基于CB1/PI3K/Akt/Nrf2通路探讨功能化苏门树脂酸纳米粒子在脑缺血再灌注损伤中的神经保护作用及机制研究

脑缺血再灌注损伤(CIRI)是缺血性脑卒中患者预后差的主要原因。我们前期研究中合成五环三萜类小分子化合物纳米粒子，对CIRI有显著神经保护作用。发现该类纳米粒子可以结合大麻素受体1（CB1），同时Nrf2及HO-1表达上调，但作用机制不清楚。预实验显示苏门树脂酸纳米粒子（SANPs）对CB1-/-小鼠的神经保护作用明显下降，同时抑制CIRI引起的铁离子代谢相关蛋白表达上调与神经元死亡。我们推测SANPs通过CB1受体调控下游分子通路是减轻CIRI的重要机制。本项目拟采用CB1-/-小鼠MCAO/R和原代神经元OGD/R模型，通过抑制剂、siRNA细胞转染等干预手段，揭示SANPs在CIRI中通过CB1/PI3K/Akt/Nrf2通路，介导氧化应激与铁死亡发挥神经保护作用的分子机制。利用纳米生物技术进一步功能化SANPs，提高特异性靶向能力。通过上述研究，为CIRI治疗提供新的靶点和策略。

Cerebral ischemia reperfusion injury (CIRI) is the main reason for the poor prognosis of patients with ischemic stroke. In our previous research, the synthesis of pentacyclic triterpenoid small molecular compound nanoparticles have a significant neuroprotective effect in CIRI. We found that this type of nanoparticles can bind to cannabinoid receptor 1 (CB1) while protein expression of Nrf2 and its downstream molecule HO-1 are upregulated. However, the actual mechanism remains unclear. Our preliminary experiments showed that sumaresinolic acid nanoparticles (SA NPs) have a significantly reduced neuroprotective effect on CB1-/-mice while effectively inhibit both the upregulation of transferrin expression and neuronal death. We speculate that the regulation of downstream molecular pathways by SA NPs through CB1 receptors is an important mechanism for reducing CIRI. In this study, we applied inhibitor, Agonist and siRNA cell transfection intervention on CB1-/- mice MCAO/R and primary neuron OGD/R model to reveal the molecular mechanism of SA NPs in CIRI through the CB1/PI3K/Akt/Nrf2 pathway, thereby mediating oxidative stress and ferroptosis. We further functionalized SA NPs by using nano-biological techniques to improve their specific targeting ability. The results from this study suggest new targets and strategies for the treatment of CIRI.