Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia

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.

Randomized controlled trial of intermittent hypoxia in Parkinson’s disease: study rationale and protocol

“…In this study, we therefore also included a longer-term follow-up of one month after the intervention period to assess the longer-term stability of effects on clinical symptoms and blood-based markers. Recent evidence suggests that interspersion of hypoxia with either hyperoxia or hypercapnia might respectively enable a more rapid recovery after hypoxia or enhance the potency of effect on mitochondrial metabolism, providing an opportunity for comparison to the current protocol [20,79,80]. This study includes a relatively low number of participants, which hampers its power to detect smaller treatment effects on several included standardized scales.…”

Relationship between Hypoxia and Hypercapnia Tolerance and Life Expectancy

“…It should be noted that the role of carbon dioxide in the gero-protective effect of intermittent hypoxic exposures can be implemented due to its influence on molecular and cellular mechanisms of adaptation to harmful stimuli: stimulation of angiogenesis, enhancement of the antioxidant activity of cellular enzymes, modulation of apoptosis, increase in proliferative activity, reprogramming of mitochondrial metabolism, and stimulation of chaperones [ 48 ].…”

“…According to recent data, increased CO 2 (PCO 2 ≈ 50 mmHg) levels under intermittent hypercapnic–hypoxic exposure have a positive effect on a number of key gero-protective molecular cellular mechanisms [ 48 ]. Among these mechanisms, a number of researchers highlight the active activation of angiogenesis [ 49 , 50 , 51 ].…”

“…Additionally, hypercapnia and hypoxic pre-conditioning lead to increased levels of antioxidant enzymes such as superoxide dismutase and catalase, which counteract oxidative stress and prevent cellular damage. Moreover, these environmental stressors can modulate apoptotic pathways, thereby reducing neuronal apoptosis and promoting cell survival under challenging conditions [ 48 ].…”