10% carbon dioxide improves cognitive function after subarachnoid hemorrhage in rats: inhibiting neuronal apoptosis through the PI3K/AKT signaling pathway

Tang, Liuyang1,#; Wen, Daochen1,#; Huang, Zichao1; Lei, Xingwei1; Li, Xiaoguo1; Zhu, Yajun1; Hai, Su2,*;Guo, Zongduo11


1Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

2Department of Neurosurgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, China

Abstract

Many patients experience long-term cognitive dysfunction after subarachnoid hemorrhage (SAH), and effective treatments are currently lacking. Carbon dioxide (CO2), an inexpensive and easily produced gas, forms carbonic acid when dissolved in water. Studies have suggested that hypercapnia may have neuroprotective effects. However, the optimal concentration of CO2 for therapeutic inhalation is still unclear. This study aimed to investigate the effects of various CO2 concentrations on cognitive function in SAH rats and to explore the potential molecular mechanisms involved. In this study, we established a rat model of SAH by endovascular perforation of the internal carotid artery. The rat models inhaled CO2 at concentrations of 10%, 20%, or 30%, for 1 hour after modeling. The results showed that inhalation of 10% CO2 improved cortical blood flow following SAH, while higher concentrations of CO2 (20% and 30%) worsened cortical hypoperfusion. The partial pressure of CO2 did not change 1 hour after SAH, but it significantly increased with the inhalation of 10% CO2. Additionally, 10% CO2 effectively inhibited neuronal apoptosis, enhanced locomotor activity, and improved memory and learning abilities in SAH rats. Moreover, 10% CO2 upregulated the phosphorylation of phosphatidylinositol 3 kinase) and protein kinase B, increased the expression of Bcl-2, and decreased the expression of Bax. In conclusion, inhaling 10% CO2 restores cerebral perfusion, inhibits neuronal apoptosis, and improves cognitive function in SAH rats. In contrast, higher concentrations of CO2 led to worsened hypoperfusion. The neuroprotective effect of 10% CO2 may occur through the activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway.

蛛网膜下腔出血（SAH）后，许多患者会长期存在认知功能障碍，但目前缺乏有效治疗手段。二氧化碳（CO₂）作为一种廉价易得的气体，溶于水可形成碳酸。研究表明高碳酸血症可能具有神经保护作用，但治疗性吸入的最佳CO₂浓度尚未明确。本研究旨在探究不同浓度CO₂对SAH大鼠认知功能的影响及其潜在分子机制。

研究方法：
通过颈内动脉血管内穿孔法建立SAH大鼠模型。造模后分别给予10%、20%或30%浓度CO₂吸入1小时。结果显示：

  1. 血流动力学效应：10% CO₂可改善SAH后皮层血流，而更高浓度（20%和30%）则加重皮层低灌注；

  2. 血气参数：SAH后1小时CO₂分压无变化，但10% CO₂吸入组显著升高；

  3. 神经行为学：10% CO₂能有效抑制神经元凋亡，增强SAH大鼠运动活性并改善记忆学习能力；

  4. 分子机制：10% CO₂可上调磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）磷酸化水平，增加抗凋亡蛋白Bcl-2表达，同时降低促凋亡蛋白Bax表达。

结论：

  • 10% CO₂吸入能恢复脑灌注、抑制神经元凋亡并改善SAH大鼠认知功能，而高浓度CO₂则加重低灌注；

  • 10% CO₂的神经保护作用可能通过激活PI3K/Akt信号通路实现。