虾青素纳米载药颗粒在蛛网膜下腔出血后脑微循环障碍中的保护作用及机制研究

Microcerebrovascular dysfunction after subarachnoid hemorrhage (SAH) usually brings poor outcomes to the patients. However,the underlying mechanisms have not been well elucidated. The latest research suggested that the inflammatory response, oxidative damage, and microthrombosis are all involved in the onset and development of microcerebrovascular dysfunction after SAH. According to our previous studies, oral administration with astaxanthin (ATX) could alleviate inflammatory response and oxidative damage in the brain, and could suppress microthrombosis after SAH. We therefore hypothesize that microcerebrovascular dysfunction after SAH is alleviated by ATX, due to its potency of anti-inflammation, antioxidation, and antithrombosis. Furthermore, our present study is aimed to establish a novel magnetic targeting and biological targeting nanomaterial to load ATX, which may be a targeting drug delivery system to overcome the poor water-solubility and bioavailable efficiency of ATX. Meanwhile, ATX could be administrated intravenously targeting the cerebral microcirculation, using the magnetic and biological targeting capabilities of the nanopaticle. The protective effects of ATX and the specific mechanisms against microcerebrovascular dysfunction after SAH will be explored through kinds of SAH models using a cranial window. Moreover, the pharmacological characteristics and the protective effects against microcerebrovascular dysfunction after SAH of ATX-loading nanoparticles will be studied. The current study will establish a rationale for the nanoparticles-loading treatment, and provide a novel therapeutic strategy for microcerebrovascular dysfunction after SAH.

蛛网膜下腔出血(SAH)后脑微循环障碍严重影响患者预后，而其病理机制尚不十分明确。国内外最新研究发现，SAH后炎症反应、氧化损伤与微血栓形成均参与脑微循环障碍的发生与进展。前期研究我们发现，大鼠口服虾青素能够显著减轻SAH后脑组织的炎症反应、氧化损伤并抑制微血栓的形成。基于此，我们推测虾青素可以通过抗炎症、抗氧化和抗血栓形成等作用有效缓解SAH后脑微循环障碍。然而，目前的虾青素不溶于水且生物利用度差，不利于临床应用，为克服这一缺点，我们拟制备一种新颖的具有磁靶向性和生物靶向性的纳米材料负载虾青素，经静脉给药后引导虾青素靶向至脑微循环，并结合多种SAH模型和闭合颅窗模型，研究虾青素纳米载药颗粒的药理学特征及其在SAH后脑微循环障碍中的保护作用，探讨虾青素对SAH后脑微循环障碍的保护机制。这一研究将为SAH后脑微循障碍的纳米载药治疗奠定理论基础，同时为SAH后脑微循环障碍提供新的治疗策略。

脑微循环主要由软脑膜动脉和穿动脉组成，参与调节和维持不同脑灌注压情况下的血管阻力(收缩或舒张)，直接参与脑组织的血液供应以及脑血流量的调节，一旦脑微循环发生功能障碍，将引起脑功能障碍、脑组织不可逆损害等一系列严重后果。蛛网膜下腔出血（SAH）后脑微循环障碍使得神经血管单元的整体性遭到破坏，最终引起延迟性脑缺血，从而导致患者预后不良。本研究通过在不同的时间点以不同的给药方式，借助经大（小）鼠颅窗观察微血管活体染色的方法，精准观测SAH前后和虾青素给药前后微循环的变化。发现口服及静脉虾青素均能显著减轻SAH后脑微循环炎症刺激和氧化损伤，进一步减轻早期脑损伤（EBI）。同时，在前期工作基础上制备出具有大载药量且兼具良好水溶性、稳定性、磁靶向和生物靶向性的纳米颗粒，结合闭合颅窗模型经静脉给药，通过SAH动物模型实验，发现载药颗粒对SAH后脑微循环障碍的保护作用及机制研究，大大提高虾青素的有效靶剂量，从而最大程度的发挥虾青素在SAH后脑微循环障碍中的保护作用，顺利解决了诸多神经保护药物不能静脉给药和靶向定位的难题。同时，开启了一种高分子材料联合药物治疗对SAH后脑微循环障碍治疗的新模式，为临床改善SAH患者的预后做出转化医学积极、有效的尝试，具有重要的临床指导意义。