Role of Mitochondrial Permeability Transition Pore in Intermittent Hypoxia-Induced Cardiac and Neuronal Protection

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We have investigated protective effects of intermittent hypoxic training (IHT) in three experimental models. In experiments on isolated hearts from adult and old guinea pigs, perfused under Langendorff mode, the effect of the intermittent hypoxia on reperfusion injury and activation of mitochondrial permeability transition pore (mPTP) was studied. It was shown that 7-day course of the IHT led to decrease of mitochondrial permeability tran­sition, increased efficiency of the heart in both adult and old animals. Cardiac reperfusion was followed by an increased cardiac contractility and decrease of an oxygen cost of myocardial work. On the heart mitochondria from adult and old rats subjected to IHT, we studied the sensitivity of mPTP opening to its inductor, phenylarsine oxide (PAO). We have found that IHT used in regime II (8% O2 gas mixture) resulted in a twofold decrease as compared with the control in the PAO-induced adult rat heart mitochondria swelling, which was completely abolished in the presence of an inhibitor – cyclosporin A (10–5 mol/l). We have estimated the sensitivity of mPTP opening based on two parameters: alterations of mitochondrial swelling and release of mitochondrial substances (mitochondrial factor). We have demonstrated that old rat heart mitochondria are more sensitive to PAO (that induces the CsA-sensitive mPTP opening and mPTP-dependent release of mitochondrial factor) than adult rat heart mitochondria. Therefore, we have observed protective effect of IHT on PAO-induced mPTP-opening and mPTP-dependent factor release from old rat heart mitochondria. In experiments on the rat hemiparkinsonian model induced by 6-hydroxydopamine (6-OHDA), we have demonstrated that the used IHT course prevented pharmacologically induced unilateral dopaminergic neuronal loss. The most significant neuroprotective effect was observed in case when IHT course carried out prior and after 6-OHDA injection. Prevention of DAergic nigral neurons apoptosis upon the action of 6-OHDA is apparently due to the protective effect of IHT on mPTP opening. By reference to the obtained data, we conclude that IHT, due to its cardio- and neuroprotective effects, can be used as a protective procedure preventing mPTP opening in aging, in a number of chronic pathologies induced by oxidative stress, and also in neurodegenerative diseases.