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 β-amyloid demonstrate weakened endothelium-dependent dilation of cerebral vessels, which attested to impaired production of endothelial NO. At the same time, toxic β-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. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 8, pp. 132–135, August, 2006     

Nitric Oxide as a Factor of Genetically Determined Resistance to Stress Damages and Adaptive Protection

August rats are more resistant to stress-induced gastric damages than Wistar rats. These interstrain differences were abolished after blockade of nitric oxide (NO) synthesis with NO-synthase inhibitor L-NNA, which indicates that NO contributes to genetically determined resistance to stress-induced injuries. Repeated treatment with L-NNA caused gastric ulceration in Wistar, but not in August rats. This is probably related to higher basal production and more intensive accumulation of NO in August rats compared to Wistar rats. Administration of L-NNA during adaptation to hypoxia suppressed its protective effects on the stomach in stress, which indicates that NO acts as the factor of adaptive protection.     

Effects of Preconditioning on the Resistance to Acute Hypobaric Hypoxia and Their Correction with Selective Antagonists of Nicotinic Receptors

Hypobaric hypoxic preconditioning increased the resistance of low resistant and highly resistant rats to acute hypobaric hypoxia at a critical height. Intergroup differences in the resistance of rats to acute hypobaric hypoxia were not observed after hypobaric hypoxia and one variational series with a wide range of resistance (4.5-24.5 min) appeared. Methyllycaconitine, an antagonist of subtype α₇ nicotinic cholinergic receptors, abolished the influence of hypobaric hypoxia on low resistant rats, but had no effect on highly resistant animals. Mecamylamine, a preferential antagonist of subtype α₄β₂ and α₃-containing cholinergic receptors, did not modulate the effect of hypobaric hypoxia. By contrast, hypobaric hypoxia abolished the effect of mecamylamine on the resistance of rats that were not trained under conditions of hypobaric hypoxia (low resistant and highly resistant animals with low sensitivity to hypobaric hypoxia). We conclude that the same effect of hypobaric hypoxia is mediated by various mechanisms, which involve different nicotinic cholinergic receptors. They differ from the resistance mechanisms in non-trained rats.     

Changes in the Activity of Amyloid-Degrading Metallopeptidases Leads to Disruption of Memory in Rats

In old male Wistar rats (older than 12 months), or adult males (3–4 months) subjected to prenatal hypoxia (7% O₂, 3 h, E14), a disruption of short-term memory was observed. Prenatal hypoxia also led to a decrease in the brain cortex of the levels of expression of the metallopeptidases neprilysin (NEP) and endothelinconverting enzyme (ECE-1) which regulate some neuropeptides and are the main amyloid–beta (Αβ)-degrading enzymes. Moreover we have demonstrated a significant decrease (by 2.7 times) of NEP activity in the sensorimotor cortex of old rats and of adult rats subjected to prenatal hypoxia (by 1.7 times). To confirm possible involvement of these enzymes in memory we have performed an analysis of the effect of microinjections of phosphoramidon – an inhibitor of NEP and ECE-1, and thiorphan – an inhibitor of NEP – into the rat sensorimotor cortex. Using a two-level radial maze test, disruption of short-term memory was observed 60 and 120 min after i.c. injections of phosphoramidon (10^–2 M) and 30 and 60 min after i.c. injections of thiorphan (10^–2 M). Thus, involvement of NEP and ECE-1 in short-term memory observed in this study allows us to suggest that one of the main factors in disruption of cognitive functions after prenatal hypoxia or in the process of ageing could be a decrease in the level of expression and activity of metallopeptidases participating in metabolism of Αβ and other neuropeptides.     

Noopept efficiency in experimental Alzheimer disease (cognitive deficiency caused by β-amyloid25–35 injection into Meynert basal nuclei of rats)

Experiments on adult Wistar rats showed that injection of β-amyloid_(25–35) (2 μg) into Meynert basal nuclei caused long-term memory deficiency which was detected 24 days after this injection by the memory trace retrieval in conditioned passive avoidance reflex (CPAR). The effects of noopept, an original nootropic and neuroprotective dipeptide, on the severity of this cognitive deficiency were studied. Preventive (for 7 days before the injury) intraperitoneal injections of noopept in a dose of 0.5 mg/kg completely prevented mnestic disorders under conditions of this model. Noopept exhibited a significant normalizing effect, if the treatment was started 15 days after the injury, when neurodegenerative changes in the basal nuclei, cortex, and hippocampus were still acutely pronounced. The mechanisms of this effect of the drug are studied, including, in addition to the choline-positive effect, its multicomponent neuroprotective effect and stimulation of production of antibodies to β-amyloid_(25–35). Noopept efficiency in many models of Alzheimer disease, its high bioavailability and low toxicity suggest this dipeptide for further studies as a potential agent for the treatment of this condition (initial and moderate phases). __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 146, No. 7, pp. 84–88, July, 2008     

Phagocytosis and LPS alter the maturation state of β-amyloid precursor protein and induce different Aβ peptide release signatures in human mononuclear phagocytes

Background  

The classic neuritic β-amyloid plaque of Alzheimer's disease (AD) is typically associated with activated microglia and neuroinflammation. Similarly, cerebrovascular β-amyloid (Aβ) deposits are surrounded by perivascular macrophages. Both observations indicate a contribution of the mononuclear phagocyte system to the development of β-amyloid.     

Antiamnestic Effects of Antibodies to Glutamate in Experimental Alzheimer’s Disease

Experiments on rats showed that neurodegenerative brain damage caused by administration of neurotoxic fragment of β-amyloid protein Aβ_25-35 in a dose of 2 μg into Meynert giant cell nucleus leads to long-term memory impairment in rats. Intranasal administration of antibodies to glutamate in a dose of 300 μg/kg 1 h after damage restores learning capacity of the experimental animals in the conditioned passive avoidance paradigm.     

Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage

Background  

Anti-Aβ immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Aβ antibodies to 19- and 23-month old APP-transgenic mice.     

Role of ATP-sensitive K<Superscript>+</Superscript>-channels in antiarrhythmic and cardioprotective action of adaptation to intermittent hypobaric hypoxia

Mature Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 30 sessions). This mode of adaptation enhanced heart tolerance to the arrhythmogenic action of 45-min coronary occlusion, but does not affect the infarction size/risk area ratio. In some series, the rats were exposed to more severe intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) followed by 20-min coronary occlusion and 3-h reperfusion one day after the last hypoxia session. In this case, adaptation reduced the infarction size/risk area ratio and enhanced cardiac tolerance to the arrhythmogenic effect of reperfusion, but had no effect on the incidence of ventricular arrhythmia during ischemia. We found that the cardioprotective and antiarrhythmic effects of adaptation to an altitude of 7000 m and the antiarrhythmic effect of 5000-m adaptation were mediated via activation of K_ATP channels. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 395–398, April, 2008     

Donepezil Eliminates Suppressive Effects of β-Amyloid Peptide (1-42) on Long-Term Potentiation in the Hippocampus

β-Amyloid peptide 1-42 in a concentration of 200 nM impairs induction of long-term posttetanic potentiation of population spike in CA1 pyramidal neurons in rat hippocampal slices. Application of donepezil, a drug used for the treatment of Alzheimer disease, in a concentration of 1 μM eliminates the suppressive effect of β-amyloid peptide 1-42 on long-term posttenanic potentiation in the hippocampus.     

Donor of nitric oxide improves, while NO-synthase inhibitor impairs resistance and adaptation to strenous physical exercise

It is shown that NO donor (dinitrosyl iron complexes) 1.5-fold improves, while NO-synthase blocker (Nω-nitro-L-arginine) 1.5-fold impairs the resistance to strenuous exercise in experimental animals. Animals adapted to physical exercise swim 22.1±2.0 min, while control (nonadapted) animals only 13.6±1.8 min. Administration of NO donor during adaptation prolongs swimming 1.6-fold in comparison with adaptation and 2.6-fold in comparison with the control. Inhibitor of NO-synthase completely abolishes adaptation to physical exercise. Our findings demonstrate the involvement of NO into mechanisms of organism's resistance to physical load and the possibility of modulating physical capacity and adaptation to strenous physical exercise. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 4, pp. 381–384, April, 1998     

Hexapeptides HLDF-6 and PEDF-6 restore memory in rats after chronic intracerebroventricular treatment with β-amyloid peptide Aβ(25–35)

Effects of homologous peptides HLDF-6 and PEDF-6 on behavior of animals with experimental Alzheimer’s disease induced by chronic intracerebroventricular administration of β-amyloid peptide Aβ(25–35) were studied in the zoosocial recognition test and Morris water maze. Peptides HLDF-6 and PEDF-6 possessed neuroprotective activity and counteracted the toxic effect of Aβ(25–35). Peptides HLDF-6 and PEDF-6 mainly improved long-term memory and working memory, respectively. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 3, pp. 292–296, March, 2006     

Studies of the Effects of Central Administration of β-Amyloid Peptide (25–35): Pathomorphological Changes in the Hippocampus and Impairment of Spatial Memory

The possible link between amnesia induced by central administration of β-amyloid (25–35) (Aβ(25–35)) and neurodegenerative changes in the hippocampus was studied. Male Wistar rats received single intracerebroventricular injections of Aβ(25–35) at a dose of 15 nmoles and one month later were trained in an eight-arm radial maze. Training was followed by histological assessment of the state of the hippocampus on brain sections stained with hematoxylin and eosin. Aβ(25–35) induced impairments in long-term (reference) and working memory on testing in the maze. There was a moderate reduction in the number of neurons in hippocampal field CA1; there was no change in the number of cells in field CA3. The numbers of errors made by the animals on testing in the maze were found to correlate negatively with the numbers of nerve cells in hippocampal field CA1. Thus, this is the first demonstration that impairments of learning and memory induced by single doses of Aβ(25–35) are specifically associated with neurodegenerative changes in hippocampal field CA1 in rats. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 54, No. 5, pp. 705–711, September–October, 2004.     

Differences in behavioral patterns and resistance to stress-induced gastric ulceration between August and Wistar rats adapted and unadapted to hypoxia

The incidence of gastric ulceration induced by acute emotional stress in Wistar rats is 3 times higher than in August rats, and the mean number of gastric ulcers in Wistar rats 6.3-fold surpassed that in August rats. Wistar rats predisposed to stress-induced ulceration displayed suppressed locomotor and exploratory activities in the open field test, while August rats had more stable behavioral patterns and enhanced exploratory activity after stress. Short-term preadaptation to hypobaric hypoxia for 6 days attenuated stress-induced gastric ulceration, whereas long-term adaptation (40 days) aggravated the severity of gastric ulcers in August and Wistar rats. The interstrain differences in stress-induced ulceration persisted after adaptation. The data suggest that these differences are related to genetically determined peculiarities of production and metabolism of NO and glucocorticoids in August and Wistar rats. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 12, pp. 638–641, December, 1999     

Role of restricted nitric oxide overproduction in the cardioprotective effect of adaptation to intermittent hypoxia

Adaptation to intermittent normobaric hypoxia is cardioprotective and can stimulate nitric oxide (NO) synthesis. However the role of nitric oxide (NO) in prevention of ischemia-reperfusion (IR) injury of myocardium is controversial. This study was focused on evaluating the effect of adaptation to hypoxia and IR on NO production and development of nitrative stress in the myocardium. Adaptation to hypoxia tended to increase NO production, which was determined by the total level of plasma nitrite and nitrate, and prevented IR-induced NO overproduction. The IR-induced NO overproduction was associated with significant 3-nitrotyrosine (3-NT) accumulation in the left ventricle but not in septum or aorta. In hypoxia-adapted rats, 3-NT after IR was similar to that of control rats without IR. IHC induced marked accumulation of HIF-1alpha in the left ventricle. We suggest that HIF-1alpha contributes to NO-synthase expression during adaptation to hypoxia and thereby facilitates the increase in NO production. NO, in turn, may subsequently prevent NO overproduction during IR by a negative feedback mechanism.     

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.     

Effects of acute hypobaric hypoxia on the nitric oxide system of the rat cerebral cortex: Protective role of nitric oxide inhibitors

Exposure to hypobaric hypoxia produces neuropsychological disorders. The brain nitrergic system was investigated following hypobaric hypoxia in the presence or absence of nitric oxide synthase (NOS) inhibitors. Adult rats were exposed to a simulated altitude of 8325 m (27,000 ft) for 7 h and killed after 0, 1, 3, 5, and 10 days of recovery. In addition to normobaric controls, three experimental groups were studied: i) subjected to hypobaric hypoxia without inhibitors; ii) subjected to hypobaric hypoxia and treated with 7-nitroindazole; iii) subjected to hypobaric hypoxia and treated with N(omega)-nitro-l-arginine methyl ester (l-NAME). Cerebral cortex was assayed by immunohistochemistry, Western blotting, and enzymatic assays. In animals subjected to hypobaric hypoxia without inhibitors, there was an increase in neuronal nitric oxide synthase (nNOS) immunoreactivity and Ca(2+)-dependent NOS activity from 0 to 1 days of reoxygenation. In these animals, inducible nitric oxide synthase (iNOS) expression and Ca(2+)-independent activity were undetectable, but nitrotyrosine immunoreactivity was found in some neurons. Administration of either inhibitor prevented the increase in nNOS immunoreactivity and enzymatic activity provoked by hypobaric hypoxia. Concomitantly, nitrotyrosine immunoreactivity decreased progressively. In conclusion, activation of the nitrergic system constitutes a cortical response to hypobaric hypoxia and the administration of NOS inhibitors could provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaric hypoxia.     

Tolerance to acute hypoxia maximally increases in case of joint effect of normobaric hypoxia and permissive hypercapnia in rats

IntroductionWe studied the comparative efficacy of independent and combined effects of normobaric hypoxia (90 mmHg) and permissive hypercapnia (50 mmHg) in increasing the tolerance of rats to acute hypobaric hypoxia.MethodsWe determined the time to loss of pose and life duration as a measure to assess the degree of tolerance of animals to hypobaric hypoxia by exposing them to an altitude of 11,500 m (barometric = 180 mmHg).ResultsExposure to hypercapnic hypoxia increased the tolerance to acute hypobaric hypoxia compared to exposure to normobaric hypoxia or permissive hypercapnia alone.DiscussionThe positive effects of hypercapnia and hypercapnic hypoxia occurred after one exposure, and increasing the number of exposures proportionally increased the tolerance to acute hypobaric hypoxia. The effect of permissive hypercapnia on increasing the tolerance to acute hypobaric hypoxia was found to be significantly greater than that of exposure to normobaric hypoxia. Therefore, we propose that hypercapnia is the dominant factor in increasing tolerance to acute hypobaric hypoxia.ConclusionTolerance to acute hypoxia maximally increases in case of joint effect of normobaric hypoxia and permissive hypercapnia.     

Effect of antioxidants pQ510 and resveratrol on regulatory function of the endothelium in rats with modeled arterial hypertension

We studied the effects of antioxidants resveratrol and pQ510 on physiological parameters and the state of endothelial NO-synthase as a marker of the regulatory function of the endothelium in the aorta of rats with modeled arterial hypertension. The antioxidants promoted recovery of stable NO metabolites in rat serum and maintained expression of endothelial NO-synthase at a normal level. These effects were confirmed by correction of blood pressure and endothelium-dependent vascular dilation assessed by endothelial dysfunction coefficient. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 6, pp. 619–622, June, 2007     

β-Amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins

Background  

Recent studies suggest that hypercholesterolemia, an established risk factor for atherosclerosis, is also a risk factor for Alzheimer's disease. The myeloid scavenger receptor CD36 binds oxidized lipoproteins that accumulate with hypercholesterolemia and mediates their clearance from the circulation and peripheral tissues. Recently, we demonstrated that CD36 also binds fibrillar β-amyloid and initiates a signaling cascade that regulates microglial recruitment and activation. As increased lipoprotein oxidation and accumulation of lipid peroxidation products have been reported in Alzheimer's disease, we investigated whether β-amyloid altered oxidized lipoprotein clearance via CD36.