| 代小兰,竺东杰,陈小丽,李红霞.白芍总苷通过抑制内质网应激减轻大鼠脑缺血再灌注损伤的研究[J].浙江中西医结合杂志,2021,31(1): |
| 白芍总苷通过抑制内质网应激减轻大鼠脑缺血再灌注损伤的研究 |
| Effects of Total Paeony Glycoside on Reducing Cerebral Ischemia Reperfusion Injury by Inhibiting Endoplasmic Reticulum Stress |
| 投稿时间：2020-07-19 修订日期：2020-10-23 |
| DOI： |
| 中文关键词: 白芍总苷 脑缺血再灌注 内质网应激 炎症 细胞凋亡 |
| 英文关键词:Total paeony glycoside Cerebral ischemia-reperfusion Endoplasmic reticulum stress Inflammation Apoptosis |
| 基金项目:宁波市自然科学基金项目（No.2018A610415） |
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| 中文摘要: |
| 目的 探讨白芍总苷（TGP）对大鼠脑缺血再灌注（I/R）损伤的保护作用及其机制。方法 将240只实验用SD大鼠随机分为假手术组，模型组，TGP低（50mg/kg）、中（100mg/kg）、高（200mg/kg）剂量组和尼莫地平（NMP，15mg/kg）组，每组40只。采用线栓法阻断大脑中动脉2h复制大鼠脑I/R模型，造模前7d开始1次/d灌胃给药（假手术组和模型组灌胃给予生理盐水）。24h后，采用mNSS评分法评价大鼠神经功能，伊文思蓝渗透法检测血脑屏障（BBB）通透性，TTC染色法检测脑组织梗死体积，HE染色法和TUNEL染色法分别检测脑组织病理学改变和神经细胞凋亡，ELISA法检测肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）水平，Western blot法检测葡萄糖调控蛋白78（GRP78）、磷酸化胰腺内质网激酶（p-PERK）、C/EBP同源蛋白（CHOP）、核因子-?B（NF-?B）、激活型半胱胺酸蛋白酶-12（Cleaved Caspase-12）、激活型半胱胺酸蛋白酶-3（Cleaved Caspase-3）蛋白表达。结果 与模型组比较，TGP中、高剂量组和NMP组mNSS评分降低[(9.98±1.07)分、(6.41±0.83)分、(8.26±0.95)分比(14.63±1.52)分，P均<0.01]、伊文思蓝渗透量降低[(7.76±1.50)μg/g、(5.49±1.13)μg/g、(7.31±1.20)μg/g比(12.71±2.04)μg/g，P均<0.01]、脑梗死体积降低[(24.93±4.12)%、(16.52±3.05)%、(19.08±3.71)%比(39.48±5.16)%，P均<0.01]；大脑皮质神经细胞形态结构损伤和凋亡明显改善，凋亡指数（AI）降低[(43.51±6.27)%、(22.34±4.85)%、(37.29±5.36)%比(68.15±8.43)%，P均<0.01]；TNF-α水平降低[(1.77±0.24)ng/mL、(1.61±0.19)ng/mL、(1.89±0.26)ng/mL比(2.26±0.31)ng/mL，P均<0.01]、IL-1β水平降低[(41.76±6.21)pg/mL、(36.98±5.73) pg/mL、(41.15±6.40)pg/mL比(52.64±7.02)pg/mL，P均<0.01]、IL-6水平降低[(15.72±3.14)pg/mL、(9.84±2.63)pg/mL、(13.07±2.91)pg/mL比(21.34±3.85) pg/mL，P均<0.01]；GRP78表达量降低[(0.41±0.09)、(0.18±0.05)、(0.27±0.08)比(0.96±0.21)，P均<0.01]、p-PERK表达量降低[(0.75±0.14)、(0.24±0.05)、(0.38±0.09)比(0.94±0.19)，P<0.05或P<0.01]、CHOP表达量降低[(0.14±0.04)、(0.07±0.03)、(0.19±0.05)比(0.44±0.10)，P均<0.01]、NF-?B表达量降低[(0.67±0.15)、(0.67±0.15)、(0.58±0.13)比(0.89±0.18)，P均<0.01]、Cleaved Caspase-12表达量降低[(0.74±0.16)、(0.52±0.11)、(0.61±0.15)比(0.95±0.22)，P<0.05或P<0.01]、Cleaved Caspase-3表达量降低[(0.18±0.06)、(0.12±0.03)、(0.35±0.08)比(0.64±0.13)，P均<0.01]。与NMP组比较，TGP高剂量组mNSS评分降低[(6.41±0.83)分比(8.26±0.95)分，P<0.01]、伊文思蓝渗透量降低[(5.49±1.13)μg/g比(7.31±1.20)μg/g，P<0.01]；神经细胞形态结构损伤明显改善，AI降低[(22.34±4.85)%比(37.29±5.36)%，P<0.01]；TNF-α水平降低[(1.61±0.19) ng/mL比(1.89±0.26)ng/mL，P<0.05]、IL-6水平降低[(9.84±2.63)pg/mL比(13.07±2.91)pg/mL，P<0.05]；GRP78表达量降低[(0.18±0.05)比(0.27±0.08)，P<0.01]、p-PERK表达量降低[(0.24±0.05)比(0.38±0.09)，P<0.01]、CHOP表达量降低[(0.07±0.03)比(0.19±0.05)，P<0.01]、NF-?B表达量降低[(0.67±0.15)比(0.58±0.13)，P<0.05]、Cleaved Caspase-3表达量降低[(0.12±0.03)比(0.35±0.08)，P<0.01]。结论 TGP对大鼠脑I/R损伤具有保护作用，其机制可能与抑制内质网应激相关炎症和凋亡通路有关。 |
| 英文摘要: |
| Objective To investigate the protective effect and mechanism of total paeony glycoside (TGP) on cerebral ischemia-reperfusion (I/R) injury in rats. Methods 240 expremental SD rats were randomly divided into sham operation group, model group, TGP low (50 mg/kg), medium (100 mg/kg), high (200 mg/kg) dose group and nimodipine (NMP) 15 mg/kg group, n=40. The rat model with cerebral I/R was established by blocking the middle cerebral artery for 2 hours, and the the drugs were given for 7d before modelin by intragastric administration. 24h after reperfusion, the evaluation of neurological was assessed by mNSS score, the permeability of BBB was measured by Evans blue permeation method and the infarct volume of brain tissue was detected by TTC staining. The pathological change of brain tissue was examined by HE staining and the apoptosis was observed by TUNEL method. The level of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) were detected by ELISA; the expression of GRP78, p-PERK, CHOP, NF-?B, Cleaved Caspase-12, Cleaved Caspase-3 were determined by Western blot. Results Compared with model group, the mNSS score [(9.98±1.07) score, (6.41±0.83) score, (8.26±0.95) score vs (14.63±1.52) score, P<0.01], Evans blue permeation [(7.76±1.50)μg/g, (5.49±1.13)μg/g, (7.31±1.20)μg/g vs (12.71±2.04)μg/g, P<0.01], brain infarct volume [(24.93±4.12)%, (16.52±3.05)%, (19.08±3.71)% vs (39.48±5.16)%, P<0.01] in TGP medium, high dose group and NMP group were decreased. The cerebral cortical nerve cell morphological damage and apoptosis were significantly improved, and apoptosis index (AI) was decreased [(43.51±6.27)%, (22.34±4.85)%, (37.29±5.36)% vs (68.15±8.43)%, P<0.01]. The level of TNF-α [(1.77±0.24)ng/mL, (1.61±0.19)ng/mL, (1.89±0.26)ng/mL vs (2.26±0.31)ng/mL, P<0.01], IL-1β [(41.76±6.21)pg/mL, (36.98±5.73) pg/mL, (41.15±6.40)pg/mL vs (52.64±7.02)pg/mL, P<0.01], IL-6 [(15.72±3.14)pg/mL, (9.84±2.63)pg/mL, (13.07±2.91)pg/mL vs (21.34±3.85) pg/mL, P<0.01] were decreased. The expression of GRP78[(0.41±0.09), (0.18±0.05), (0.27±0.08) vs (0.96±0.21), P<0.01], p-PERK [(0.75±0.14), (0.24±0.05), (0.38±0.09) vs (0.94±0.19), P<0.05 or P<0.01], CHOP [(0.14±0.04), (0.07±0.03), (0.19±0.05) vs (0.44±0.10), P<0.01], NF-?B[(0.67±0.15)、(0.67±0.15), (0.58±0.13) vs (0.89±0.18), P<0.01], Cleaved Caspase-12 [(0.74±0.16), (0.52±0.11), (0.61±0.15) vs (0.95±0.22), P<0.05 or P<0.01], Cleaved Caspase-3 [(0.18±0.06), (0.12±0.03), (0.35±0.08) vs (0.64±0.13), P<0.01]were decreased. Compared with the NMP group, the mNSS score [(6.41±0.83) score vs (8.26±0.95) score, P<0.01], Evans blue permeation [(5.49±1.13)μg/g vs (7.31±1.20)μg/g, P<0.01] in TGP high dose group were decreased. The cerebral cortical nerve cell morphological damage was significantly improved and the AI was decreased [(22.34±4.85)% vs (37.29±5.36)%, P<0.01]. The level of TNF-α[(1.61±0.19)ng/mL vs (1.89±0.26)ng/mL, P<0.05], IL-6 [(9.84±2.63)pg/mL vs (13.07±2.91)pg/mL, P<0.05] were decreased. The expression of GRP78 [(0.18±0.05) vs (0.27±0.08), P<0.01], p-PERK[(0.24±0.05) vs (0.38±0.09), P<0.01], CHOP [(0.07±0.03) vs (0.19±0.05), P<0.01], NF-?B [(0.67±0.15) vs (0.58±0.13), P<0.05], Cleaved Caspase-3 [(0.12±0.03) vs (0.35±0.08), P<0.01] were decreased. Conclusion TGP has protective effect on the rat with cerebral I/R injury; which mechanism may be related to the inhibition of endoplasmic reticulum stress-related inflammation and apoptosis pathways. |
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