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.

[Prevention of the brain neurodegeneration in rats with experimental Alzheimer's disease by adaptation to hypoxia].

The study focused on a possibility of preventing brain neurodegeneration by adaptation to intermittent hypoxia (AH) in rats with experimental Alzheimer's disease (AD) modeled by injection of a neurotoxic bert-amyloid peptide fragment (Ab) into n. basalis magnocellularis. AH was produ- ced in an altitude chamber (4.000 m; 4 hours daily; 14 days). The following results were obtained after fifteen days of the Ab injection: (1) AH substantially prevented the memory impairment induced by Ab, which was determined using the conditioned avoidance reflex test; (2) the AH significantly restricted the enhanced oxidative stress, which was determined spectrophotometrically by thiobarbituric acid-reactive substance level in the hippocampus; (3) the AH completely prevented Ab-induced nitric oxide (NO) overproduction in brain, which was measured by tissue level of nitrite and nitrate; (4) pathologically changed and dead neurons (Niessle staining) were absent in the brain cortex of rats exposed to AH before the Ab injection. Therefore AH seems to effectively prevent oxidative and nitrosative stress thereby providing protection of brain against neurodegeneration and preservation of cognitive function in experimental AD.

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.

[The effects of adaptation to hypoxia on the resistance to neurodegenerative disorders in the brain of rats of different genetic strains].

The aim of the study was to compare the protective effects of adaptation to altitude hypoxia (AH) on neurodegenerative brain disorders (NBD) induced with infusion of beta-amyloid peptides (Abeta) into the brain (imitation of Alzheimer's disease) of rats belonging to two species: Wistar rats (WR) and August rats (AR). Previously it was shown by the authors that WR were less resistant to memory function impairment and open-field activities, induced with Abeta infusion compared with AR. This study showed that preliminary AH significantly restricted brain function impairment induced by Abeta in WR, so AH demonstrated the protective effect in WR. In contrast, in AR preliminary AH provoked those impairments induced by Abeta. The AH protective effect in WR was associated with activation of stress-limiting systems (antioxidant system, NO system). Lack of AH protective effect in AR was associated with lack of activation of these systems in these rats. Thus, the different AH effects on NBD development in WR and AR are obviously determined by hereditary peculiarities of stress-limiting systems in WR and AR.

Synthesis of HSP70 in blood leukocytes as a marker of stress resistance during adaptation.

The effect of preadaptation to non-damaging emotional stress on the synthesis of HSP70 (stress-limiting factor) in peripheral blood leukocytes was studied in experiments on August and Wistar rats characterized by different sensitivity of the gastric mucosa to stress-induced injury. It was found that preadaptation improves stress resistance of Wistar rats characterized by lower innate resistance to acute mental stress and activates HSP70 synthesis in blood leukocytes. In August rats characterized by higher resistance to acute stress, adaptation reduced the resistance to stress-induced injuries, which was accompanied by the absence of activation of HSP70 synthesis in leukocytes compared to the level observed in nonadapted rats during acute stress. Thus, the intensity of HSP70 synthesis in peripheral blood leukocytes can serve as a marker of changes in animal resistance to acute stress caused by adaptation to non-damaging stress exposures and probably to other environmental factors.

Synthesis of heat shock proteins (HSP70) in blood leukocytes as a criterion of the resistance to stress injury.

The resistance of August rats to ulceration of the gastric mucosa induced by acute emotional stress was higher than in Wistar rats. August rats exhibited not only more potent activation of the protective nitric oxide system and mobilization of the immune system, but also increased synthesis of cytoprotective heat shock proteins HSP70 in blood leukocytes under stress conditions. Our results indicate that HSP70 protein synthesis in blood leukocytes during stress reflects organism's resistance to stress and, probably, to other adverse factors.

Mechanism of adaptation of the vascular system to chronic changes in nitric oxide level in the organism.

We studied the possibility of directed modulation of the efficiency of NO storage in rats due to adaptation to the chronic changes in plasma NO level. The efficiency of NO storage increased during long-term maintenance of high plasma level of NO and decreased in NO-deficient states. The compensatory changes in NO storage capacity of vessels depending on its organism content represent a new mechanism of adaptation of the cardiovascular system to chronic excess or deficit of NO, while directed modulation of this process can be important for the protection of the organism against both surplus or shortage of NO.

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.

[Correction of NO-dependent cardiovascular disorders by adaptation to hypoxia]. / Korrektsiia NO-zavisimykh serdechno-sosudistykh narushenii s pomoshch'iu adaptatsii k gipoksii.

Spontaneously hypertensive rats (SHR-SP) were adapted to intermittent hypobaric hypoxia in an altitude chamber for 40 days. The adaptation to hypoxia prevented an excessive endothelium-dependent relaxation and hypotension characteristic of myocardial infarction. The adaptation also attenuated the increase in blood pressure and prevented impairment of the endothelium-dependent relaxation in SHR-SP. The universal nature of the adaptation allows to use it for correcting many cardiovascular disorders related to diverse alterations of NO metabolism.

[The role of preventing nitric oxide deficiency in the antihypertensive effect of adaptation to hypoxia]. / Rol' preduprezhdeniia defitsita oksida azota v antigipertenzivnom éffekte adaptatsii k gipoksii.

Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. Adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5-6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate a significant role of correction of endothelial NO deficiency in the antihypertensive effect of adaptation to hypoxia.

[Nitrogen oxide storage as a factor of adaptive defence]. / Deponirovanie oksida azota kak faktor adaptivnoi zashchity]

Adaptation to environmental factors possesses multiple NO-dependent protective effects and stimulates the NO storage. An adaptation to a mild stress was shown to reduce the death rate in rats from 57% to 8% and to prevent a heat shock-induced hypotension and endothelial overactivation. Treatment of the rats with the NO-synthase inhibitor L-NNA interfered with the NO storage and formation of protective effects, while the NO donor dinitrosyl iron complex facilitated the NO storage and simulated the adaptive defence. The data obtained suggest an important role of the NO storage in adaptive defence of the organism.

[Prevention of nitric oxide hyperproduction by adaptation to stressor effects]. / Preduprezhdenie giperproduktsii oksida azota s pomoshch'iu adaptatsii k stressornym vozdeistviiam.

As was shown earlier, acute hypotensive shock induced by nitrogen oxide (NO) hyperproduction can be prevented by dosed adaptation to environmental factors. In this work we tested the hypothesis that the mechanism of this adaptive effect is based on limiting NO hyperproduction. It was shown that rat adaptation to stress completely prevented arterial depression and sharply increased revival rate of the animals after heat shock. Hypotension induced by heat shock was accompanied by almost 2.5-fold increase in NO production (EPR analysis) as compared to the control. At the background of preadaptation, heat shock did not increase NO production relative to the animals not subjected to heat shock. The data obtained agree with the proposal that the adaptation initiates NO-dependent mechanisms of limiting NO hyperproduction. Such limiting seems to be negatively regulated by NO.

[Selective inhibition of inducible NO-synthase by nonselective inhibitor]. / Otsenka vozmozhnosti izbiratel'nogo ingibirovaniia indutsibel'noi NO-sintazy s pomoshch'iu neselektivnogo ingibitora.

The study has shown that Nw-nitro-L-arginine, a nonselective nitric oxide (NO) inhibitor, in low non-vasoactive doses (10 mg/kg) exerted a protective effect in heat shock as demonstrated by a decrease in the mortality rate and prevention of acute hypotension in rats. The L-NNA in the same dose inhibited the basal NO production but left unaffected a carbachol-activated NO production. The findings suggest a possibility in principle of preferential inhibition of inducible NO-synthase in pathological conditions related to the NO overproduction using non-vasoactive doses of L-NNA the nonselective NO-synthase inhibitor.

[The protective effect of nitric oxide in heat shock]. / Zashchitnyi éffekt okisi azota pri teplovom shoke.

Hyperproduction of the endogenous vasodilator nitric oxide (NO) is a main cause of arterial pressure during shocks of various origin. Here we show that the introduction of an exogenous NO donor, dinitrosyl iron complexes, reliably decreases mortality in rats due to heat shock from 57% to 8%. Simultaneously, dinitrosyl iron complexes prevent acute hypotension, excessive inhibition of vasoconstrictory, and enhancement of vasodilatory reactions related to NO hyperproduction. We propose that the protective effect of exogenous NO is due to inhibition of excessive synthesis of endogenous NO according to the negative feedback mechanism. Since dinitrosyl iron complex is a compound in which endogenous NO is deposited in the body under natural conditions, this NO donor is a promising means of prevention and therapy of pathological states related to both NO efficiency and hyperproduction.

[The protective effect of a NO-synthase inhibitor in heat shock]. / Zashchitnyi éffekt ingibitora NO-sintazy pri teplovom shoke.

Acute hypotension related to the excessive production of a potent endogenous vasodilator nitric oxide (NO) is a most important link of heat shock pathogenesis. It was shown that inhibition of inducible NO-synthase by N(W)-nitro-L-arginine (L-NNA) at 10 mg/kg reduces the mortality of animals due to heat shock, prevents the fall of arterial blood pressure and abnormal inhibition of constriction and stimulation of dilation reactions related to NO hyperproduction. A total blockade of NO synthesis by L-NNA at 300 mg/kg did not exert a protective effect from heat shock. The data obtained suggest the importance of inducible NO-synthase in heat shock pathogenesis and show promise for the application of selective inhibition of inducible NO-synthase at pathological states related to NO hyperproduction.