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Abstract：
The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood-brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic-hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.
摘要：
该综述介绍了有关缺氧和高碳酸血症在其共同影响（高碳酸血症缺氧）过程中神经保护作用相互增强的假设的形成阶段和实验确认。主要关注间歇性高碳酸血症缺氧时脑缺血耐受形成的机制和信号通路。重要的是,与单独应用相比，缺氧和高碳酸血症的联合作用具有更明显的神经保护作用。一些信号系统与低氧刺激（HIF-1α，A1受体)，而其他人(NF-κB，抗氧化活性，抑制细胞凋亡，选择性血脑屏障通透性的维持）主要由高碳酸血症调节。大多数参与大脑对缺血耐受性形成的分子和细胞机制是由于过量二氧化碳和氧缺乏（ATP依赖性钾通道，监护人,内质网应激,线粒体代谢重编程)。总的来说,实验研究表明，高碳酸血症在其与缺氧联合作用的神经保护作用中占主导地位。最近的临床研究表明，高碳酸血症-低氧训练在治疗儿童脑瘫和儿童糖尿病性多发性神经病中的有效性。将高碳酸血症缺氧与神经/心脏/细胞保护信号通路的药理调节剂相结合，可能有望将实验研究转化为临床医学。
