«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

27卷

期数:

2021年03期

页码:

222-228

栏目:

基础医学

出版日期:

2021-05-30

文章信息/Info

Title:

Effect of intermittent hypoxic intervention on neurological function recovery in cerebral ischemic rats

文章编号:

1006-8147(2021)03-0222-07

作者:

苏悦¹; 史昱¹; 姜俐洋¹; 2; 黄传¹; 万春晓¹

1.天津医科大学总医院康复医学科，天津 300052；2.天津市海河医院康复医学科，天津 300350

Author(s):

SU Yue¹; SHI Yu¹; JIANG Li-yang¹; 2; HUANG Chuan¹; WAN Chun-xiao¹

1.Department of Rehabilitation Medicine，General Hospital，Tianjin Medical University，Tianjin 300052，China；2.Department of Rehabilitation Medicine，Tianjin Haihe Hospital，Tianjin 300350，China

关键词:

间歇性低氧; 脑缺血; AMPK; PGC-1α; 神经保护

Keywords:

intermittent hypoxia; cerebral ischemia; AMPK; PGC-1α; neuroprotection

分类号:

R493,R743

DOI:

-

文献标志码:

A

摘要:

目的：探究脑缺血后间歇性低氧干预的神经保护作用及机制。方法：8周龄雄性Sprague-Dawley（SD）大鼠随机分为假手术组（SHAM，n=6）、脑缺血-静息组（MCAO-SED，n=7）和脑缺血-间歇性低氧组（MCAO-IH，n=7）。术后1周开始对MCAO-IH组进行低氧干预，持续4周。每周进行改良神经损伤程度评分（mNSS）；干预4周后采用MRI检测大鼠脑梗死体积；Western 印迹法检测脑皮质梗死边缘区脑组织腺苷酸活化蛋白激酶（AMPK）和过氧化物酶体增殖物激活受体γ辅激活因子-1α（PGC-1α）的表达量。 结果：与MCAO-SED组相比，MCAO-IH组死亡率无差异（14.29%，P>0.05）；mNSS评分显著降低（P<0.05）；脑梗死体积明显减小（P<0.01）；梗死边缘区AMPK和PGC-1α表达量显著升高（PAMPK<0.001，PPGC-1α<0.05）。相关性分析结果显示，梗死边缘区AMPK和PGC-1α表达量与mNSS评分之间均呈显著负相关（P<0.05）。结论：间歇性低氧干预可通过上调脑组织中AMPK和PGC-1α蛋白表达，进而减小脑梗死体积，促进运动功能恢复，可能通过激活AMPK/PGC-1α信号通路发挥神经保护作用。

Abstract:

Objective: To explore the neuroprotective effect and mechanism of intermittent hypoxia intervention after cerebral ischemia.Methods: 8-week male Sprague-Dawley（SD） rats were randomly divided into sham operation group（SHAM，n=6），MCAO-Sedentary group （MCAO-SED，n=7） and MCAO-Intermittent Hypoxia group（MCAO-IH，n=7）. In MCAO-IH group，hypoxia was conducted 1 week after operation and lasted for 4 weeks. The modified neurological severity score（mNSS） was performed weekly. After 4 weeks of intervention，MRI was used to detect cerebral infarct volume in rats; Western blotting was used to detect the expression of AMPK and PGC-1α in the peri-infarction region. Results: Compared with MCAO-SED group，MCAO-IH group performed the same mortality rate（14.29%，P>0.05），decreased mNSS score（P<0.05），decreased infarct volume（P<0.01），and increased the expression of AMPK and PGC-1α（PAMPK<0.001，PPGC-1α<0.05）. Correlation analysis results showed that the expression of AMPK and PGC-1α in the peri-infarction region were significantly negatively correlated with mNSS score（P<0.05）. Conclusion：Intermittent hypoxia can increase the expression of AMPK and PGC-1α in brain tissue，thereby reducing the infarct volume and promoting the recovery of motor function after cerebral ischemia. It may play a neuroprotective role by activating AMPK/PGC-1α signaling pathway.

参考文献/References:

[1] Benjamin E J，Blaha M J，Chiuve S E，et al. Heart Disease and Stroke Statistics-2017 Update： a report from the American Heart Association[J]. Circulation，2017，135（10）：e146
[2] Dale E A，Mitchell G S. Spinal vascular endothelial growth factor （VEGF） and erythropoietin（EPO） induced phrenic motor facilitation after repetitive acute intermittent hypoxia[J]. Respir Physiol Neurobiol，2013，185（3）：481
[3] Gutierrez D V，Clark M，Nwanna O，et al. Intermittent hypoxia training after C2 hemisection modifies the expression of PTEN and mTOR[J]. Exp Neurol，2013，248：45
[4] 徐凯月，孟祥雪，黄传，等. 间歇性低氧干预提高心梗大鼠心功能和运动耐量[J]. 天津医科大学学报，2019，25（5）：459
[5] Baillieul S，Chacaroun S，Doutreleau S，et al. Hypoxic conditioning and the central nervous system：a new therapeutic opportunity for brain and spinal cord injuries? [J]. Exp Biol Med，2017，242（11）：1198
[6] Spasié M R，Callaerts P，Norga K K. AMP-activated protein kinase（AMPK） molecular crossroad for metabolic control and survival of neurons[J]. Neuroscientist，2009，15（4）：309
[7] Colombo S L，Moncada S. AMPKalpha1 regulates the antioxidant status of vascular endothelial cells[J]. Biochem J，2009，421（2）：163
[8] St-Pierre J，Drori S，Uldry M，et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators[J]. Cell，2006，127（2）：397
[9] Longa E Z，Weinstein P R，Carlson S，et al. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke，1989， 20（1）：84
[10] Tsai Y W，Yang Y R，Chen G H，et al. The time window of intermittent hypoxia intervention after middle cerebral artery occlusion[J]. Chin J Physiol，2008，51（5）：324
[11] Chen J，Li Y，Wang L，et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats[J]. Stroke，2001，32（4）：1005
[12] Swanson R A，Morton M T，Tsao-Wu G，et al. A semiautomated method for measuring brain infarct volume[J]. J Cereb Blood Flow Metab，1990，10（2）：290
[13] Verges S，Chacaroun S，Godin-Ribuot D，et al. Hypoxic conditioning as a new therapeutic modality[J]. Front Pediatr，2015（3）：58
[14] Zhu J Y，Zhu Z，Ren Y P，et al. Role of the Nrdp1 in brain injury induced by chronic intermittent hypoxia in rats via regulating the protein levels of ErbB3[J]. Neurotox Res，2020，38：124
[15] Zhang Y C，Cao H C，Qiu X H，et al. Neuroprotective effects of Adenosine A1 receptor signaling on cognitive impairment induced by chronic intermittent hypoxia in mice[J]. Front Cell Neurosci，2020，14：202
[16] Qiao Y，Liu Z，Yan X，et al. Effect of intermittent hypoxia on neuro-functional recovery post brain ischemia in mice[J]. J Mol Neurosci ：MN，2015，55（4）：923
[17] Zhu L L，Zhao T，Li H S，et al. Neurogenesis in the adult rat brain after intermittent hypoxia [J]. Brain Res，2005，1055（1/6）:45
[18] Tsai Y W，Yang Y R，Wang P S，et al. Intermittent hypoxia after transient focal ischemia induces hippocampal neurogenesis and c-Fos expression and reverses spatial memory deficits in rats [J]. PloS One，2011，6（8）：e24001
[19] Naidu A，Peters D M，Tan A Q，et al. Daily acute intermittent hypoxia to improve walking function in persons with subacute spinal cord injury：a randomized clinical trial study protocol[J]. BMC Neurol，2020，20（1）：273
[20] Hassan A，Arnold B M，Caine S，et al. Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia-and plasticity-associated protein expression[J]. PloS One，2018，13（5）：e0197486
[21] Cui L L，Golubczyk D，Jolkkonen J. Top 3 behavioral tests in cell therapy studies after stroke：difficult to stop a moving train[J]. Stroke，2017，48（11）：3165
[22] Ritzl A，Meisel S，Wittsack H J，et al. Development of brain infarct volume as assessed by magnetic resonance imaging （MRI）：follow-up of diffusion-weighted MRI lesions[J]. JMRI，2004，20（2）：201
[23] Tipirneni-Sajja A，Christensen S，Straka M，et al. Prediction of final infarct volume on subacute MRI by quantifying cerebral edema in ischemic stroke[J]. J Cereb Blood Flow Metab，2017，37（8）：3077
[24] Diekhorst L，Gómez-de Frutos M C，Laso-García F，et al. Mesenchymal stem cells from adipose tissue do not improve functional recovery after ischemic stroke in hypertensive rats[J]. Stroke，2020，51：342
[25] Yang C J，DeMars K M，Alexander J C，et al. Sustained neurological recovery after stroke in aged rats treated with a novel prostacyclin analog[J]. Stroke，2017，48：1948
[26] Kim Y，Kim Y S，Kim H Y，et al. Early treatment with poly（ADP-Ribose） polymerase-1 inhibitor（JPI-289） reduces infarct volume and improves long-term behavior in an animal model of ischemic stroke[J]. Mol Neurobiol，2018，55（9）：7153
[27] Carling D. AMPK signalling in health and disease[J]. Curr Opin Cell Biol，2017，45：31
[28] Jiang S，Li T，Ji T，et al. AMPK：potential therapeutic target for ischemic stroke [J]. Theranostics，2018，8（16）：4535
[29] Thomas A，Belaidi E，Moulin S，et al. Chronic intermittent hypoxia impairs insulin sensitivity but improves whole-body glucose tolerance by activating skeletal muscle AMPK[J]. Diabetes，2017，66（12）：2942
[30] Perim R R，Fields D P，Mitchell G S. Spinal AMP kinase activity differentially regulates phrenic motor plasticity[J]. J Appl Physiol，2020，128（3）：523
[31] Toyama E Q，Herzig S，Courchet J，et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress[J]. Science，2016，351（6270）：275
[32] Yu J，Li X，Matei N，et al. Ezetimibe，a NPC1L1 inhibitor，attenuates neuronal apoptosis through AMPK dependent autophagy activation after MCAO in rats[J]. Exp Neurol，2018，307：12
[33] Yun C W，Lee J H，Lee S H. Hypoxia-induced PGC-1α regulates mitochondrial function and tumorigenesis of colorectal cancer cells [J]. Anticancer Res，2019，39（9）：4865
[34] Wareski P，Vaarmann A，Choubey V，et al. PGC-1{alpha} and PGC-1{beta} regulate mitochondrial density in neurons[J]. J Biol Chem，2009，284（32）：21379
[35] Yu K，Kuang S，Wang C，et al. Changes in mitochondria-associated protein expression and mitochondrial function in response to 2 weeks of enriched environment training after cerebral ischaemia- reperfusion injury[J]. J Mol Neurosci ：MN，2020，70（3）：413
[36] Zhang Q，Liang X C. Effects of mitochondrial dysfunction via AMPK/PGC-1α signal pathway on pathogenic mechanism of diabetic peripheral neuropathy and the protective effects of chinese medicine[J]. Chin J Integr Med，2019，25（5）：386
[37] Cantó C，Gerhart-Hines Z，Feige J N，et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity[J]. Nature，2009，458（7241）:1056
[38] Ashabi G，Khodagholi F，Khalaj L，et al. Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats：interference of AMPK/PGC-1α pathway[J]. Metab Brain Dis，2014，29（1）：47
[39] Chen C Y，Tsai Y L，Kao C L，et al. Effect of mild intermittent hypoxia on glucose tolerance，muscle morphology and AMPK-PGC-1alpha signaling[J]. Chin J Physiol，2010，53（1）：62

相似文献/References:

[1]徐凯月,孟祥雪,黄 传,等.间歇性低氧干预提高心梗大鼠心功能和运动耐量[J].天津医科大学学报,2019,25(05):459.
　XU Kai-yue,MENG Xiang-xue,HUANG Chuan,et al.Intermittent hypoxia intervention improves cardiac function and exercise tolerance of rats with myocardial infarction[J].Journal of Tianjin Medical University,2019,25(03):459.
[2]丁心语,王俊懿,黄传,等.间歇性低氧通过MEK/ERK信号改善小鼠心肌梗死后心功能恢复[J].天津医科大学学报,2024,30(04):350.[doi:10.20135/j.issn.1006-8147.2024.04.0350]
　DING Xinyu,WANG Junyi,HUANG Chuan,et al.Intermittent hypoxia improves cardiac function recovery after myocardial infarction in mice via MEK/ERK signaling[J].Journal of Tianjin Medical University,2024,30(03):350.[doi:10.20135/j.issn.1006-8147.2024.04.0350]

备注/Memo

备注/Memo:

基金项目 国家重点研发计划（2017YFC1308504）；天津特支计划高层次创新团队项目； 天津市自然科学基金重点项目（18JCZDJC98900）；天津市卫生局重点发展项目（16KJ122）；国家重点研发计划（2017YFC 1104004）
作者简介 苏悦（1996-），女，硕士在读，研究方向：康复医学与理疗学；
通信作者：万春晓，E-mail：cwan@tmu.edu.cn。

常用功能

更新日期/Last Update: 2021-05-30