Phenotype Shifting in Astrocytes Account for Benefits of Intra-Arterial Selective Cooling Infusion in Hypertensive Rats of Ischemic Stroke

  • Neurotherapeutics. 2022 Jan;19(1):386-398. doi: 10.1007/s13311-022-01186-y.
Luling Wang  1  2  3  4 ,  Longfei Wu  1 ,  Yunxia Duan  1 ,  Shuaili Xu  1 ,  Yuyao Yang  5 ,  Jidong Yin  4 ,  Ye Lang  6 ,  Zongen Gao  6 ,  Chuanjie Wu  1 ,  Zaigang Lv  6 ,  Jingfei Shi  1 ,  Di Wu  7  8  9 ,  Xunming Ji  10  11  12
Affiliations
  • 1. Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China.
  • 2. Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Beijing, China.
  • 3. Center of Stroke, Beijing Institute of Brain Disorders, Beijing, China.
  • 4. Department of Emergency, Aviation General Hospital of China Medical University & Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beijing, China.
  • 5. Department of Emergency, Xuanwu Hospital, Capital Medical University, Beijing, China.
  • 6. Department of Neurology, Shengli Oilfield Central Hospital, Shandong, China.
  • 7. Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China. [email protected].
  • 8. Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Beijing, China. [email protected].
  • 9. Center of Stroke, Beijing Institute of Brain Disorders, Beijing, China. [email protected].
  • 10. Department of Neurology and China-America Institute of Neuroscience, Xuanwu Hospital, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China. [email protected].
  • 11. Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Beijing, China. [email protected].
  • 12. Center of Stroke, Beijing Institute of Brain Disorders, Beijing, China. [email protected].
PMID: 35044645 DOI: 10.1007/s13311-022-01186-y
Abstract

The translational failure of neuroprotective therapies in stroke may be influenced by the mismatch of existing comorbidities between animal models and patients. Previous studies found that single-target neuroprotective agents reduced infarction in Sprague-Dawley but not in spontaneously hypertensive rats. It is of great interest to explore whether multi-target neuroprotectants and stroke models with comorbidities should be used in further translational researches. Ischemic stroke was induced in normotensive or hypertensive rats by 90- or 120-min middle cerebral artery occlusion (MCAO) and reperfusion. Intra-Arterial Selective Cooling Infusion (IA-SCI) was started at the onset of reperfusion for 30 minutes. Acute neurological deficits, infarct volumes, gene expression and markers of A1-like and A2-like astrocytes were evaluated. In further analysis, TNFα and IL-1α were administrated intracerebroventricularly, phenotype shifting of astrocytes and infarct volumes were assessed. Normobaric oxygen treatment, as a negative control, was also assessed in hypertensive rats. IA-SCI led to similar benefits in normotensive rats with 120-min MCAO and hypertensive rats with both 90-min and 120-min MCAO, including mitigated functional deficit and reduced infarct volumes. IA-SCI shifted astrocyte phenotypes partly by downregulating A1-like astrocytes and upregulating A2-like astrocytes in both RNA and protein levels. Upregulated A1-type astrocyte markers levels, induced by intracerebroventricular injection of TNFα and IL-1α, were closely related to increased infarct volumes in hypertensive rats, despite receiving IA-SCI treatment. In addition, infarct volumes and A1/A2-like genes were not affected by normobaric oxygen treatment. IA-SCI reduced infarction in both normotensive and hypertensive rats. Our results demonstrated the neuroprotective effects of IA-SCI in hypertensive rats may be related with phenotype shifting of astrocytes.

Keywords
Astrocytes; Hypertension; Hypothermia; Ischemic stroke; Neuroprotection.
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