our study demonstrates that the intranasal application of chitosan hydrogel loaded with Ica-encapsulated PEG-PLGA could effectively deliver Ica into the brain and enhance its neuroprotective effect.
血管性痴呆（VaD）严重影响患者的生活质量。淫羊藿苷（Ica）具有治疗 VaD 的神经保护潜力，但它的口服生物利用度和血脑屏障（BBB）通透性仍然是挑战。本研究引入了一种基于聚乙二醇-聚乳酸-羟基乙酸共聚物（PEG-PLGA）负载壳聚糖水凝胶的二元配方，专门用于鼻内给药，提高神经保护剂的脑内递送效果。该配方经过优化，以促进 BBB 穿越，对其粒径、形态、载药量、体外释放和体内分布进行了考察。利用双侧颈总动脉闭塞（BCCAO）大鼠模型，评估了这种二元配方对壳聚糖水凝胶和载有 Ica 的 PEG-PLGA 纳米颗粒的治疗效果。鼻内给药后，慢性脑低灌注（CCH）大鼠的认知功能得到明显改善。进一步的机制评估，利用免疫组织化学（IHC）、RT-PCR 和 ELISA，发现突触可塑性相关蛋白如 SYP 和 PSD-95 的转录增强，海马炎症标志物如 IL-1β 和 TNF-α显著减少，表明该配方在缓解认知障碍方面具有潜力。与其他两种配方相比，二元配方中脑源性神经营养因子（BDNF）/原肌球蛋白相关激酶 B（TrkB）通路显著激活。我们的研究表明，载有 Ica 的 PEG-PLGA 包封的壳聚糖水凝胶的鼻内应用可以有效地将 Ica 递送到大脑，并增强其神经保护作用。
