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

• Published in: Neurotherapeutics 2022, Vol.19 (1), p.386-398
• Main Authors: Wang, Luling, Wu, Longfei, Duan, Yunxia, Xu, Shuaili, Yang, Yuyao, Yin, Jidong, Lang, Ye, Gao, Zongen, Wu, Chuanjie, Lv, Zaigang, Shi, Jingfei, Wu, Di, Ji, Xunming
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Astrocytes; Astrocytes - metabolism; Biomedical and Life Sciences; Biomedicine; Cerebral blood flow; Cerebral infarction; Disease Models, Animal; Gene expression; Genotype & phenotype; Humans; Hypertension; Hypertension - complications; Hypertension - therapy; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - therapy; Ischemia; Ischemic Stroke; Neurobiology; Neurological diseases; Neurology; Neuroprotection; Neuroprotective agents; Neuroprotective Agents - pharmacology; Neurosciences; Neurosurgery; Original; Original Article; Oxygen; Oxygen - metabolism; Oxygen - pharmacology; Phenotype; Phenotypes; Rats; Rats, Sprague-Dawley; Reperfusion; Rodents; Stroke; Stroke - metabolism; Stroke - therapy; Translation; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-022-01186-y

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.