Chinese Journal of Tissue Engineering Research ›› 2024, Vol. 28 ›› Issue (7): 1063-1069.doi: 10.12307/2024.119

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Hydroxysafflor yellow A intervenes astrocyte lipocalin 2 expression after cerebral ischemia/reperfusion injury

Liu Kexin1, Song Lijuan1, 2 , 3, Wu Yige1, Han Guangyuan1, Miao Zhuyue1, Wei Ruheng1, Xiao Baoguo4, Ma Cungen1, Huang Jianjun1, 3   

  1. 1Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, Shanxi Province, China; 2Key Laboratory of Cell Physiology Jointly Established by Province and Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China; 3Department of Neurosurgery, Sinopharm Tongmei General Hospital, Datong 037003, Shanxi Province, China; 4Institute of Neurology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200025, China
  • Received:2022-12-30 Accepted:2023-03-14 Online:2024-03-08 Published:2023-07-17
  • Contact: Huang Jianjun, Master, Chief physician, Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, Shanxi Province, China; Department of Neurosurgery, Sinopharm Tongmei General Hospital, Datong 037003, Shanxi Province, China Song Lijuan, MD, Associate professor, Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, Shanxi Province, China; Key Laboratory of Cell Physiology Jointly Established by Province and Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China; Department of Neurosurgery, Sinopharm Tongmei General Hospital, Datong 037003, Shanxi Province, China
  • About author:Liu Kexin, Master, Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, Shanxi Province, China Song Lijuan, MD, Associate professor, Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, Shanxi Province, China; Key Laboratory of Cell Physiology Jointly Established by Province and Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China; Department of Neurosurgery, Sinopharm Tongmei General Hospital, Datong 037003, Shanxi Province, China
  • Supported by:
    National Natural Science Foundation of China, No. 82004028 (to SLJ); Horizontal Project of Sinopharm Tongmei General Hospital, No. 202209SY01 (to SLJ); China Postdoctoral Science Foundation, No. 2020M680912 (to SLJ); Cardiovascular Special Fund Project of National Regional Traditional Chinese Medicine Medical Center of Affiliated Hospital of Shanxi University of Chinese Medicine in 2021, No. XGZX202115 (to SLJ); Discipline Construction Fund of Shanxi University of Chinese Medicine (to MCG); Leading Team of Medical Science and Technology of Shanxi Province, No. 2020TD05 (to MCG); Young Scientists Cultivation Project of Shanxi University of Chinese Medicine in 2021, No. 2021PY-QN-09 (to SLJ); The 2022 Scientific and Technological Innovation Team of Shanxi University of Chinese Medicine, No. 2022TD2010 (to SLJ); 2022 Shanxi Provincial Science and Technology Innovation Talent Team, No. 202204051001028 (to SLJ)

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Abstract: BACKGROUND: Ischemic stroke is a serious threat to human health. After ischemia and hypoxia, astrocyte expresses lipocalin-2 in large amounts to aggravate brain injury, but the specific mechanism is not clear. Hydroxysafflor yellow A has anti-ischemia, anti-oxidation, anti-thrombosis and anti-inflammatory effects. However, whether hydroxysafflor yellow A affects the expression of lipocalin-2 in astrocytes after cerebral ischemia and hypoxia and its mechanism are not clear. 
OBJECTIVE: To investigate the effect and mechanism of hydroxysafflor yellow A on the expression of lipocalin-2 in astrocytes after cerebral ischemia and reperfusion.
METHODS: (1) Thirty adult SD rats were randomly divided into three groups: sham operation group, middle cerebral artery occlusion and reperfusion group, and hydroxysafflor yellow A group. The middle cerebral artery occlusion and reperfusion model was established in the latter two groups, and hydroxysafflor yellow A group was intraperitoneally injected with 12 mg/kg hydroxysafflor yellow A after reperfusion. Longa score was used to evaluate the degree of neurological impairment. Infarct volume was determined by TTC staining. JAK2/STAT3 pathway and lipocalin-2 expression were detected by western blot assay and immunofluorescence. Levels of interleukin 1β, interleukin 6 and tumor necrosis factor α were detected by ELISA. (2) Astrocytes were divided into four groups: Normal group, glucose-oxygen deprivation group, hydroxysafflor yellow A group and AG490 group. In the latter three groups, glucose-oxygen deprivation and glucose-oxygen recovery models were established. Astrocytes were treated with 75 μmol/L hydroxysafflor yellow A and 10 μmol/L tyrosine phosphorylation inhibitor AG490 for 8 hours during glucose-oxygen deprivation, respectively. The mechanism of hydroxysafflor yellow A on lipocalin-2 was further verified.  
RESULTS AND CONCLUSION: (1) Compared with the sham operation group, cerebral infarction was significantly increased in the middle cerebral artery occlusion and reperfusion group, accompanied by aggravated neurological impairment (P < 0.01). Hydroxysafflor yellow A treatment could reduce cerebral infarction volume and improve neurological function (P < 0.01). (2) The expressions of p-JAK2, p-STAT3 and lipocalin-2 in the middle cerebral artery occlusion and reperfusion group were higher than those in the sham operation group (P < 0.01). Hydroxysafflor yellow A treatment reduced the expressions of JAK2, STAT3 and lipocalin-2 (P < 0.01). (3) The expression levels of interleukin 1β, interleukin-6 and tumor necrosis factor α in the middle cerebral artery occlusion and reperfusion group were higher than those in the sham operation group (P < 0.01). Hydroxysafflor yellow A inhibited the expressions of interleukin 1β, interleukin-6 and tumor necrosis factor α (P < 0.01). (4) In vitro, the expressions of p-JAK2, p-STAT3 and lipocalin-2 in the glucose-oxygen deprivation group were significantly higher than those in the normal group (P < 0.01). After adding AG490, the phosphorylation of JAK2 and STAT3 decreased, and the expression of lipocalin-2 was inhibited (P < 0.01). The results suggest that hydroxysafflor yellow A may inhibit the expression of lipocalin-2 in astrocytes after ischemia and hypoxia by regulating the JAK2/STAT3 signaling pathway, thereby reducing brain injury.

Key words: cerebral ischemia, astrocyte, hydroxysafflor yellow A, lipocalin-2, JAK2, STAT3

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