桦木酸（BA）纳米棒由植物源性生物活性分子BA自组装合成，能突破血脑屏障，靶向治疗缺血性脑损伤，但相关机制尚不清楚。申请者前期研究提示：BA纳米棒可以靶向激活大麻素2型受体（CB2）。炎症反应时CB2受体在小胶质细胞中高表达，其激活能促进小胶质细胞M2极化，具有神经保护作用。我们的预实验发现BA纳米棒可抑制脑缺血区NF-κB的活性，而NF-κB的失活能促进小胶质细胞M2极化。因此，我们提出假说：BA纳米棒能靶向激活CB2受体，通过其下游的cAMP/PKA信号通路负性调节NF-κB的活性，促进小胶质细胞M2极化，改善缺血性脑损伤。本项目将通过体外和体内实验，重点研究CB2受体及下游cAMP/PKA/NF-κB信号轴在BA纳米棒调控小胶质细胞极化中的作用。研究结果将初步阐明BA纳米棒治疗缺血性脑损伤的作用机制，为BA纳米棒在缺血性脑损伤中的应用和开发以CB2受体为靶点的神经保护剂提供理论依据。

Betulinic acid (BA) nanorods are synthesized by self-assembly of plant derived bioactive molecule BA, BA nanorods can break through the blood-brain barrier and targeted treat ischemic brain injury, but the mechanism remains unclear. Our previous studies suggested that BA nanorods could target and activate cannabinoid receptor type2 (CB2). CB2 receptor is highly expressed in microglia in inflammatory reaction, and its activation can promote the microglia to M2 polarization and play a neuroprotective role. Our preliminary study found that BA nanorods can inhibit the activity of NF-κB in cerebral ischemic area, while the inactivation of NF-κB can promote the microglia to M2 polarization. Therefore, we propose the hypothesis that BA nanorods can target and activate CB2 receptors, which could negatively regulate NF-κB activity through its downstream cAMP/PKA signaling pathway, promote microglia to M2 polarization, and improve ischemic brain injury. This project will focus on the role of CB2 receptor and downstream cAMP/PKA/NF-κB signal axis in the regulation of microglial polarization by BA nanorods in vitro and in vivo. The results will preliminarily clarify the mechanism of BA nanorods in the treatment of ischemic brain injury, and provide theoretical basis for the application of BA nanorods in ischemic brain injury and the development of neuroprotective agents targeting CB2 receptor.