Hypercapnia Modulates the Activity of Adenosine A1 Receptors and mitoK+ATP-Channels in Rat Brain When Exposed to Intermittent Hypoxia.

The mechanisms and signaling pathways of the neuroprotective effects of hypercapnia and its combination with hypoxia are not studied sufficiently. The study aims to test the hypothesis of the potentiating effect of hypercapnia on the systems of adaptation to hypoxia, directly associated with A1-adenosine receptors and mitochondrial ATP-dependent K+ -channels (mitoK+ATP-channels). We evaluated the relative number of A1-adenosine receptors and mitoK+ATP-channels in astrocytes obtained from male Wistar rats exposed to various respiratory conditions (15 times of hypoxia and/or hypercapnia). In addition, the relative number of these molecules in astrocytes was evaluated on an in vitro model of chemical hypoxia, as well as in the cerebral cortex after photothrombotic damage. This study indicates an increase in the relative number of A1-adenosine receptors in astrocytes and in cells next to the stroke region of the cerebral cortex in rats exposed to hypoxia and hypercapnic hypoxia, but not hypercapnia alone. Hypercapnia and hypoxia increase the relative number of mitoK+ATP-channels in astrocytes and in cells of the peri-infarct region of the cerebral cortex in rats. In an in vitro study, hypercapnia mitigates the effects of acute chemical hypoxia observed in astrocytes for A1-adenosine receptors and mitoK+ATP-channels. Hypercapnia, unlike hypoxia, does not affect the relative number of A1 receptors to adenosine. At the same time, both hypercapnia and hypoxia increase the relative number of mitoK+ATP-channels, which can potentiate their protective effects with combined exposure.

Hypercapnia and Hypoxia Stimulate Proliferation of Astrocytes and Neurons In Vitro.

We compared proliferative activity and hypoxic tolerance in a co-culture of neurons and astrocytes in vitro after preliminary exposure to normobaric hypoxia and/or permissive hypercapnia in vivo. Preliminary hypoxic exposure increased the cell index throughout the 72-h period of observation, the effect of hypercapnia was observed on days 1 and 3 of the experiment, and the effect of hypercapnic hypoxia was noted only on day 1. Preliminary hypoxic exposure has a protective effect on nerve cells under conditions of chemical hypoxia. This suggests that hypercapnia and hypoxia activate proliferative activity of nerve cells, which can be viewed as a mechanism of their neuroprotective effectiveness.

Inhibition of Apoptosis is a Potential Way to Improving Ischemic Brain Tolerance in Combined Exposure to Hypercapnia and Hypoxia.

We compared the intensity of apoptosis in the peri-infarction area of the brain after isolated and combined exposure to hypoxia and hypercapnia prior to focal ischemic stroke modeling. Hypoxia and hypercapnia reduced the number of TUNEL-positive cells in the peri-infarction area, and their combination was most effective in comparison with effects of isolated exposures. The maximum neuroprotective effect of combined exposure to hypoxia and hypercapnia in comparison with isolated exposures was determined by inhibition of apoptosis in the peri-infarction zone.

Stress of the Endoplasmic Reticulum of Neurons in Stroke Can Be Maximally Limited by Combined Exposure to Hypercapnia and Hypoxia.

We studied the expression of chaperone GRP-78 and transcription factor NF-kB during the development of ischemic tolerance of the brain after combined and isolated exposure to hypoxia and hypercapnia. Combined exposure to hypoxia and hypercapnia maximally increased the expression of chaperone GRP-78 and transcription factor NF-kB, while the formation of ischemia-induced tolerance under conditions of hypercapnic hypoxia can be associated with activation of adaptive stress mechanisms in the endoplasmic reticulum. Under these conditions, hypercapnia in combination with hypoxia is a priority factor for activation of GRP-78 and transcription factor NF-kB.

Proliferative and Synthetic Activity of Nerve Cells after Combined or Individual Exposure to Hypoxia and Hypercapnia.

We compared synthetic and proliferative activity of brain cells in rats exposed hypoxia, hypercapnia, or both prior to experimental focal stroke. The mean number of nucleolus organizer regions in penumbra neurons did not change after normobaric hypoxia, but increased after permissive hypercapnia or hypercapnic hypoxia. These data attest to activation of proliferative and synthetic functions in nerve cells, which plays an important role in the neuroprotective mechanisms under conditions of combined exposure to hypoxia and hypercapnia.

[OPTIMAL HYPERCAPNIC HYPOXIA CONDITIONS FOR INCREASING RESISTANCE TO ACUTE HYPOXIA].

The study was focused on finding an optimal length of hypercapnia-hypoxia sessions of training resistance to acute hypoxia and looking for benefits from reoxygenation intervals and intermittent training over daytime. It turned out that 3 days of a 5-minute hypercapnia-hypoxia session per day improved resistance to acute hypoxia explicitly and that a 30-minute session increased resistance to the highest rate. Two training sessions per day are no better than one session. Hypercapnia-hypoxia training with reoxygenation intervals are the least effective in comparison to the other modes of training.

[Hypercapnia--alternative hypoxia signal incentives to increase HIF-1α and erythropoietin in the brain].

Investigated the role of hypercapnic component in the mechanism of activation of HIF-1α and increase the synthesis of erythropoietin in the combined and the isolated impact of hypoxia and hypercapnia. It was found that the content of proteins of interest significantly increases both in isolated hypoxia and hypercapnia, and at their combined effect. Moreover, the hypercapnic hypoxia causes maximum activation of the synthesis and accumulation of erythropoietin HIF-1α, and permissive hypercapnia enhances their content more than hypoxic exposure.

[The role of VEGF, HSP-70 and protein S-100B in the potentiation effect of the neuroprotective effect of hypercapnic hypoxia].

Studied the role of VEGF, HSP-70 and S-100B in potentiating hypercapnia neuroprotective effect of hypoxia. Demonstrated that neuroprotective effects when exposed hypercapnic hypoxia-mediated protein synthesis increased S-100B, mainly due to the action of carbon dioxide, and not oxygen deficiency. Neuroprotective effects of HSP-70 due to hypoxia, but the combined effect of hypoxia and hypercapnia gives a significant increase in the synthesis of HSP-70 in comparison with the isolated effect of hypoxia. Vascularization activated equally as hypoxia and hypercapnia, without adding significant effects in combination. This suggests dominant effect hypercapnia, hypoxia compared in neuroprotection mechanisms related to protein S-100B, but not the protein VEGF, hypercapnia and potentiate the neuroprotective efficacy of hypoxia-related protein HSP-70.

[The role of adenosine Al receptors and mitochondrial K+ATP channels in the mechanism of increasing the resistance to acute hypoxia in the combined effects of hypoxia and hypercapnia].

We studied the role of the role of mitoK+ATp channels and Al-adenosine receptor in the mechanism of increasing the resistance to acute hypoxia after hypoxic, hypercapnic and hypercapnic-hypoxic preconditioning. It is shown that mitochondrial ATP-sensitive potassium channels and Al-adenosine receptors, an important mechanism of preconditioning have a high value to increase the resistance to acute hypoxia/ischemia in the combined effect of hypoxia and hypercapnia. However, with regard to the adenosine receptor, this mechanism is realized without the participation hypercapnic component, which apparently starts neuroprotection without activation of the adenosine Al receptors.

[Comparative efficacy of hypoxia, hypercapnia and hypercapnic hypoxia increases body resistance to acute hypoxia in rats].

The relative efficiency of trainings with isolated hypoxia, hypercapnia and hypoxia in aggregate with hypercapnia in order to enhance the resistance of organism to the effect of an extreme hypoxia was studied. The combined effect of the hypoxia and hypercapnia was shown to influence more greatly in comparison with the effect of an isolated hypoxia. This effect was supported with an increase in the time of the loss position and the time of the animal's life under the condition of an extreme hypoxia. Also it is shown that the hypercapnia in a combination to a hypoxia makes dominating impact on formation of nonspecific resistance as the isolated hypercapnia enlarges indicators of nonspecific resistance, than the isolated hypoxia more effectively.

Neuroprotective effects of individual or combined exposure to hypoxia and hypercapnia in the experiment.

We studied the effects of hypoxic, hypercapnic, and hypercapnic-hypoxic exposures on brain tolerance to ischemia. All respiratory training modes had a neuroprotective effect, but the most pronounced effect was observed after exposure to hypercapnic hypoxia. Experimental stroke in rats preliminary exposed to hypercapnic hypoxia was associated with minimal neurological deficit and motor coordination disturbances in comparison with training modes.