The Protective Effect of Uridine in a Rotenone-Induced Model of Parkinson's Disease: The Role of the Mitochondrial ATP-Dependent Potassium Channel.

The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease.

Effect of hypoxia on mitochondrial enzymes and ultrastructure in the brain cortex of rats with different tolerance to oxygen shortage.

The mitochondrial structure and the contents of subunits (NDUFV2, SDHA, Cyt b, COX1) of mitochondrial respiratory complexes I-IV as well as of the hypoxia-inducible factor (HIF-1α) in the brain cortex (BC) of rats with high resistance (HR) and low resistance (LR) to hypoxia were studied for the first time depending on the severity of hypoxia. Different regimes of 30-min hypobaric hypoxia (pO2 14, 10, and 8%) were used. It was found that cortical mitochondria responded to 30-min hypobaric hypoxia of different severity with typical and progressing changes in mitochondrial structure and function of mitochondrial enzymes. Under 14 and 10% hypoxia, animals developed compensatory structural and metabolic responses aimed at supporting the cell energy homeostasis. Consequently, these hypoxia regimes can be used for treatment in pressure chambers. At the same time, decreasing the oxygen concentration in the inhaled air to 8% led to the appearance of destructive processes in brain mitochondria. The features of mitochondrial ultrastructure and the function of respiratory enzymes in the BC of HR and LR rats exposed to normoxic and hypoxic conditions suggest that the two types of animals had two essentially distinct functional and metabolic patterns determined by different efficiency of the energy apparatus. The development of adaptive and destructive responses involved different metabolic pathways of the oxidation of energy substrates and different efficiency of the functioning of mitochondrial respiratory carriers.

Uridine as a protector against hypoxia-induced lung injury.

The effect of the activation of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the ultrastructure of rat lung in acute hypoxic hypoxia (7% of oxygen in nitrogen, exposure 30 min) was studied. It was shown that uridine, a precursor of the mitoKATP activator UDP, exerted a protective effect against hypoxic damage to the lung. The administration of uridine to animals prior to hypoxia decreased the number of mitochondria with altered ultrastructure and prevented the hypoxia-induced mitochondrial swelling. Uridine also protected the epithelial, interstitial and endothelial layers of the air-blood barrier from the hypoxia-induced hyperhydration. The protective action of uridine against hypoxia-induced lung injury was eliminated by the selective blocker of mitoKATP 5-hydroxydecanoate. These data suggest that one of the mechanisms of the positive effect of uridine is related to the activation of the mitoKATP channel, which, according to the literature and our data, is involved in the protection of tissues from hypoxia and leads to adaptation to it. A possible role of uridine in the maintenance of the mitochondrial structure upon hypoxia-induced lung injury and the optimization of oxygen supply of the organism is discussed.

Formation of lamellar bodies in rat liver mitochondria in hyperthyroidism.

In the present work, ultrastructural changes of rat liver mitochondria in hyperthyroidism were studied. Hyperthyroidism was induced in male Wistar rats by daily administration of 100 µg thyroxin per 100 g body weight for 5 days. The level of triiodothyronine and thyroxine increased 3- and 4-fold, respectively, in comparison with the same parameters in the control group, indicating the development of hyperthyroidism in experimental animals. It was found that under this experimental pathology 58% of the mitochondria are swollen, with their matrix enlightened, as compared to the control. In 40% of the profiles, the swollen mitochondria in the liver under hyperthyroidism exhibited rounded mono- or multilayer membrane structures, called lamellar bodies (LBs), presumably at different stages of their development: from the formation to the release from the organelles. Most LBs were located in the mitochondria near the nuclear zone (27%), while their number was reduced in the part of the cell adjacent to the plasma membrane. In a number of swollen mitochondria the cristae were shown to change their orientation, being directed radially toward the center of the mitochondria. We suggested that it is the first stage of formation of LBs. The second stage can be attributed to the formation of monomembrane structures in the center of the organelles. The third stage is characterized by the fact that the membrane of the lamellar bodies consists of several layers, and in this case the bodies were located closer to the outer mitochondrial membrane. The evagination of the outer mitochondrial membrane and its connection with lamellar structure can be recognized as the fourth stage of formation of LBs. At the fifth stage the developed lamellar formations exited the mitochondria. At the same time, following the exit of LBs from the mitochondria, no damage to the mitochondrial membrane was registered, and the structure of the remaining part of the mitochondria was similar to the control. The nucleus of the hepatocyte also underwent structural changes in hyperthyroidism, exhibiting changes in the membrane configuration, and chromatin condensation. The nature and structure of the LBs, as well as their functional role in the liver mitochondria in hyperthyroidism, require further investigation.