醋酸盐包封脂质体纳米粒经腹腔给药对缺血性脑卒中大鼠模型半影区的神经保护作用。
Intraperitoneal delivery of acetate-encapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke.
机构信息
King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Neuroimaging, London, UK,
University of Westminster, Research Centre for Optimal Health, London, UK.
出版信息
Int J Nanomedicine. 2019 Mar 18;14:1979-1991. doi: 10.2147/IJN.S193965. eCollection 2019.
BACKGROUND
Ischemic stroke is a devastating condition, with metabolic derangement and persistent inflammation enhancing the initial insult of ischaemia. Recombinant tissue plasminogen remains the only effective treatment but limited as therapy must commence soon after the onset of symptoms.
PURPOSE
We investigated whether acetate, which modulates many pathways including inflammation, may attenuate brain injury in stroke. As acetate has a short blood half-life and high amounts irritate the gastrointestinal tract, acetate was administered encapsulated in a liposomal nanoparticle (liposomal-encapsulated acetate, LITA).
METHODS
Transient ischemia was induced by 90 mins middle-cerebral artery occlusion (MCAO) in Sprague-Dawley rats, and LITA or control liposomes given intraperitoneally at occlusion and daily for up to two weeks post-MCAO. Magnetic resonance imaging (MRI) was used to estimate lesion volume at 24 h, 1 and 2 weeks post-MCAO and anterior lateral ventricular volume (ALVv) at 2 weeks post-MCAO. Locomotive behaviour was tested prior to the final MRI scan. After the final scan, brains were collected, and immunohistochemistry was performed.
RESULTS
Lesion volumes were decreased by ~80% from 24 h to one-week post-MCAO, in both control and LITA groups (⩽0.05). However, the lesion was increased by ~50% over the subsequent 1 to 2 weeks after MCAO in the control group (from 24.1±10.0 to 58.7±28.6 mm; ⩽0.05) but remained unchanged in the LITA group. ALVv were also attenuated by LITA treatment at 2 weeks post-MCAO (177.2±11.9% and 135.3±10.9% of contralateral ALVv for control and LITA groups, respectively; ⩽0.05). LITA-treated animals also appeared to have improved motor activity, moving with greater average velocity than control animals. Microglial immunoreactivity was ~40% lower in the LITA group compared to the control group (⩽0.05), but LITA did not modulate neurogenesis, apoptosis, histone acetylation and lipid peroxidation.
CONCLUSION
LITA appears to attenuate the harmful chronic neuroinflammation observed during brain remodeling after a focal ischemic insult.
背景
缺血性中风是一种破坏性疾病，代谢紊乱和持续的炎症会加重缺血的初始损伤。重组组织型纤溶酶原激活物仍然是唯一有效的治疗方法，但由于治疗必须在症状出现后尽快开始，因此受到限制。
目的
我们研究了乙酸是否可以通过调节炎症等多种途径来减轻中风中的脑损伤。由于乙酸的血液半衰期短，且大量乙酸会刺激胃肠道，因此将乙酸包裹在脂质体纳米颗粒中（脂质体包裹的乙酸，LITA）进行给药。
方法
通过 90 分钟的大脑中动脉阻塞（MCAO）诱导 Sprague-Dawley 大鼠短暂性缺血，并在 MCAO 时和 MCAO 后 2 周内每天通过腹腔内给予 LITA 或对照脂质体。磁共振成像（MRI）用于估计 MCAO 后 24 小时、1 周和 2 周的病变体积和 MCAO 后 2 周的前外侧脑室体积（ALVv）。在最后一次 MRI 扫描前进行运动行为测试。在最后一次扫描后，收集大脑并进行免疫组织化学分析。
结果
MCAO 后 24 小时至 1 周，对照组和 LITA 组的病变体积均减少了约 80%（均<0.05）。然而，在 MCAO 后 1 至 2 周，对照组的病变体积增加了约 50%（从 24.1±10.0 增加到 58.7±28.6 mm；均<0.05），但 LITA 组的病变体积没有变化。MCAO 后 2 周，LITA 治疗也减轻了 ALVv（对照组和 LITA 组的 ALVv 分别为 177.2±11.9%和 135.3±10.9%；均<0.05）。与对照组相比，LITA 治疗的动物似乎运动活动也有所改善，平均速度更快。与对照组相比，LITA 组的小胶质细胞免疫反应性降低了约 40%（均<0.05），但 LITA 并未调节神经发生、细胞凋亡、组蛋白乙酰化和脂质过氧化。
结论
LITA 似乎减轻了局灶性缺血性损伤后大脑重塑过程中观察到的有害慢性神经炎症。
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