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.

Keywords: A1 adenosine receptors; HIF-1α; antioxidant systems; apoptosis inhibition; blood–brain barrier permeability; chaperones; endoplasmic reticulum; hypercapnia; hypoxia; mitochondrial ATP-dependent potassium channels; neuroprotection.

Figure 1

Involvement of A1 receptors and mitoK⁺_ATP-channels in the molecular mechanisms of neuroprotective efficacy of hypercapnia and hypercapnic hypoxia [53]. Red lines indicate inhibition; green lines indicate activation/induction. HIF-1α—hypoxia-inducible factor 1-alpha; mitoK⁺_ATP channels—mitochondrial ATP-sensitive potassium channels.

Figure 2

Antioxidant protection during permissive hypercapnia. SOD—Superoxide Dismutase; GPx—Glutathione Peroxidase; pMSR—Peptide Methionine(R)-S-Oxide Reductase.

Figure 3

Impact of permissive hypercapnia and normobaric hypoxia on the chaperone GRP-78 and NF-κB factor. Green lines—activation/induction. Red lines—inhibition. EPR—endoplasmatic reticulum; HSP-70/GRP-78—the 70-kilodalton heat shock proteins; NF-κB—Nuclear factor kappa-light-chain-enhancer of activated B cells.

Figure 4

Impact of permissive hypercapnia and normobaric hypoxia on signaling pathways enhancing the synthetic and proliferative activity of nerve cells. Green lines indicate activation/induction, while red lines indicate inhibition. HIF-1α—hypoxia-inducible factor 1-alpha.

Figure 5

Impact of permissive hypercapnia and normobaric hypoxia on the key mediators of apoptotic signaling pathways [128]. Red lines indicate inhibition, while green lines indicate activation/induction. Bax—Bcl-2-associated X protein; Bcl-2—B-cell lymphoma 2; AIF—Apoptosis-inducing factor; HIF-1α—hypoxia-inducible factor 1-alpha; HSP-70—the 70-kilodalton heat shock proteins; PI3K—Phosphoinositide 3-kinases.

Figure 6

The impact of permissive hypercapnia and normobaric hypoxia on signaling pathways regulating the structural integrity of the blood–brain barrier, its selective permeability, and metabolic activity. Red lines—inhibition; green lines—activation/induction. miR—Micro ribonucleic acid; MMP-9—Matrix metalloproteinase-9; ICAM-1—Intercellular Adhesion Molecule 1; HIF-1α—hypoxia-inducible factor 1-alpha.

Figure 7

Signaling pathways of the influence of permissive hypercapnia and normobaric hypoxia on the transcription factor HIF-1α. Red lines—inhibition; green lines—activation/induction. MAPK—Mitogen-activated protein Kinase; HIF-1α—hypoxia-inducible factor 1-alpha; HSP-70—the 70-kilodalton heat shock proteins; PI3K—Phosphoinositide 3-kinases.

Figure 8

Potentiation of neuroprotective mechanisms during exposure to hypercapnia and hypoxia. Arrows indicate the directions of the detected effects of excess CO₂ and oxygen deficiency: red lines—inhibition; green lines—activation/induction by both factors; blue lines—activation/induction by only one factor. HSP-70/GRP-78—the 70-kilodalton heat shock proteins; HIF-1α—hypoxia-inducible factor 1-alpha; BBB—blood–brain barrier; mitoK⁺_ATP channels—Mitochondrial ATP-sensitive potassium channels; NF-κB—Nuclear factor kappa-light-chain-enhancer of activated B cells.