Exploration of the Effect of Stress Hyperglycemia on Therapeutic Efficacy for Acute Cerebral Infarction based on TLR4/NF-κB Pathway，Blood Brain Barrier and Oxidative Stress
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摘要:
目的 探讨应激性高血糖对依达拉奉右莰醇合重组组织型纤溶酶原激活剂（recombinant tissue plasminogen activator，rt-PA）治疗急性脑梗死（acute cerebral infarction，ACI）疗效影响，并分析该方案对TOLL样受体4（toll-like receptor 4，TLR4）/核因子-κB（nuclear factor kappa-B，NF-κB）炎症路径、血脑屏障、氧化应激的影响。 方法 选取江苏省人民医院宿迁医院2021年9月—2023年6月收治的197例ACI患者进行前瞻性研究，根据是否伴有应激性高血糖（stress hyperglycemia，SHG）分为SHG组（n = 90）、无SHG组（n = 107）。比较两组临床疗效及治疗前后TLR4/NF-κB炎症路径[TLR4、NF-κB、白介素-6（interleukin-6，IL-6）]、血脑屏障[基质金属蛋白酶-9（matrix metalloproteinase-9，MMP-9）、闭锁蛋白（occludin，OCLN）]、氧化应激[晚期氧化蛋白产物（advanced oxidation protein products，AOPP）、活性氧（reactive oxygen species，ROS）、超氧化物歧化酶（superoxide dismutase，SOD）]。比较两组预后情况及治疗期间安全性。 结果 SHG组总有效率与无SHG组比较差异无统计学意义（P > 0.05）；治疗后，两组血清TLR4、NF-κB、IL-6水平明显降低（P < 0.05），但组间比较差异无统计学意义（P > 0.05）；治疗1周后、治疗2周后，两组血清MMP-9水平呈降低趋势，OCLN水平先升高后降低（P < 0.05），但组间比较差异无统计学意义（P > 0.05）；治疗1周后、治疗2周后，两组血清AOPP、ROS水平呈降低趋势，SOD水平呈升高趋势（P < 0.05），但组间比较差异无统计学意义（P > 0.05）；SHG组预后良好率与无SHG组比较差异无统计学意义（P > 0.05）；SHG组颅内出血发生率高于无SHG组（P < 0.05）；SHG组胃肠道反应、肝生化轻度异常、发热情况与无SHG组比较差异无统计学意义（P > 0.05）。 结论 伴或不伴SHG的ACI患者接受依达拉奉右莰醇联合rt-PA治疗，疗效及TLR4/NF-κB炎症路径、保护血脑屏障、抗氧化等机制作用相当；SHG不影响短期疗效，但明显增加颅内出血风险。 Abstract:Objective To investigate the impact of stress hyperglycemia on the efficacy of edaravone and dexborneol combined with recombinant tissue plasminogen activator （rt-PA） in the treatment of acute cerebral infarction （ACI）, and to analyze the influence of this regimen on TOLL-like receptor 4 （TLR4）/nuclear factor-κB （NF-κB ） inflammatory pathway, the blood-brain barrier and oxidative stress. Methods A prospective study was conducted on 197 patients with ACI admitted to Suqian Hospital of Jiangsu Provincial People’s Hospital from September 2021 to June 2023. Patients were divided into SHG group （n = 90） and non-SHG group （n = 107） according to the presence or absence of stress hyperglycemia （SHG）. Clinical efficacy, and pre- and post-treatment levels of the TLR4/NF-κB inflammatory pathway [TLR4, NF-κB, interleukin-6 （IL-6）], blood-brain barrier [matrix metalloproteinase-9 （MMP-9）, occludin （OCLN）], oxidative stress [advanced oxidation protein product （AOPP）, reactive oxygen species （ROS）, superoxide dismutase （SOD）] were compared between the two groups. The prognosis and safety during treatment were also compared between the two groups. . After 1 week and 2 weeks of treatment, serum MMP-9 levels decreased and OCLN levels increased first and then decreased in both groups （P<0.05）, with no significant difference between groups （P > 0.05）. After 1 week and 2 weeks of treatment, the levels of serum AOPP and ROS in the two groups were decreased, while the level of SOD was increased （P < 0.05）, and there was no significant difference between the two groups （P > 0.05）. The rate of good prognosis showed no significant difference between the SHG group and the non-SHG group （P > 0.05）. The incidence of intracranial hemorrhage in SHG group was higher than that in non SHG group （P < 0.05）. There were no statistically significant differences in gastrointestinal reactions, mild liver biochemical abnormalities and fever between SHG group and non SHG group （P > 0.05）. Conclusion In ACI patients with or without SHG, treatment with edaravone and borneol combined with rt-PA demonstrates comparable therapeutic effects and mechanisms of action, including modulation of the TLR4/NF-κB inflammatory pathway, protection of the blood brain barrier, and anti-oxidant effects . SHG does not affect short-term efficacy, but significantly increases the risk of intracranial hemorrhage. -
表 1 两组临床资料比较[（$ \bar x \pm s $）/ n（%）]
Table 1. Comparison of clinical data between the two groups [（$\bar x \pm s $ ）/ n（%）]
临床资料 SHG组
（n = 90）无SHG组
（n = 107）t/χ2 P 性别 0.124 0.725 男 55（61.11） 68（63.55） 女 35（38.89） 39（36.45） 年龄（岁） 66.35 ± 3.02 65.97 ± 4.10 0.729 0.467 BMI（kg/m2） 23.62 ± 2.45 23.08 ± 3.74 1.174 0.242 发病至溶栓
时间（h）3.55 ± 0.41 3.42 ± 0.56 1.828 0.069 SBP（mmHg） 122.52 ± 10.26 124.41 ± 11.41 1.212 0.227 DBP（mmHg） 78.92 ± 9.21 80.02 ± 8.93 0.849 0.397 梗死部位 0.465 0.927 基底节 31（34.44） 38（35.51） 颞叶 25（27.78） 30（28.04） 额叶 22（24.44） 28（26.17） 顶叶 12（13.33） 11（10.28） NIHSS评分（分） 7.22 ± 1.24 7.09 ± 1.36 0.696 0.487 TOAST分型 0.524 0.464 大动脉粥样
硬化型52（57.78） 66（61.68） 心源性栓塞型 14（15.56） 13（12.15） 小动脉闭塞型 20（22.22） 23（21.50） 其他明确病因型 2（2.22） 3（2.80） 不明病因型 2（2.22） 2（1.87） 
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表 2 两组临床疗效比较 [n（%）]
Table 2. Comparison of clinical efficacy between the two groups [n（%）]
组别 n 治愈 显效 有效 无效 总有效率 SHG组 90 21（23.33） 32（35.56） 29（32.22） 8（8.89） 82（91.11） 无SHG
组107 28（26.17） 35（32.71） 36（33.64） 8（7.48） 99（92.52） χ2 0.131 P 0.718
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表 3 两组TLR4/NF-κB炎症路径比较[（$ \bar x \pm s $），n = 197]
Table 3. Comparison of TLR4/NF-κB inflammatory pathway between the two groups [ （$ \bar x \pm s $），n = 197]
指标 组别 n 治疗前 治疗1周后 治疗2周后 TLR4（ng/mL） SHG组 90 4.52 ± 0.94 3.40 ± 1.02 2.91 ± 0.75 无SHG组 107 4.38 ± 1.15 3.25 ± 0.80 2.78 ± 0.61 F F组间 = 0.855，F时间 = 5.214，F交互 = 3.211 P P组间 = 0.326，P时间 < 0.001*，P交互 < 0.001* NF-κB（ng/mL） SHG组 90 144.86 ± 16.00 122.04 ± 10.53 113.51 ± 10.68 无SHG组 107 142.90 ± 14.53 120.81 ± 9.48 110.97 ± 8.89 F F组间 = 0.941，F时间 = 3.274，F交互 = 2.514 P P组间 = 0.112，P时间 < 0.001*，P交互 = 0.012* IL-6（ng/L） SHG组 90 82.65 ± 17.22 72.00 ± 13.43 50.13 ± 10.25 无SHG组 107 80.92 ± 19.35 69.34 ± 11.58 48.59 ± 9.11 F F组间 = 0.754，F时间 = 6.223，F交互 = 2.568 P P组间 = 0.408，P时间 < 0.001*，P交互 = 0.011* *P < 0.05。
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表 4 两组血脑屏障比较[（$\bar x \pm s $），n = 197]
Table 4. Comparison of blood brain barrier between the two groups [（$ \bar x \pm s $ ），n = 197]
指标 组别 n 治疗前 治疗1周后 治疗2周后 MMP-9（ng/mL） SHG组 90 42.56 ± 10.83 34.00 ± 10.19 18.16 ± 6.00 无SHG组 107 41.90 ± 11.25 32.94 ± 9.78 17.52 ± 5.05 F F组间 = 0.635，F时间 = 8.554，F交互 = 4.112 P P组间 = 0.502，P时间 < 0.001*，P交互 < 0.001* OCLN（ng/mL） SHG组 90 381.44 ± 62.50 691.55 ± 57.21 175.60 ± 46.33 无SHG组 107 376.59 ± 58.81 694.00 ± 52.08 173.73 ± 44.95 F F组间 = 0.711，F时间 = 9.632，F交互 = 3.654 P P组间 = 0.463，P时间 < 0.001*，P交互 < 0.001* *P < 0.05。
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表 5 两组氧化应激比较[（$\bar x \pm s$），n = 197]
Table 5. Comparison of oxidative stress between the two groups [（$ \bar x \pm s $），n = 197]
指标 组别 n 治疗前 治疗1周后 治疗2周后 AOPP（μmol/L） SHG组 90 21.65 ± 6.98 17.29 ± 5.71 14.80 ± 4.93 无SHG组 107 20.73 ± 6.40 16.99 ± 5.58 14.22 ± 4.57 F F组间 = 0.277，F时间 = 4.116，F交互 = 2.890 P P组间 = 0.714，P时间 < 0.001*，P交互 = 0.004* ROS（U/mL） SHG组 90 183.11 ± 22.93 146.59 ± 21.04 121.04 ± 20.66 无SHG组 107 180.85 ± 24.07 144.93 ± 23.75 119.65 ± 18.53 F F组间 = 0.326，F时间 = 5.032，F交互 = 3.264 P P组间 = 0.678，P时间 < 0.001*，P交互 = 0.001* SOD（U/mL） SHG组 90 19.10 ± 3.58 21.67 ± 6.18 24.91 ± 8.00 无SHG组 107 18.78 ± 4.16 22.07 ± 5.35 25.78 ± 7.02 F F组间 = 0.449，F时间 = 6.187，F交互 = 4.816 P P组间 = 0.602，P时间 < 0.001*，P交互 < 0.001* *P < 0.05。
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表 6 两组预后情况及安全性比较[n（%）]
Table 6. Comparison of prognosis and safety between the two groups [n（%）]
组别 n 预后 不良反应 良好 不良 颅内出血 胃肠道反应 肝生化轻度异常 发热 SHG组 90 66（73.33） 24（26.67） 7（7.78） 2（2.22） 0（0.00） 1（1.11） 无SHG组 107 81（75.70） 26（24.30） 1（0.93） 1（0.93） 1（0.93） 1（0.93） χ2 0.145 - - - - P 0.704 0.018* 0.485 0.362 0.913 注：“-”表示Fisher精确概率法没有χ2值；*P < 0.05。
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