[APPswe/PS1dE9/Blg Transgenic Mouse Line for Modeling Cerebral Amyloid Angiopathy Associated with Alzheimer's Disease].

Alzheimer's disease (AD) is the most common proteinopathy, which is accompanied by a steady decrease in the patient's cognitive functions with a simultaneous accumulation of amyloid plaques in brain tissues. Amyloid plaques are extracellular aggregates of amyloid ß (Aß) and are associated with neuroinflammation and neurodegeneration. Unlike humans and all other mammals, rats and mice do not reproduce AD-like pathology because there are three amino acid substitutions in their Aß. Amyloid plaques form in the brains of transgenic mice with overexpression of human Aß, and such mice are therefore possible to use in biomedicine to model the key features of AD. The transgenic mouse line APPswe/PS1dE9 is widely used as an animal model to study the molecular mechanisms of AD. A study was made to characterize the APPswe/PS1dE9/Blg subline, which was obtained by crossing APPswe/PS1dE9 mice on a CH3 genetic background with C57Bl6/Chg mice. No difference in offspring's survival and fertility was observed in the subline compared to wild-type control mice. Histological analysis of the brain in the APPswe/PS1dE9/Blg line confirmed the main neuromorphological features of AD and showed that amyloid plaques progressively increase in number and size during aging. The APPswe/PS1dE9/Blg line was assumed to provide a convenient model for developing therapeutic strategies to slow down AD progression.

[Electroretinography in evaluation of neuroprotective effect in an experimental model of glaucoma]. / Elektroretinografiya v otsenke neiroprotektornogo effekta na modeli eksperimental'noi glaukomy.

For drugs that have a therapeutic effect on glaucoma through mechanisms not associated with decreasing intraocular pressure (IOP), special attention is paid to the choice of effectiveness criteria. The article examines the possibility of using a- and waves of electroretinography (ERG) in preclinical studies to predict the effectiveness of glaucoma drug candidates. PURPOSE: To examine the possibility of reliably associating changes in the amplitude of a- and ERG waves with functional changes in the retina of experimental glaucoma rats with morphological evidence of loss of functional integrity of the retina. MATERIAL AND METHODS: The study was carried out in the laboratory of the Research Institute of Pharmacology of Living Systems of the Belgorod State University. Adult outbred rats were used as a test system. Experimental glaucoma was modelled by multiple injections of hyaluronic acid into the anterior chamber of the eye; they were examined by recording the time history of intraocular pressure changes, and performing ERG, ophthalmoscopy, and histological examination of the retina and subcortical centers of vision. The following groups were formed: intact, pathology control, positive control. RESULTS: The development of glaucoma in experimental rats was accompanied by neuronal death in the ganglionic layer of the retina; at the same time, characteristic changes were observed in the subcortical visual centers. A change in the ERG was recorded: for thewave, there was a dependence on the degree of changes in the ganglionic layer of the retina, change in the wave can also indicate the involvement of amacrine and horizontal cells in the process; for the a-wave, a correlation with the results of photoreceptor layer histology was noted, which was characterized as a deviation from the norm developing against the background of hydrodynamic load in the eye chambers. CONCLUSION: ERG is suitable for use in preclinical studies of glaucoma drugs as an indicative in vivo method for diagnosing the state of the retina in animals. The use of this method is especially valuable for conducting preclinical studies of drugs that involve long-term use when ophthalmoscopy and intraocular pressure alone cannot fully characterize the course of glaucoma, and animal euthanasia seems unnecessary and inhumane.

Assessment of the Nephroprotective Properties of the Erythropoietin Mimetic Peptide and Infliximab in Kidney Ischemia-Reperfusion Injury in Rats.

Chronic kidney disease (CKD) or acute kidney injury (AKI) causes impaired kidney function, leading to cognitive impairment, neuropathy, and cerebrovascular disease. Due to kidney damage, toxins stay in the blood rather than leaving the body through the urine, and brain function is affected by kidney-brain interaction. The present study aimed to investigate the protective effects of erythropoietin mimetic peptide (pHBSP) and infliximab on ischemic renal reperfusion injury. The experiment was performed on 70 white male Wistar laboratory rats which received recombinant erythropoietin, pHBSP, and infliximab. Under anesthesia, traumatic vascular clamps were applied to the left renal pedicle for 40 min, and nephrectomy was performed on the right. Functional tests and laboratory tests were performed 5 min and 24 h after the reperfusion.  Thereafter, 24 h after the surgery, the plasma creatinine and urea levels in the sham-operated animals were obtained at 45.9±0.8 mmol/L and 6.7±0.2 mmol/L, respectively. Plasma creatinine and urea levels in the control group animals were 102.63±3.6 mmol/L and 21.80±1.29 mmol/L, respectively. The administration of pHBSP and infliximab to the animals with ischemia-reperfusion kidney injury has a pronounced nephroprotective effect, as compared to erythropoietin. There was a significant decrease in blood levels of creatinine and urea, improvement of microcirculation in the kidney, normalization of glomerular filtration rate, and fractional sodium excretion. The results of the study demonstrated pointed to the prospects of pHBSP and infliximab administration in ischemia-reperfusion kidney injury and justified the feasibility of further research in this field.

Study of Endothelial Protective Activity of Phenol-Derived Thrombin and Arginase-2 Inhibitors KUD-259 and KUD-974.

We performed correction of endothelial dysfunction with phenol derivatives KUD-259 and KUD-974 containing heteroatomic and heterocyclic structures. Pharmacological activity of KUD-259 and KUD-974 surpassed that of L-norvaline, a non-selective arginase inhibitor.

[Comparative evaluation of the osteoprotective effects of resveratrol and resveratrol/enalapril combination in the treatment of experimental osteoporosis].

The osteoprotective effect of resveratrol and a combination of resveratrol with enalapril has been investigated in white Wistar female rats with experimental osteoporosis. It is established that, in rats after ovariectomy, the endothelial dysfunction of microcirculation vessels of the osteal tissue is developed, resulting in the occurrence of osteoporosis. Resveratrol and the combination of resveratrol with enalapril prevented depression of the microcirculation level in the osteal tissue, thus preventing the thinning of osteal trabecules and preventing their microfractures.

[Correction of endothelial dysfunction by L-arginine under experimental pre-eclampsia conditions].

The ADMA-like pre-eclampsia in pregnant rats was modeled by daily introduction of L-NAME in a dose of 25 mg/kg for 7 days. L-arginine (200 mg/kg) prevented the development of arterial hypertension and a decrease in placentary microcirculation and microalbuminuria. The possibility of using L-arginine for the prevention of competitive eNOS inhibition by ADMA is discussed.

[Integrated assessment of endothelio- and cardioprotective activity of macrolide antibiotics in nitric oxide deficiency model].

Experiments on laboratory animals with nitric oxide deficiency modeled by the introduction of L-NAME (NO-synthase inhibitor) revealed the endothelio- and cardioprotective effects of clarithromycin, josamycin, roxithromycin, midecamycin and azythromycin. The administration of these macrolides leads to a decrease in the resulting area of the diagram of functional indices of the state of vessels and myocardium, which is approaching the corresponding area for intact animals.

[Experimental study of cardioprotective and endothelioprotective action of macrolides and azalides].

The cardioprotective and endothelioprotective effects of the macrolide antibiotics roxithromycin, azythromycin, and midecamycin have been studied on laboratory animals with models of the coronaro-occlusional myocardial infarction and endothelial dysfunction. The drugs led to a dose-dependent decrease in lethality, reduced the zone of necrosis of the left ventricle after coronary occlusion, and produced a positive effect on the functioning of endothelium.

Correction of endothelial dysfunction with impaza preparation in complex with enalapril and losartan during modeling of NO deficiency.

Modeling of NO deficiency by administration of L-NAME to rats led to the development of arterial hypertension and endothelial dysfunction. Pronounced endothelium and cardioprotective effects of impaza under these experimental conditions manifested more markedly during combined administration of the preparation with standard hypotensive preparations enalapril and losartan.

Comparative study of potential endothelioprotectors and impaza in modeled nitric oxide deficiency.

Experimental NO deficiency induced by L-NAME injection led to the development of arterial hypertension, endothelial dysfunction, and cardiomyocyte hypertrophy and reduced blood content of nitrates and nitrites. Impaza, NO donors, activators of NO-synthase, antioxidants, and antihypertensive preparations produced endothelium-protective effect of different degree.

[Pharmacological correction of experimental chronic limb ischemia].

In tests on a group of 250 rats, we studied (i) the level of microcirculation in the muscles of a healthy limb in the norm and (ii) the dynamics of microcirculation for 6 h after treatment with pentoxifylline in a dose of 60 mg/kg dose and L-arginine in a dose of 30 and 200 mg/kg. The chronic ischemia was modeled by excision of basic femoral artery. There was no significant difference in pentoxyfilline-treated animals in comparison to the control. In the group treated with L-arginine in a dose of 30 mg/kg, a significant increase in microcirculation was observed on the 28-th day of experiment. In the group treated with L-arginine in a dose of 200 mg/kg, there was an increase of microcirculation in all terms of the experiment in comparison to the control. The results of laser doppler flow measurements are correlated with the results of morphological investigation.

[Endothelioprotective properties of L-arginine in a nitric oxide deficiency model].

In laboratory animals with endothelial dysfunction (nitric oxide deficiency) modeled by the introduction of NO-synthase inhibitor L-NAME, the activation of endothelioprotective effects of enalapril, lozartan, amlodipine, indapamide and nebivolol is revealed for their introduction in combination with L-arginine. This result was confirmed by the behavior of a generalizing parameter, the coefficient of endothelial dysfunction (CED) calculated using the results of tests on endothelium-dependent and -independent vasodilation.

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.

Prooxidant effects of nitrofurantoin.

We studied the possibility of using prooxidant effects of nitrofurantoin (furadonin) for stimulation of the natural antioxidant systems for preventing myocardial damage after coronary occlusion. A pronounced cardioprotective effect of the drug was observed.

[Prophylactic syrups for population of environmentally polluted areas]. / Siropy profilakticheskogo haznacheniia dlia naseleniia zon ékologicheskogo zagriazneniia.

The formulas and manufacture technology of the prophylactic syrups for population living in zones of radioactive pollution were developed. The basic raw material for syrups were infusions of herb having various radioprotective properties. As additional raw material was used food supplement "Adaptin".

[A simple gauge of volumetric blood flow velocity]. / Prostoi izmeritel' ob''emnoi skorosti krovotoka.

A device for measuring the blood flow volume velocity based on the principle of blood drops count per an unit of time was developed. The device is simple to manufacture, has an appropriate precision, a wide scale of measurements and can continuously record the blood flow dynamics during an experiment.

[Complex formation of lithium hydroxybutyrate with ions of Na+, K+, Ba2+, Mg2+, and Ca2+]. / Kompleksoobrazovanie litiia oksibutirata s ionami Na+, K+, Ba2+, Mg2+, and Ca2+.

The interaction of lithium hydrobutyrate (LiR) with ions of Na+, K+, Ba2+, Mg2+ and Ca2+ was studied. The coordination is implemented by atoms of oxygen of the carboxyl group. R forms the most stable complexes with ions of Mg2+ and Ca2+. Complexes of CaR+ and CaR2 types are formed with ions of Mg2+ and Ca2+. For LiR complex the logarithm of stability constant (lg K) is 0.7 +/- 0.3, for CaR+ - 2.0 +/- 0.2 and for CaR2 - 0.2 +/- 0.3. The interaction of lithium hydroxybutyrate with ions of Ca2+ and Mg2+ may be of great importance in the mechanism of its cardiotropic effect.

[General principles of heart rate control during burst stimulation of the vagus nerve in various animals]. / Obshchie printsipy upravleneniia serdechnym ritmom pri zalpovom razdrazhenii bluzhdaiushchego nerva u razlichnykh zhivotnykh.

In experiments on frogs, rats, rabbits, cats, dogs and simians the synchronization of cardiac and vagal rhythms was achieved during stimulation of vagus nerve. The relative bounds of the synchronization ranges were not dependent on the species of animal or level of sympathetic activity. In this connection, the whole variety of the cardiochronotropic reactions in vertebrates may be described with a general mathematical equation: B = A (0.769-0.098 log2N), where A is a current heart rate, B--the heart rate during the vagus nerve stimulation with bursts of N supramaximal pulses.

[Cardiotropic properties of lithium oxybutyrate in an experiment and in the clinic]. / Kardiotropnye svoistva litiia oksibutirata v éksperimente i klinike.

Lithium oxybutyrate was shown to exert pronounced coronarolytic effects, to increase volume velocity of the coronary blood flow, to improve blood supply to ischemic myocardial areas thereby providing oxygen reserve. Lithium oxybutyrate improves the functional state of the ischemic focus, limits zone of experimental myocardial necroses, exerts an antifibrillatory action, increases pain sensitivity threshold. A high efficacy of the drug was established during clinical study in patients with cardiac rhythm disorders.

[Controlled sinus arrhythmia during burst stimulation of the vagus nerve]. / Upravliaemaia sinusovaia aritmiia pri zalpovom razdrazhenii bluzhdaiushchego nerva.

In experiments on anesthesized cats and rats the desynchronization of the heart rate and burst stimulation of the vagus brought about severe sinus arrhythmia. Analysis of the functional dependence between the P--S interval (atrial wave of the ECG--moment of vagus stimulation) and the P--P interval showed periodical alterations in pacemaker sensitivity to the effect of the vagus during each cardiac cycle. It is supposed that natural vagus arrhythmia is the result of discoordination between heart automacy and efferent vagus bursts of central origin.