[Effect of adaptation to hypoxia on expression of NO synthase isoforms in rat myocardium].

Previously we have shown that adaptation to hypoxia (AH) is cardio- and vasoprotective in myocardial ischemic and reperfusion injury and this protection is associated with restriction of nitrosative stress. The present study was focused on further elucidation of NO-dependent mechanisms of AH by identifying specific NO synthases (NOS) that could play the major role in AH protection. AH was performed in a normobaric hypoxic chamber by breathing hypoxic gas mixture (9.5-10% O2) for 5-10 min with intervening 4 min normoxia (5-8 cycles daily for 21 days). Expression of neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) protein was measured in the left ventricular myocardium using Western blot analysis with respective antibodies. AH educed iNOS protein expression by 71% (p < 0.05) whereas eNOS protein expression tended to be reduced by 41% compared to control (p < 0.05). nNOS protein expression remained unchanged after AH. Selective iNOS inhibition can mimic the AH-induced protection. Therefore protective effects of AH could be at least partially due to restriction of iNOS and, probably, eNOS expression.

Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia.

We report here studies addressing the possibility of preventing neurodegenerative changes in the brain using adaptation to periodic hypoxia in rats with experimental Alzheimer's disease induced by administration of the neurotoxic peptide fragment of beta-amyloid (Ab) into the basal magnocellular nucleus. Adaptation to periodic hypoxia was performed in a barochamber (4000 m, 4 h per day, 14 days). The following results were obtained 15 days after administration of Ab. 1. Adaptation to periodic hypoxia significantly blocked Ab-induced memory degradation in rats, as assessed by testing a conditioned passive avoidance reflex. 2. Adaptation to periodic hypoxia significantly restricted increases in oxidative stress, measured spectrophotometrically in the hippocampus in terms of the content of thiobarbituric acid-reactive secondary lipid peroxidation products. 3. Adaptation to periodic hypoxia completely prevented the overproduction of NO in the brains of rats with experimental Alzheimer's disease, as measured in terms of increases in tissue levels of stable NO metabolites, i.e., nitrites and nitrates. 4. The cerebral cortex of rats given Ab injections after adaptation to periodic hypoxia did not contain neurons with pathomorphological changes or dead neurons (Nissl staining), which were typical in animals with experimental Alzheimer's disease. Thus, adaptation to periodic hypoxia effectively prevented oxidative and nitrosative stress, protecting against neurodegenerative changes and protecting cognitive functions in experimental Alzheimer's disease.

Role of nitric oxide in prevention of cognitive disorders in neurodegenerative brain injuries in rats.

NO synthesis disturbances play an important role in the development of neurodegenerative damage in Alzheimer disease. We previously showed that adaptation to intermittent hypobaric hypoxia prevents cognitive disturbances in rats with experimental Alzheimer disease. Here we evaluated the role of NO in cognitive disorders and development of adaptive protection during experimental Alzheimer disease. Adaptation to hypoxia in rats was performed in a hypobaric pressure chamber at a simulated altitude of 4000 m (4 h per day for 14 days). Alzheimer disease was simulated by bilateral injections of a toxic fragment of beta-amyloid (25-35) into n. basalis magnocellularis. For evaluation of the role of NO in the development and prevention of memory disorders, the rats received intraperitoneally either NO-synthase inhibitor N omega-nitro-L-arginin (L-NNA, 20 mg/kg, every other day for 14 days) or NO-donor dinitrosyl iron complex (200 microg/kg daily for 14 days). NO-synthase inhibitor potentiated the damaging effect of beta-amyloid, abolished the protective effect of adaptation to hypoxia, and produced memory disorders in rats similar to those observed during experimental Alzheimer disease. In contrast, the increase in NO level in the body provided by injections of the NO-donor produced a protective effect against memory disorders caused by beta-amyloid similar to that induced by adaptation to hypoxia. We concluded that reduced NO production in the organism plays an important role in the development of cognitive disorders produced by injections of beta-amyloid, while prevention of NO deficit by administration of NO-donors or non-pharmacological stimulation of NO synthesis can provide a protective effect in experimental Alzheimer disease.

Adaptation to hypoxia prevents disturbances in cerebral blood flow during neurodegenerative process.

The rats with neurodegenerative brain disorder induced by administration of a toxic fragment of beta-amyloid demonstrate weakened endothelium-dependent dilation of cerebral vessels, which attested to impaired production of endothelial NO. At the same time, toxic beta-amyloid fragment induced the formation of NO depots in the walls of cerebral vessels, which indirectly attests to NO overproduction in the brain tissue. Preadaptation to hypoxia prevented endothelial dysfunction and improved the efficiency of NO storage. Our results suggest that adaptation to hypoxia protects the brain from various changes in NO production during neurodegenerative damage.

Resistance to neurodegenerative brain damage in August and Wistar rats.

In Wistar and August rats characterized by different resistance to acute emotional stress we compared the resistance to neurodegenerative brain damage (model of Alzheimers disease) produced by administration of a neurotoxic peptide fragment (25-35) beta-amyloid into the brain. August rats were more resistant to acute stress and development of neurodegenerative disorders compared to Wistar rats. This conclusion was derived from studying animal behavior in conditioned passive avoidance task and open-field test that characterize cognitive function of the brain. Administration of beta-amyloid modulated the behavior of Wistar rats, which reflected the impairment of memory and orientation and exploratory activity in these animals. These disturbances in Wistar rats were accompanied by activation of lipid peroxidation in the hippocampus.