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

Abstract

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.

The Oxidative Stress-Induced Increase in the Membrane Expression of the Water-Permeable Channel Aquaporin-4 in Astrocytes Is Regulated by Caveolin-1 Phosphorylation

“…This could account for why there is currently little consensus regarding whether AQP4 changes in expression levels is upregulated in animal models of stroke, as variations in the stroke model, the duration of reperfusion, and the methods used to determine AQP4 levels can all affect the outcome. For instance, it was observed in a recent study that, while AQP4 protein levels in the cortex are elevated by increasing levels of hypoxia, the effect is exacerbated by additional hypercapnia only in the animals that have undergone the more severe oxygen-deprivation treatments; paradoxically, CO 2 caused a decrease in AQP4 expression in animals given air containing a near-normal amount of oxygen (Yang et al, 2016 ). Oxidative stress probably elicits a similarly graded response, the consequences of which may be therapeutically relevant.…”

Hypercapnia induces IL-1β overproduction via activation of NLRP3 inflammasome: implication in cognitive impairment in hypoxemic adult rats

“…no.1063180500) and were mechanically ventilated for 3 h using a small-animal ventilator (SAR-1000, CWE, Ardmore, PA, USA). The tidal volume was set at 9 ml/kg body weight, the respiratory rate was 45 breaths/min, and inspiratory to expiratory ratio was 1:1 [ 22 ]. Mechanical ventilation was performed using a gas tank containing either room air (S group), a gas mixture containing 5% CO 2 , 21% O 2 , 74% N 2 (Hypercapnia group), 16% O 2 , 84% N 2 (Hypoxemia group), or 5% CO 2 , 16% O 2 , and 79% N 2 (HH group).…”

Neuroprotection by hypercapnia in brain ischemic injury followed by persistent hypoxia: an in vivo and in vitro experimental study

“…[18][19][20] In our previous study, hypercapnia exerted bene cial effects under mild to moderate hypoxemia and augmented the detrimental effects on the brain during severe hypoxemia in a rat model of hypoxiaischemia. [7] However, BBB dysfunction did not further deteriorate after combined exposure to moderate hypoxia and hypercapnia in this animal model. Moreover, little is known about how the hypercapnia affects molecular and functional changes, such as hypoxia-induced disruption of the TJs, in BBB dysfunction.…”

“…In our previous study, our ndings suggested that the addition of hypercapnia aggravated the injury after CCA ligation along with severe hypoxemia (PaO 2 < 50 mmHg), but hypercapnia produced protective effects against HIinduced brain damage in rats treated with mild to moderate systemic hypoxia (15% and 18% O 2 , PaO 2 > 50 mmHg). [7] It is possible that the severe injury exceeded the short-term therapeutic potential of exposure to hypercapnia gas. The large volume of ischemic tissue may have overwhelmed any possible bene t of hypercapnia gas exposure.…”