Effects of Acute Systemic Hypoxia and Hypercapnia on Brain Damage in a Rat Model of Hypoxia-Ischemia

• Published in: PloS one Vol. 11; no. 12; p. e0167359
• Main Authors: Yang, Wanchao, Zhang, Xuezhong, Wang, Nan, Tan, Jing, Fang, Xianhai, Wang, Qi, Tao, Tao, Li, Wenzhi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Anesthesiology; Animals; Anoxia; Apoptosis; Aquaporin 4; Aquaporin 4 - genetics; Aquaporins; Biology and Life Sciences; Biotin; Blood; Blood flow; Blood Gas Analysis; Blood pressure; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - physiopathology; Brain; Brain damage; Brain Edema - blood; Brain Edema - chemically induced; Brain Edema - physiopathology; Brain Injuries - physiopathology; Brain Injuries - therapy; Brain injury; Brain Ischemia - physiopathology; Brain Ischemia - therapy; Brain research; Carbon dioxide; Carbon Dioxide - metabolism; Carbon Dioxide - therapeutic use; Carotid artery; Carotid Artery, Common - drug effects; Carotid Artery, Common - physiopathology; Cerebral blood flow; Cerebrovascular Circulation - drug effects; Cortex; Cytometry; Damage assessment; Disease Models, Animal; DNA nucleotidylexotransferase; Edema; Education; Flow cytometry; Hippocampus; Humans; Hypercapnia; Hypercapnia - physiopathology; Hypoxemia; Hypoxia; Hypoxia - physiopathology; Immunofluorescence; Ischemia; Kinases; Laboratory animals; Ligation; Medicine and Health Sciences; Metabolism; Neurons; Neuroprotection; Ostomy; Permeability; Proteins; Rats; Research and Analysis Methods; Risk factors; Rodents; Traumatic brain injury; Ventilation; Western blotting; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0167359

Therapeutic hypercapnia has the potential for neuroprotection after global cerebral ischemia. Here we further investigated the effects of different degrees of acute systemic hypoxia in combination with hypercapnia on brain damage in a rat model of hypoxia and ischemia. Adult wistar rats underwent unilateral common carotid artery (CCA) ligation for 60 min followed by ventilation with normoxic or systemic hypoxic gas containing 11%O2,13%O2,15%O2 and 18%O2 (targeted to PaO2 30-39 mmHg, 40-49 mmHg, 50-59 mmHg, and 60-69 mmHg, respectively) or systemic hypoxic gas containing 8% carbon dioxide (targeted to PaCO2 60-80 mmHg) for 180 min. The mean artery pressure (MAP), blood gas, and cerebral blood flow (CBF) were evaluated. The cortical vascular permeability and brain edema were examined. The ipsilateral cortex damage and the percentage of hippocampal apoptotic neurons were evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) assay as well as flow cytometry, respectively. Immunofluorescence and western blotting were performed to determine aquaporin-4 (AQP4) expression. In rats treated with severe hypoxia (PaO2 < 50 mmHg), hypercapnia augmented the decline of MAP with cortical CBF and damaged blood-brain barrier permeability (p < 0.05). In contrast, in rats treated with mild to moderate hypoxia (PaO2 > 50 mmHg), hypercapnia protected against these pathophysiological changes. Moreover, hypercapnia treatment significantly reduced brain damage in the ischemic ipsilateral cortex and decreased the percentage of apoptotic neurons in the hippocampus after the CCA ligated rats were exposed to mild or moderate hypoxemia (PaO2 > 50 mmHg); especially under mild hypoxemia (PaO2 > 60 mmHg), hypercapnia significantly attenuated the expression of AQP4 protein with brain edema (p < 0.05). Hypercapnia exerts beneficial effects under mild to moderate hypoxemia and augments detrimental effects under severe hypoxemia on brain damage in a rat model of hypoxia-ischemia.