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Title: Effects of electroacupuncture on repairing neurological damage following ischemic stroke based on miR-381-mediated SDF-1/CXCR4 signaling pathway.
Author: Song X, Qin H, Li Y, Niu Y, Guo N, Zhang S.
Journal: Zhongguo Zhen Jiu; 2024 Feb 12; 44(2):175-181. PubMed ID: 38373763.
Abstract:
OBJECTIVES: To investigate the effects of electroacupuncture (EA) on the miR-381, leucine-rich repeat C4 protein (LRRC4), and downstream stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signaling pathway in rat model of ischemic stroke, and to explore the mechanism by which EA improves neurological damage following ischemic stroke. METHODS: Among 50 SPF male SD rats, 10 rats were randomly selected into a sham surgery group, and the remaining rats were used to establish the middle cerebral artery occlusion (MCAO) model. The 30 successfully modeled rats were randomly divided into a model group, an EA group, and an agonist group, with 10 rats in each group. The rats in the EA group received EA at "Baihui" (GV 20) and "Dazhui" (GV 14), with disperse-dense wave, a frequency of 2 Hz/10 Hz, and a current intensity of 1 mA, 30 min per session, once daily for a total of 14 days. The rats in the agonist group received miR-381 agonist injections into the lateral ventricle, with 10 μL per injection, every 7 days for a total of 2 injections. After intervention, ZeaLonga neurobehavioral deficit score was observed in each group. HE staining was performed to observe the morphological changes in the ischemic brain tissue of rats in each group. ELISA was used to measure the levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and nerve growth factor (NGF) in serum. Western blot was employed to detect the protein expression of LRRC4, SDF-1, CXCR4, and extracellular regulated protein kinase 1 (ERK1) in the ischemic brain tissue. Real-time PCR was utilized to assess the expression of miR-381 and LRRC4, SDF-1, CXCR4, ERK1 mRNA in the ischemic brain tissue. RESULTS: After intervention, the brain tissue showed disordered cell arrangement, reduced quantity, and significant interstitial edema, with numerous vacuoles in the model group. The pathological changes mentioned above were alleviated in the brain tissue of rats in the EA group and the agonist group. Compared with the sham surgery group, the rats in the model group exhibited increased ZeaLonga neurobehavioral deficit scores, elevated levels of serum TNF-α and IL-6 (P<0.01), and decreased serum NGF level (P<0.01)；the protein expression of SDF-1, CXCR4 and ERK1 in ischemic brain tissue was reduced (P<0.01), while LRRC4 protein expression was increased (P<0.01)；the expression of miR-381, as well as SDF-1, CXCR4 and ERK1 mRNA in ischemic brain tissue was decreased (P<0.01), while LRRC4 mRNA expression was increased (P<0.01). Compared with the model group, the rats in the EA group and the agonist group showed decreased ZeaLonga neurobehavioral deficit scores and reduced levels of serum TNF-α and IL-6 (P<0.05, P<0.01), and increased serum NGF levels (P<0.05, P<0.01); the protein expression of SDF-1, CXCR4 and ERK1 in ischemic brain tissue was increased (P<0.01), while LRRC4 protein expression was decreased (P<0.01)；the expression of miR-381, as well as SDF-1, CXCR4 and ERK1 mRNA in ischemic brain tissue was increased (P<0.05, P<0.01), while LRRC4 mRNA expression was decreased (P<0.01). CONCLUSIONS: EA at "Baihui" (GV 20) and "Dazhui" (GV 14) may promote the repair of neurological damage following ischemic stroke by up-regulating miR-381 to selectively inhibit LRRC4 expression, thereby activating the SDF-1/CXCR4 signaling pathway. 目的: 观察电针对缺血性脑卒中模型大鼠miR-381、富含亮氨酸重复序列C4蛋白（LRRC4）及其下游基质细胞衍生因子1（SDF-1）/趋化因子受体4（CXCR4）信号通路的影响，探讨电针改善缺血性脑卒中神经损伤的作用机制。方法: 从50只雄性SPF级SD大鼠中随机选取10只作为假手术组，剩余大鼠制备大脑中动脉栓塞（MCAO）模型，将造模成功的30只大鼠随机分为模型组、电针组和激动剂组，每组10只。电针组大鼠于“百会”“大椎”行电针干预，选用疏密波，频率2 Hz/10 Hz，电流强度1 mA，每次30 min，每日1次，共干预14 d。激动剂组大鼠于侧脑室注射miR-381激动剂，每次10 μL，7 d 1次，注射2次。干预后，观察各组大鼠ZeaLonga神经功能缺损评分；HE染色法观察各组大鼠缺血侧脑组织形态；ELISA法测定血清肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）和神经生长因子（NGF）含量；Western blot法检测缺血侧脑组织LRRC4、SDF-1、CXCR4、细胞外信号调节激酶1（ERK1）蛋白表达；实时荧光定量PCR法检测缺血侧脑组织miR-381及LRRC4、SDF-1、CXCR4、ERK1 mRNA表达。结果: 干预后，模型组大鼠脑组织细胞排列紊乱、数量减少，可见大量空泡，间质水肿明显；电针组和激动剂组大鼠脑组织细胞上述病理变化减轻。与假手术组比较，模型组大鼠ZeaLonga神经功能缺损评分及血清TNF-α、IL-6含量升高（P<0.01），血清NGF含量降低（P<0.01）；缺血侧脑组织SDF-1、CXCR4、ERK1蛋白表达降低（P<0.01），LRRC4蛋白表达升高（P<0.01）；缺血侧脑组织miR-381及SDF-1、CXCR4、ERK1 mRNA表达降低（P<0.01），LRRC4 mRNA表达升高（P<0.01）。与模型组比较，电针组、激动剂组大鼠ZeaLonga神经功能缺损评分及血清TNF-α、IL-6含量降低（P<0.05，P<0.01），血清NGF含量升高（P<0.05，P<0.01）；缺血侧脑组织SDF-1、CXCR4、ERK1蛋白表达升高（P<0.01），LRRC4蛋白表达降低（P<0.01）；缺血侧脑组织miR-381及SDF-1、CXCR4、ERK1 mRNA表达升高（P<0.05，P<0.01），LRRC4 mRNA表达降低（P<0.01）。结论: 电针“百会”“大椎”可通过上调miR-381靶向抑制LRRC4表达，进而激活SDF-1/CXCR4信号通路，对缺血性脑卒中后神经损伤修复起到一定的促进作用。.

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