sodium-oxybate and Hypoxia

We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the γ-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into γ-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis.

Topics: Alzheimer Disease; Animals; Butylene Glycols; Butyrates; gamma-Aminobutyric Acid; Humans; Hypoxia; Sodium Oxybate

Topics: Adrenal Cortex Hormones; Analgesia; Cardiac Glycosides; Cardiomegaly; Diazepam; Dose-Response Relationship, Drug; Female; Heart Failure; Heart Valve Prosthesis; Humans; Hypoxia; Labor, Obstetric; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Care; Sodium Oxybate; Trichloroethylene

Topics: Adjuvants, Anesthesia; Bradycardia; Child; Critical Illness; Female; Humans; Hypoxia; Play and Playthings; Sodium Oxybate

Interaction between the products of intestinal bacteria and the intestinal epithelial cells is a key event in understanding the biological, physiological, and pathological functions of the intestinal epithelium. Here, we examined the effect of butyrate, one of the major intestinal bacterial products, on hypoxia-inducible factor-1 (HIF-1) activity under hypoxic conditions in intestinal epithelial cells. HIF-1 activity was assessed by luciferase assay using cytoplasmic extracts of intestinal epithelial cells, Caco-2, and IEC-6 cells. These cells were transiently transfected with hypoxia response element (HRE)-luciferase reporter plasmids and cultured under hypoxic conditions in the presence or absence of sodium butyrate (NaB). The effect of NaB on HRE DNA binding activity in Caco-2 cells under hypoxic conditions was assessed by electrophoretic mobility shift assay. Expression of a hypoxia-responsive gene encoding intestinal trefoil factor (ITF) in Caco-2 cells after NaB treatment was assessed using reverse-transcription PCR. The barrier function of Caco-2 cells under hypoxic conditions was also evaluated by transepithelial electrical resistance measurement. NaB suppressed up-regulation of HIF-1 transcriptional activity under hypoxic conditions in Caco-2 and IEC-6 cells. In parallel, NaB reduced HRE DNA binding activity under the same conditions. Furthermore, NaB down-regulated enhanced transcription of ITF gene. Addition of NaB under hypoxic conditions delayed recovery of transepithelial electrical resistance of the monolayers after hypoxia-reoxygenation treatment. These findings indicate that NaB suppresses HIF-1 transcriptional activity on hypoxia-responsive genes by reducing the HRE DNA binding activity under hypoxic conditions in intestinal epithelial cells.

Topics: Animals; Butyrates; Caco-2 Cells; Cell Line; Cell Line, Tumor; Cells, Cultured; Down-Regulation; Electrophysiology; Epithelial Cells; Fatty Acids; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Intestinal Mucosa; Intestines; Luciferases; Mucins; Muscle Proteins; Peptides; Plasmids; Rats; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Sodium Oxybate; Time Factors; Transcription Factors; Transfection; Trefoil Factor-2; Up-Regulation

Dysoxia can be defined as ATP flux decreasing in proportion to O2 availability with preserved ATP demand. Hepatic venous beta-hydroxybutyrate-to-acetoacetate ratio (beta-OHB/AcAc) estimates liver mitochondrial NADH/NAD and may detect the onset of dysoxia. During partial dysoxia (as opposed to anoxia), however, flow may be adequate in some liver regions, diluting effluent from dysoxic regions, thereby rendering venous beta-OHB/AcAc unreliable. To address this concern, we estimated tissue ATP while gradually reducing liver blood flow of swine to zero in a nuclear magnetic resonance spectrometer. ATP flux decreasing with O2 availability was taken as O2 uptake (VO2) decreasing in proportion to O2 delivery (QO2); and preserved ATP demand was taken as increasing Pi/ATP. VO2, tissue Pi/ATP, and venous beta-OHB/AcAc were plotted against QO2 to identify critical inflection points. Tissue dysoxia required mean QO2 for the group to be critical for both VO2 and for Pi/ATP. Critical QO2 values for VO2 and Pi/ATP of 4.07 +/- 1.07 and 2.39 +/- 1.18 (SE) ml . 100 g-1 . min-1, respectively, were not statistically significantly different but not clearly the same, suggesting the possibility that dysoxia might have commenced after VO2 began decreasing, i.e., that there could have been "O2 conformity." Critical QO2 for venous beta-OHB/AcAc was 2.44 +/- 0.46 ml . 100 g-1 . min-1 (P = NS), nearly the same as that for Pi/ATP, supporting venous beta-OHB/AcAc as a detector of dysoxia. All issues considered, tissue mitochondrial redox state seems to be an appropriate detector of dysoxia in liver.

Topics: Acetoacetates; Adenosine Triphosphate; Animals; Blood Gas Analysis; Blood Pressure; Hypoxia; Liver Circulation; Magnetic Resonance Spectroscopy; Mitochondria, Liver; NAD; Oxidation-Reduction; Oxygen Consumption; Sodium Oxybate; Swine

Topics: Animals; Blood Gas Analysis; Cats; Female; GABA Agonists; gamma-Aminobutyric Acid; Hemodynamics; Hyperoxia; Hypoxia; Male; Oxygen; Receptors, GABA; Respiration; Sodium Oxybate

Study of the electric activity of small intestine smooth muscle in vagotomized rats demonstrated diminution and disturbance of intestinal motility. These changes were most expressed within 30 days after vagotomy. Injection of antihypoxant sodium gamma-oxybutyrate and antioxidant dibunol to the vagotomized rats resulted in normalization of intestinal motility.

Topics: Animals; Antioxidants; Butylated Hydroxytoluene; Drug Evaluation, Preclinical; Electromyography; Gastrointestinal Motility; Hypoxia; Intestine, Small; Male; Muscle, Smooth; Rats; Sodium Oxybate; Time Factors; Vagotomy, Truncal; Vagus Nerve

Topics: Adolescent; Adult; Bronchitis; Chronic Disease; Humans; Hypoxia; Middle Aged; Oxygen Consumption; Sodium Oxybate

The protective effect of the narcoanalgetics, viadril (hydroxydione sodium succinate) and administered intraperitoneally in doses of 5 and 20 mg/kg was studied in the experiment on 146 pregnant noninbred white rats with simulated hemic hypoxia in the late pregnancy (the 19th day). The aforementioned rats were studied for the composition of the peripheral blood, their weight gain oxidative isoenzymes (LDH), pH and pO2 in the blood. Wilson's technique was used for the assessment of the fetal status. The offspring was studied with regard to the weight increment, the rate of postnatal mortality, behavioral reactions, etc. It was stated that viadril strengthened the resistance of pregnant animals to hypoxia and contributed to the alleviation of late sequela of posthypoxic changes in the fetus and newborn.

Topics: Animals; Animals, Newborn; Female; Fetal Hypoxia; Fetus; Hydroxybutyrates; Hypoxia; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Pregnanediones; Rats; Sodium Oxybate

Topics: Animals; Antioxidants; Butylated Hydroxytoluene; Hydroxybutyrates; Hypoxia; Isoniazid; Lipid Peroxidation; Mice; Sodium Oxybate; Terphenyl Compounds; Tuberculosis

In the experiments on the anesthesized cats sodium hydroxybutyrate and piracetam, in contrast to glyo-6, have been shown to slow down the growth rate of creatine phosphokinase activity in the blood of the coronary sinus during 60-min occlusion of the coronary artery. At the same time, in the experiments on rats with 3-day myocardial infarction GABA derivatives like glyo-6 failed to influence the final size of cardiac necrosis. It may be concluded that anti-ischemic action of some drugs may be expressed only in the reduction of the rate of ischemic lesion development in the heart, but not in the limitation of the infarction size.

Topics: Animals; Cats; Hypoxia; Male; Myocardial Infarction; Piracetam; Pyridoxine; Rats; Sodium Oxybate

Topics: Forearm; Hand; Humans; Hydroxybutyrates; Hypoxia; Ischemia; Microcirculation; Sodium Oxybate; Tourniquets

Experiments on rats and mice were made to study the antianamnestic and antihypoxic effects of some GABA derivatives. Cetyl GABA, sodium and lithium hydroxybutyrates and phenibut were shown to be able to decrease the retrograde amnesia caused by electroshock in passive avoidance performance. As regards the degree of the antianamnestic effect, the above-mentioned non-cyclic derivatives of GABA are not inferior to the standard nootropic drug piracetam, a derivative of cyclic GABA. Antihypoxic activity of sodium hydroxybutyrate, cetyl GABA, phenibut and lioresal studied in experimental hypoxic hypoxia compares very favourably with that of piracetam. The compounds under consideration manifest their protective action against damaging factors in doses which do not provoke muscle relaxation or any types of central depression. According to the data obtained one may conclude that the nootropic effect is exhibited by not only piracetam, a derivative of cyclic GABA, but also by some of its non-cyclic derivatives.

Topics: Amnesia; Amnesia, Retrograde; Animals; Avoidance Learning; Baclofen; Butyrates; Conditioning, Classical; gamma-Aminobutyric Acid; Humans; Hydroxybutyrates; Hypoxia; Lithium; Mice; Organometallic Compounds; Piracetam; Sodium Oxybate

This paper presents the results of the application of sodium hydroxybutyrate as 5% sugar syrup for the treatment of glaucoma patients. Common ophthalmological investigation methods and the oxyhemography were used. Fifty-two primary glaucoma patients (99 eyes) in various stages of disease and with different intraocular pressure levels were investigated. It was found that due to sodium hydroxybutyrate in 36 patients (69%) with statistical significance the visual field limits enlarged; in 15 patients visual acuity improved. The drug was efficient in the initial and developed glaucoma with normalized ophthalmotonus level. Significant improvement of the oxygen metabolism--oxygen saturation level of arterial blood and compensatory mechanisms functions of oxygenation-reduction processes in the majority of the patients was found. On the ground of the obtained findings the authors make a conclusion about the expediency of including 5% sodium hydroxybutyrate syrup in the complex treatment of primary glaucoma patients.

Topics: Adult; Aged; Female; Glaucoma; Humans; Hydroxybutyrates; Hypoxia; Intraocular Pressure; Male; Middle Aged; Oxidation-Reduction; Oxygen; Oxygen Consumption; Sodium Oxybate; Visual Fields

It was shown that depakine (valproate) increases the lifespan of mice under hypoxic hypoxia, delays the appearance of rhythm disturbances and increases the total duration of ECG maintenance in rats in a low pressure chamber. Depakine was found to reduce the background level of lactate in brain and cardiac tissues and to prevent lactate accumulation characteristic of hypoxia, as well as the shift in its standard ratio with pyruvate. Comparison of depakine with other GABA-ergic compounds with the use of the tests cited revealed that as regards the nature of its protective effect in hypoxia, depakine is close to sodium hydroxybutyrate and succinic semi-aldehyde. By antihypoxic action depakine significantly exceeds piracetam. Analysis of the effects of the inhibitors of various reactions of the "GABA shunt" suggests that the inhibition of succinic semi-aldehyde dehydrogenase accompanied by the enhanced NAD-dependent reduction of succinic semi-aldehyde to gamma-hydroxybutyric acid plays an important part in depakine antihypoxic action.

Topics: 4-Aminobutyrate Transaminase; Aminooxyacetic Acid; Animals; Brain; Dose-Response Relationship, Drug; Electrocardiography; Hypoxia; Lactates; Mice; Myocardium; Phenothiazines; Phenytoin; Piracetam; Sodium Oxybate; Transaminases

Topics: Animals; Brain; Hydroxybutyrates; Hypoxia; Male; Rats; Sodium Oxybate

The cerebral protection afforded by each of several preparations of gamma-hydroxybutyrate (GHB) was examined in the hypoxic (FiO2 = 0.05) mouse model. The greatest increase in survival time (85%) occurred after pretreatment with 300 mg/kg given as buffered gamma-butyrolactone (GBL). Compared with previous studies employing the same hypoxic model, this increase was less than that observed with certain barbiturates and equal to that observed with certain anesthetics. The cerebral and systemic metabolic and vascular effects of each of several preparations of GHB were examined in a canine model. The cerebral metabolic rate for oxygen (CMRO2) tended to increase after GHB 100 mg/kg, then progressively decreased after cumulative doses of 600 mg/kg and 1100 mg/kg. The greatest depression in CMRO2 (48%) occurred with 1100 mg/kg given as unbuffered GBL. With each preparation and at every dose, a reduction in cerebral blood flow (CBF) exceeded the reduction in CMRO2. The major systemic effect was an almost two-thirds reduction in cardiac output at the largest doses. Assuming no species difference the cerebral protection observed with GHB is probably limited by both the reduction in cardiac output and the unfavorable relationship of cerebral oxygen supply to demand (CBF/CMRO2). Brain biopsies taken after the cumulative dose of GHB 1100 mg/kg showed a trend toward lower phosphocreatine levels and higher lactate and lactate/pyruvate levels than in untreated dogs.

Topics: 4-Butyrolactone; Animals; Brain; Cerebrovascular Circulation; Disease Models, Animal; Dogs; Furans; Hydroxybutyrates; Hypoxia; Male; Mice; Oxygen; Sodium Oxybate