Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia.

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.

Hypercapnic hypoxia as a rehabilitation method for patients after ischemic stroke.

INTRODUCTION: Experimental studies on animals have demonstrated a higher neuroprotective efficacy of hypercapnic hypoxia compared to normocapnic hypoxia. Respiratory training with hypercapnic hypoxia has shown a positive impact on the functional state of the nervous system in children with cerebral palsy (CP). It can be presumed that the combined effect of moderate hypercapnia and hypoxia will be promising for clinical application within the context of early rehabilitation after ischemic stroke. METHODS: A randomized triple-blind placebo-controlled study was conducted on 102 patients with ischemic stroke, aged 63.07 ± 12.1 years. All patients were diagnosed with ischemic stroke based on neuroimaging criteria and/or clinical criteria within the 48-72 hour timeframe. The experimental group (n = 50) underwent daily respiratory training with hypercapnic hypoxia (FetCO2 5-6%, FetO2 15-16%) using the 'Carbonic' device for 7-11 sessions of 20 minutes each day during the treatment process. The control group (placebo, n = 52) underwent training on a similar device modified for breathing atmospheric air. Neurological examinations were conducted on all patients before the study and on the day after completing the training course. RESULTS: The standard treatment demonstrated effectiveness in terms of neurological status scales in both groups. Intermittent exposure to hypercapnic hypoxia proved more effective in improving neurological function indicators in patients compared to the placebo group: NIHSS scale scores were 40% lower than in the placebo group (p < 0.001); mRS scale scores were 35% lower (p < 0.001); B-ADL-I and RMI indices were higher by 26% (p < 0.01) and 36% (p < 0.001), respectively; MoCA scale results were 13% higher (p < 0.05); HADS and BDI-II scale scores were lower by 35% (p < 0.05) and 25% (p < 0.05), respectively. The increase in MMSE scale scores in the intervention group was 54% higher (p < 0.001), and MoCA scale scores increased by 25% (p < 0.001). CONCLUSION: Respiratory training with hypercapnic hypoxia improves the functional state of the nervous system in patients with ischemic stroke. After conducting further clarifying studies, hypercapnic hypoxia can be considered as an effective method of neurorehabilitation, which can be used as early as 48-72 hours after the onset of stroke.

Hypercapnia potentiates HIF-1α activation in the brain of rats exposed to intermittent hypoxia.

The mechanisms and signalling pathways of the neuroprotective effect of hypercapnia and its combination with hypoxia are poorly understood. The study aims to test the hypothesis about the potentiating effect of hypercapnia on hypoxia adaptation systems directly related to hypoxia-induced factor 1α (HIF-1α). In this study we assessed HIF-1α content in hippocampal extracts and astrocytes obtained from Wistar male rats exposed to different respiratory conditions (7- or 15-fold of hypoxia and/or hypercapnia). In addition, HIF-1α content in astrocytes was assessed in in vitro model of chemical hypoxia as well as in the cerebral cortex after photothrombotic damage of this brain region. This study indicates increased levels of HIF1α in hippocampal extracts, astrocytes, and in cells of the near-stroke region of the cerebral cortex in rats exposed to hypoxia and hypercapnic hypoxia, but not hypercapnia alone. In in vitro study, hypercapnia facilitates the effects of acute chemical hypoxia observed in astrocytes. Thus, hypercapnia does not increase the level of transcription factor HIF-1α. However, the combined effects of hypercapnia and hypoxia in in vitro simulations of acute chemical hypoxia potentiate the accumulation of HIF-1α.

Hypercapnic hypoxia as a potential means to extend life expectancy and improve physiological activity in mice.

The application of combined hypoxia and hypercapnia (hypercapnic hypoxia) during respiratory exercises results in a maximum increase in resistance to acute hypoxia and ischemic tolerance of the brain. The results of those researches allow the assumption that hypercapnic hypoxia is a promising method for prophylaxis, treatment, and rehabilitation, as well as a means to increase life expectancy. The study was conducted to verify the hypothesis that it is possible to extend the life span through regular courses of respiratory exercises with hypercapnic hypoxia. In the present experimental research carried out on mice, the geroprotective effect of regular hypercapnic-hypoxic exercises (PO2-90 mm Hg and PCO2-50 mm Hg) was assessed in the context of the average life expectancy and the main criteria of its quality (reproductive function, muscle strength, and behavior). Results suggest that with regular training, life span is extended significantly by 16%. This result was accompanied by improved reproductive and cognitive functions, increased motor and search activities, and physical stamina in old age mices. This important phenomenon is accompanied by improved reproductive and cognitive functions, high motor function and search activity, as well as better physical stamina in old-aged mices. Recurring respiratory training under combined hypoxia and hypercapnia (hypercapnic hypoxia) during the lifetime significantly extended the life span of mice in the experiments.

Cerebrovascular and systemic hemodynamic response to carbon dioxide in humans.

BACKGROUND: Arterial partial pressure alteration of CO2 ((Equation is included in full-text article.)) affects not only the cerebral blood flow velocity but also the systemic arterial blood pressure (BP). At the same time, BP can affect the cerebral blood flow. The objective of the present research is to study the impact of the (Equation is included in full-text article.)level on cerebrovascular CO2 reactivity ((Equation is included in full-text article.)) and BP as well as the impact of BP upon (Equation is included in full-text article.)alteration by hypercapnia and hypocapnia. MATERIALS AND METHODS: Cerebral blood flow velocity was recorded by means of transcranial Doppler in both middle cerebral arteries (MCAv left and right). The mean arterial pressure (MAP) was studied using the finger photoplethysmography method, arterial blood oxygen saturation was estimated by the pulse oximetry method, and end-tidal (Equation is included in full-text article.)((Equation is included in full-text article.)) was measured with an infrared capnograph. After a recording of the reference values of all the parameters, all the volunteers underwent a rebreathing as well as a hyperventilation. RESULTS: At rest, (Equation is included in full-text article.)was 33.6 (SD 3.1) mmHg. At rebreathing, MCAv increased at 38 mmHg (Equation is included in full-text article.), MAP - at 43 mmHg (Equation is included in full-text article.). By hyperventilation, MCAv decreased at 28 mmHg (Equation is included in full-text article.), MAP - at 26 mmHg (Equation is included in full-text article.). When (Equation is included in full-text article.)reached 43 mmHg, (Equation is included in full-text article.)increased from 2.3 (SD 1.4) to 3.3 (SD 1.2)%/mmHg (P<0.01). When (Equation is included in full-text article.)decreased to 26 mmHg, (Equation is included in full-text article.)increased from -3.6 (SD 2.5) to -5.9 (SD 3.9)%/mmHg (P<0.01). CONCLUSION: Within the alteration of (Equation is included in full-text article.)above 43 and under 26 mmHg, BP increased and decreased, respectively, leading to a change in (Equation is included in full-text article.).