内源性油酰乙醇胺的速效经鼻纳米给药系统用于缺血型脑卒中的康复治疗

Leading to more and more deaths and disabilities, stroke has become a serious threat to human health. What’s more, few effective drugs are available in clinic till now. According to our previous researches, N-oleoylethanolane (OEA) can protect against acute and chronic ischemic injury and improve spatial cognitive deficits in mice. However, OEA is a water-insoluble molecule with a fatty acid-based structure, which would become a major barrier to its absorption. The nasal cavity is only connection to between the brain and the environment, and hence, the nose-to-brain drug delivery has been considered to be the potential most efficient and fast-acting way for the diseases of the central nervous system. Considering the characteristics of stroke, we hope to develop a kind of fast acting, intranasal delivered nanodrug for stroke therapy. And a systemic experiment would carried to evaluate the properties, the in vivo absorption, and the in vivo neuroprotective effect of the nanodrug. The project could offer a feasible program for the clinic application of OEA, and provide new ideas for the development of neuroprotective formulations. And the research could also illuminate the absorption behavior of nasal preparations, and provide new insight for designing more effective nose-to-brain dosage for diseases of the central nervous system.

缺血型脑卒中正严重威胁着国人健康，然而临床上却几乎没有疗效尚可的神经保护药物用于缺血型脑卒中的康复治疗。本课题组前期研究表明，内源性油酰乙醇胺(OEA)具有较好的神经保护作用，但其水溶性极差，无法满足制剂需求。鼻腔是大脑与外环境相连的唯一通道，因此经鼻给药被认为是治疗大脑疾病最有效的且起效最快的给药方式，而临床上尚无此类药物应用。为了改善OEA的水溶性，促进OEA的临床应用，同时结合脑卒中发病突然、病情严重且急需救治的特点，申请人希望将其制备成能够快速起效的、经鼻给药纳米制剂用于缺血型脑卒中患者的治疗，并对该速效经鼻给药制剂的体外性质、体内吸收行为、体内神经保护作用效果进行系统评价。本课题能够为OEA的临床应用提供一种新的可行方案，并为新型神经保护作用制剂的研发提供新的思路和方案；同时本课题还能明确经鼻给药制剂的体内吸收行为，为治疗大脑疾病的经鼻给药制剂研发提供重要的理论和实验依据。

缺血型脑卒中正严重威胁着国人健康，然而临床上却几乎没有疗效尚可的神经保护药物用于缺血型脑卒中的康复治疗。本课题组前期研究表明，内源性油酰乙醇胺(OEA)具有较好的神经保护作用，但其水溶性极差，无法满足制剂需求。为了改善OEA的水溶性，促进OEA的临床应用，申请人将其制备成了OEA纳米制剂(OEA NPs)用于缺血型脑卒中患者的治疗，并对OEA NPs的体外性质、体内吸收行为、体内神经保护作用效果进行系统评价。结果表明：.1、通过在OEA分子和载体大豆卵磷脂（SPC）之间形成氢键，大大提高了OEA的生物利用度；.2、OEA NPs 的粒径为80 nm 左右，能够在水中保持较好的稳定性，OEA的载药量为8.21±0.18 wt%，并且在48 h内缓慢持续的释放药物；.3、体内评价实验表明，OEA NPs能够明显增加大脑中动脉栓塞模型(MCAO)大鼠的生存率，其14天的生存率由45.8%提高到了83.3%，术后的动物行为学表现也有明显的改善，Garcia评分大幅增加；.4、TTC染色实验表明，OEA NPs能够明显减小MCAO模型大鼠的脑梗死体积和脑水肿率；水迷宫实验表明，OEA NPs能够明显改善MCAO模型大鼠受损的学习记忆功能;.5、Tunel 染色实验表明OEA NPs能够减少MCAO引起的神经元的凋亡;.6、GFAP染色和Iba-1实验表明，OEA NPs能将再灌注时的炎症反应降低到非常轻微的程度。 .综上所述，OEA NPs非常可能成为潜在的治疗脑卒中的神经保护制剂，从而为广大脑卒中患者带来希望。