Therapeutic hypercapnia improves functional recovery and attenuates injury via antiapoptotic mechanisms in a rat focal cerebral ischemia/reperfusion model.
Recent studies have demonstrated neuroprotective effects of therapeutic hypercapnia for different forms of brain injury. However, few studies have assessed the neuroprotective and neurobehavioral effects of hypercapnia in focal cerebral ischemia, and the underlying mechanisms are still unclear. Here, we investigated the effects of therapeutic hypercapnia in focal cerebral ischemia in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model. Adult male Sprague Dawley rats were subjected to 90 min of MCAO/R and subsequently exposed to increased carbon dioxide (CO2) levels to maintain arterial blood CO2 tension (PaCO2) between 80 and 100 mmHg for 2h. Neurological deficits were evaluated with the corner test at days 1, 7, 14, and 28. Infarction volume and apoptotic changes were assessed by 2, 3, 7-triphenyltetrazolium chloride (TTC) staining, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining at 24h after reperfusion. Apoptosis-related proteins (Bcl-2, Bax, cytochrome c, and caspase-3) were investigated by western blotting. The results of this study showed that therapeutic hypercapnia significantly reduced infarct volume and improved neurological scores after MCAO/R. Moreover, hypercapnia treatment increased the survival rate at 28 days after reperfusion. The TUNEL-positive neurons in the ipsilateral cortex were significantly decreased in the hypercapnia group. Mitochondrial Bcl-2 and Bax cortical expression levels were significantly higher and lower, respectively, in hypercapnia-treated rats. In addition, hypercapnia treatment decreased cytosolic cytochrome c and cleaved caspase-3 expression and increased cytosolic Bax expression. These findings indicate that therapeutic hypercapnia preserves brain tissue and promotes functional neurological recovery through antiapoptotic mechanisms.
Department of Anesthesiology, the Second Affiliated Hospital of Harbin Medical University, the Hei Long Jiang Province key Lab of Research on Anesthesiology and Critical Care Medicine, Harbin 150081, China. Electronic address: taot1985@gmail.com.
Tao
T
Tao
Yan
Y
Liu
Jingyue
J
Zhang
Yongmei
Y
Xu
Wenzhi
W
Li
Meng
M
Zhao
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002245:Carbon Dioxide / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology
D002245:Carbon Dioxide
Focal cerebral ischemia; Neuronal apoptosis; Therapeutic hypercapnia