Experimental Models Of Hypoxia Research Articles

Evidences That Sympathetic Overactivity and Neurogenic Hypertension Correlate with Changes in the Respiratory Pattern in Rodent Models of Experimental Hypoxia.

The main question of this chapter is as follows: What is the contribution of changes in the sympathetic-respiratory coupling to the hypertension observed in some experimental models of hypoxia? Although there is evidence supporting the concept that sympathetic-respiratory coupling is increased in different models of experimental hypoxia [chronic intermittent hypoxia (CIH) and sustained hypoxia (SH)], it was also observed that in some strains of rats and in mice, these experimental models of hypoxia do not affect the sympathetic-respiratory coupling and the baseline arterial pressure. The data from studies performed in rats (different strains, male and female, and in the natural sleep cycle) and mice submitted to chronic CIH or SH are critically discussed. The main message from these studies performed in freely moving rodents and in the in situ working heart-brainstem preparation is that experimental hypoxia changes the respiratory pattern, which correlates with increased sympathetic activity and may explain the hypertension observed in male and female rats previously submitted to CIH or SH.

Նիկոտինոիլ L- պրոլինի հակահիպօքսանտային ազդեցության ուսումնասիրությունը

The influence of nicotinoil L-proline on the survival rate of animals in various experimental models of hypoxia was studied. It was shown that nicotinoil L-proline at a dose of 10 mg/kg under the conditions of a hemic model of hypoxia caused by sodium nitrite exhibits an antihypoxic effect contributing to an increase in the survival time of mice by 28.53%

Serotonergic mechanisms associated with experimental models of hypoxia: A systematic review.

The aim of this systematic review was to explore and discuss the literature concerning the effects of hypoxia or anoxia during the perinatal period on the serotoninergic network in rodents, through mechanisms that lead to changes in serotonergic neurons, levels, segments of central nervous system affected, 5-HT transporter, and 5-HT receptor. Literature searches were performed in Embase, Medline (PubMed), Web of Science, and SCOPUS, from April to July 2021, with a total of 1045 published studies found. Using a predefined protocol, as registered on the CAMARADES website, 10 articles were included in this review. The PRISMA statement was used for reporting this systematic review. The internal validity was assessed using the SYRCLE's risk of bias tool. Our main findings show that hypoxia in the first days of postnatal life led to a disturbance in the serotonergic system with reduced in 5-HT fibers, reduced brain levels of 5-HT and 5-HIAA, reduced SERT protein expression, and reduced receptor 5-HT7 . Putative mechanisms involving damage in the serotoninergic system include retrograde cell death resulting from primary damage mainly in forebrain areas, which impairs remote areas including serotonergic raphe nuclei. Other probable mechanisms associated with the serotoninergic network damage may be triggered by excitotoxic lesion and neuroinflammation. Hypoxia at the beginning of an animal's life leads to modification of the serotonergic components associated with putative mechanisms that include cell damage and neuroinflammation.

Mentat® ameliorates hypoxia-induced attention deficyt hyperactivity disorder like behavior in rats

Introduction and aim. The objective of the study was to evaluate the effect of MentatR an herbal formulation in experimental models of hypoxia-induced attention deficit hyperactive disorder (ADHD) like behavior in rats. Material and methods. MentatR was evaluated at the dose of 100 and 200 mg/kg body weight. per oral., in two experimental models of hypoxia in Wistar rats. In the first model, after parturition, on a postnatal day 2 (PND-2), the pups were subjected to hypoxic exposure for 10 minutes to induce neonatal hypoxia. Pups were weaned from dams on PND-21 and subjected to drug treatments for 10 days. In the second model, phenytoin 150 mg/kg. b.wt. p.o. was administered orally to all pregnant animals throughout gestation to induce intrauterine hypoxia. Pups were subjected to assigned treatments after weaning. Behavioral and biochemical parameters relevant to ADHD were assessed. Results. In the positive control group, hypoxic exposure resulted in significant changes in cognitive and neurologic skills compared to normal control. Open field test, elevated plus maze test, and Acetylcholine esterase levels showed a significant increase in positive control compared to normal control. In treatment groups, there was a dose-dependent decrease in all the above parameters compared to positive control. Dopamine and Nor-epinephrine levels in brain homogenate were decreased in positive control which subsequently increased with MentatR treatment. Conclusion. MentatR showed a neuroprotective effect in different experimental models of ADHD. It may be recommended for the effective/preventive management of ADHD, especially associated with memory impairment and neurologic conditions.

Dexamethasone vs COVID-19: An experimental study in line with the preliminary findings of a large trial.

BackgroundThe preliminary report of the RECOVERY large randomised controlled trial indicated a promising survival effect for dexamethasone therapy of coronavirus disease 2019 (COVID‐19). This study aimed to investigate the anti‐hypoxic activities of dexamethasone to understand a possible mechanism of its action in hypoxia‐induced lethality through experimental models of hypoxia.MethodsIn this investigation, 84 Male BALB/c mice were randomly divided into groups of seven (12 groups). Treatment groups received 10 days of dexamethasone intraperitoneal injection at both human dose (~0.1 mg/kg) and the animal does (~1 mg/kg). Control negative and positive groups were treated with 10 ml/kg of normal saline and 30 mg/kg of propranolol, respectively. Three experimental models of hypoxia, asphyctic, circulatory, and hemic were applied in this study.ResultsThe findings showed that dexamethasone significantly prolonged the latency for death in the asphyctic model concerning the control group in both humans (P < .0001) and animal dose (P < .0001). The results were also highly significant for both doses in the hemic model (P < .001). In the circulatory model, although a small increase was observed in death prolongation, results were not statistically significant for both doses in this model (P > .05).ConclusionsThis experimental in vivo investigation demonstrated an excellent protective effect for 10 days of dexamethasone treatment against hypoxia, especially in asphyctic and hemic models. In addition to promising dexamethasone outcomes, using propranolol as the positive control illustrated a very substantial anti‐hypoxic effect even much better than dexamethasone in all models. It seems that propranolol would be a safe, potential, and prudent choice to invest in treating COVID‐19 patients.

Protective effects of ethanolic extract of Lemon Beebrush (Aloysia citrodora) leaf against hypoxia-induced lethality in mice

Lemon Beebrush, known as Lippia citroiodora and Aloysia citrodora is a known medicinal plant in Iran. Many biological activities have been reported from this plant. In spite of many works, nothing is known about protective effect of A. citrodora against hypoxia conditions. In this study, protective effects of A. citrodora leaf extract against hypoxia-induced lethality in mice were evaluated by three experimental models of hypoxia, asphyctic, haemic and circulatory. Its phenol and flavonoid contents and antioxidant activity were also evaluated. Statistically significant protective activities were established in some doses of extract in three models. Antihypoxic activity was especially pronounced in circulatory hypoxia where extract at 62.5 mg kg-1 prolonged the latency for death with respect to control group (p&lt;0.01). The effect was dose dependent. At 250 mg kg-1, it prolonged the latency for death with the same activity of propranolol (20 mg kg-1), that used as positive control (p&gt;0.05). Extract showed weak activity in haemic model. Only at the highest tested dose, 250 mg kg-1, it significantly prolonged latency for death with respect to control group (p&lt;0.05). Extract at this dose showed the same activity of propranolol which used as positive control (p&gt;0.05). In asphytic model, extract at the highest tested dose showed statistically significant activity respect to the control. At 250 mg kg-1, it significantly prolonged the latency for death (26.84 ± 4.11 vs. 19.45 ± 1.13 min, p = 0.0006). At 125 mg kg-1, it also prolonged survival time but this increase was not significantly different. Phenytoin that used as positive control kept mice alive for 29.60 ± 2.51 min (p&lt;0.0001). Extract at 250 mg kg-1 showed the same activity of phenytoin (p&gt;0.05). The total phenolic content was 342.9 ± 11.5 mg gallic acid equivalent/g of extract powder and flavonoid content was 90.2 ± 7.8 mg quercetin equivalent/g of extract powder. IC50 for DPPH radical-scavenging activity was 21.97 ± 2.4 mg/ml. The presence of polyphenols in this plant may be a proposal mechanism for reported antihypoxic activities.

Protective effects of methanolic extract of Vicia cracca against hypoxia-induced lethality in mice

Vicia genus has 45 species in Iran. Many protective and biological activities have been reported from these species. In spite of many works, nothing is known about protective effect of V. cracca against hypoxia conditions. In this study, protective effects of V. cracca extract against hypoxia-induced lethality in mice were evaluated by three experimental models of hypoxia, asphyctic, haemic and circulatory. Statistically significant protective activities were observed in some doses of extract in three models. Antihypoxic activity was especially pronounced in asphyctic model. Extract at 200 mg/kg prolonged survival time (27.37 ± 4.0 min) but was not comparable with that of phenytoin (39.80 ± 1.92). At 100 mg/kg it also prolonged survival time (24.76 ± 3.7 min) which was so higher than control group. In haemic model, V. cracca extract significantly and dose dependently prolonged survival time as compared to control group. At 200 mg/kg, extract was being capable of keeping the mice alive for 15.38 ± 1.93 min. It was also effective in circulatory model. V. cracca extract at 200 mg/kg prolonged survival time (16.84 ± 1.47 min) that was statistically significant as compared to control group (13.14 ± 0.51 min). V. cracca extract showed a very good protective effect against the hypoxia in some models. Specifically, they produced significant and dose-dependent effect on the model of asphytic and haemic hypoxia. The presence of polyphenols in this plant may be a proposal mechanism for reported antihypoxic activities of this plant.

Antihypoxic activities of Crataegus pentaegyn and Crataegus microphylla fruits-an in vivo assay

The aim of this study was to evaluate anti-hypoxia activity of polyphenolic extracts of Crataegus microphylla and Crataegus pentaegyn on mice. Three experimental models of hypoxia were considered, including asphyctic hypoxia, haemic hypoxia, and circulatory hypoxia. Polyphenolic extract of both plants exhibited significant anti-hypoxic activity and prolonged animal survival time. Anti-hypoia activity of C. pentaegyn was found to be superior to that of C. microphylla in circulatory and asphyctic hypoxia. Antihypoxic activity of these extracts may be attributed to their phenolic compounds.

Changes of the plasma metabolome of newly born piglets subjected to postnatal hypoxia and resuscitation with air

Perinatal hypoxic-ischemic brain damage is a major cause of mortality and morbidity in the neonatal period. Currently, limited ranges of biochemical tests assessing the intensity and duration of hypoxia are ready for clinical use. However, the need to initiate hypothermia therapy early after the clinical suspicion of hypoxic-ischemic encephalopathy requires the availability of early and reliable hypoxia markers. We have sought these biomarkers in an experimental model of hypoxia reoxygenation. Hypoxia and hypotension were induced in newborn piglets following a standardized model and reoxygenation was carried out using room air (RA). An untargeted liquid chromatography-time of flight mass spectrometry (LC-TOFMS) approach was used to assess changes in the metabolomic profile of plasma samples after intense hypoxia and upon reoxygenation. At the end of hypoxia, the plasma metabolome showed an increased plasma concentration of analytes reflecting a metabolic adaptation to prolonged anaerobiosis. However, after resuscitation, metabolite levels returned to the starting values. Severe hypoxia induces early, significant, and transient changes of specific metabolites in the plasma metabolome, which represent a snapshot of the biochemical adaptation of mammals to intense hypoxia. These metabolites could have applicability in predicting the severity of hypoxia in the clinical setting.

Oleanolic acid: a promising neuroprotective agent for cerebral ischemia.

Oleanolic acid: a promising neuroprotective agent for cerebral ischemia.

Antihypoxic activities of the golden Chanterelle Mushroom, Cantharellus cibarius (higher Basidiomycetes).

Cantharellus cibarius is an edible mushroom with worldwide distribution. Because of its good radical scavenging and strong iron-chelating activity, this mushroom was nominated for assay of antihypoxic activity. Protective effects of Chanterelle extract against hypoxia-induced lethality in mice were evaluated by 3 experimental models of hypoxia: asphyctic, hemic, and circulatory. Antihypoxic activity was especially pronounced in the hemic model. The effect was dose dependent. C. cibarius extract (600 mg kg-1) kept the mice alive for 10.07 ± 1.18 min. It significantly (P < 0.0001) and dose dependently prolonged survival time compared to control group (7.00 ± 0.63 min). Extract at 300 mg kg-1 prolonged survival time to 9.94 ± 0.87 min, which was statistically significant (P < 0.0001) compared to control group. In circulatory model, C. cibarius extract (600 mg kg-1) was effective. It prolonged latency for death significantly with regard to the control group (15.18 ± 4.21 vs. 9.84 ± 0.75 min; P < 0.001). At 300 mg kg-1, the extract also prolonged survival time (13.57 ± 0.87 min), and this effect was also statistically significant compared to the control group (P < 0.01). Extract showed no activity in the asphyctic model. Mice in the control group died of hypoxia in 28.20 ± 3.27 min. Extract (600 mg kg-1) prolonged latency for death, but this activity was not statistically significant (P < 0.05). Phenytoin prolonged latency for death to 55.00 ± 6.05 min (P < 0.0001).

Hypoxia-induced endothelial damage and microthrombosis in myocardial vessels of newborn landrace/large white piglets.

Objective. Evaluating the presence of endothelial changes in myocardial vessels in an experimental model of hypoxia and resuscitation in newborn piglets. Methods. Fifty male Landrace/Large White neonatal piglets were studied: ten of them were allocated in group A (control group, SHAM-operated). In group B (forty animals, experimental group) normocapnic hypoxia was induced by decreasing inspired concentration of O2 to 6%–8%. When the animals developed bradycardia or severe hypotension, reoxygenation was initiated. The animals of group B were allocated in 4 subgroups of 10, according to the concentration of O2 they were resuscitated with (groups 1, 2, 3, and 4 received 18%, 21%, 40%, and 100% O2, resp.). Results. Control group animals did not show any significant endothelial lesions. Contrarily, endothelial lesions were detected in all experimental group cases. When these lesions were analyzed in the different heart zones, no significant difference in their incidence was observed; analyzing the frequency in the animals of the 4 subgroups, only microthrombosis showed a higher frequency in animals in groups 4 and 3. Conclusions. Endothelial damage represents a diffuse pathological feature in the myocardial vessels of piglets subjected to normocapnic hypoxia and resuscitation suggesting a possible role of hyperoxygenation in aggravating endothelial damage.

S100B immunoreactivity: a new marker of hypoxia-related cardiac damage in newborn piglets

Objective: The evaluation of the expression of S100B protein, in the swine heart in an experimental model of hypoxia - reoxygenation.Methods: Normocapnic hypoxia was induced in 40 male Landrace/Large White neonatal piglets by decreasing the inspired concentration of oxygen to 6–8%. When animals developed bradycardia or severe hypotension, reoxygenation was initiated. Piglets were allocated in four groups of 10, according to the oxygen concentration they were reoxygenated with: Group 1, 2, 3 and 4 resuscitated with 18%, 21%, 40% and 100% oxygen, respectively. The animals were further classified into 4 groups according with the time required for reoxygenation: group A (<15 min); group B (16–60 min); group C (>60 min); group D (deceased animals).Results: Immunostaining for S100B protein was detected in 14 out of the 40 heart samples (35%), both inside the cytoplasm of cardiomyocytes and as globular deposits in the interstitial spaces. Significant differences were observed among groups 1–4 regarding S100B expression. Reactivity for S100B in cardiac cells was detected in 50%, 50%, 10% and 33% of animals in groups 1 and 2, 3 and 4, respectively. Marked differences were also observed among groups A–D: 75%, 33%, 12% and 22% of the animals in group 1, 2, 3 and 4, respectively, showed reactivity for S100B in the heart.Conclusions: Expression of S100B protein occurred in the heart of some of newborn piglets following severe hypoxia. S100B storage in cardiomyocytes correlates with the different oxygen concentration used during reoxygenation, being higher in piglets reoxygenated with 18% and 21%, and lower in animals reoxygenated with 40% oxygen. Intermediate levels of S100B expression were found in 100% O2-treated animals. The finding of a higher percentage of S100B-immunoreactive hearts in piglets with a fast recovery and the detection of a decreased reactivity in animals with a slow and a very slow recovery clearly indicates S100B protein as an early protective factor with a positive prognostic value in asphyxiated newborn piglets.

Effect of D- and L-1,3-butanediol isomers on glycolytic and citric acid cycle intermediates in the rat brain.

DL-1,3-butanediol (DL-BD) is an ethanol dimer which affords cerebral protection in various experimental models of hypoxia and ischemia but its mechanism of action is unknown. DL-BD is a ketogenic alcohol and it has been proposed that its protective effect was accomplished through cerebral utilization of ketone bodies. Since DL-BD is a racemic, its metabolic effects could be due to D, L or both isomers. The effects of equimolar doses of DL-, D- and L-BD (25 mmol/Kg) on cerebral metabolism were studied by measuring the cortical levels of the main glycolytic (glycogen, glucose, glucose 6-phosphate, fructose 1,6-diphosphate, pyruvate and lactate) and citric acid cycle (citrate, alpha-ketoglutarate and L-malate) intermediates. The two BD isomers exerted different effects on cerebral metabolism. Unlike L-BD, D- and DL-BD treatments resulted in a slight (+10%) but significant increase in citrate level whereas L-BD treatment led to significant reduction in pyruvate (-12%) and lactate (-24%) levels. These effects were apparently not linked to hyperketonemia, since DL-BHB treatment, which mimicked hyperketonemia induced by DL-BD, had no effect on cerebral metabolites but might be due to intracerebral metabolism of BD.

Effect of 1,3-butanediol on cerebral energy metabolism. Comparison with β-hydroxybutyrate

Previous studies have shown that 1,3-butanediol (BD) has beneficial effects in experimental models of hypoxia or ischemia but the mechanism by which it exerts its protective effects remains unknown. BD is converted in the body to beta-hydroxybutyrate (BHB) and it has been proposed that its effects were linked to its ketogenic effect. The effects of BD (25 and 50 mmol/kg) on cerebral energy metabolism of rats were studied by measuring the cerebral level of energy metabolites and by evaluating the cerebral metabolic rate according to the Lowry's method. BD induced an increase in [cortical glucose]/[plasma glucose] ratio which was associated with a decrease in lactate level and an increase in glucose and glycogen stores. In contrast, BHB treatment which mimicked hyperketonemia equivalent to BD did not modify cerebral glycolysis metabolites. Calculation of the energy reserve flux after decapitation showed that BD did not reduce the cerebral metabolic rate excluding a protective effect due to a depressant, barbiturate-like, action. These results suggest that BD induces a reduction of cerebral glycolytic rate. However, the effect is not linked to hyperketonemia but might be due to intracerebral conversion of BD to BHB.

Study on pharmacological effect of bile salts, sodium scymnol sulfate, from Rhizoprionodon acutus. I. Effect of scymnol, chimaerol and sodium scymnol sulfate on cerebral anoxia.

The effects of scymnol, chimaerol and sodium scymnol sulfate, prepared from the bile of Rhizoprionodon acutus, on cerebral anoxia were investigated in experimental models of hypoxia, ischemia and histotoxic anoxia in mice. Scymnol, at a dose of 100 mg/kg, showed a significant protective action against cerebral anoxia in all of the models studied and significantly increased the partial oxygen pressure of the arterial blood. The anti-anoxic activity of scymnol was found to be slightly greater than that of idevenone. A similar protective effect of sodium scymnol sulfate was seen at doses higher than 100 mg/kg. The survival time on hypoxia was significantly prolonged in the animals pretreated with chimaerol.

An experimental model of hypoxia on isolated rat heart in recirculating system: study of fatty acid metabolism with an iodinated fatty acid

An experimental model of hypoxia was developed on isolated rat heart to study the effects of hypoxia on cardiac performance and metabolism. Fatty acid (FA) metabolism was explored by external detection with a labelled FA, iodohexadecenoic acid (IHA). Hearts, after 30 min preperfusion in an open system, were transferred in a recirculating system for 40 min and perfused with oleate, glucose, lactate, pyruvate and IHA, either in normoxia (pO2 = 660 mmHg) or in hypoxia (pO2 = 220 mmHg). After 40 min hypoxic recirculation, oxygen uptake and dynamic parameters, except the heart rate, decreased respectively by 56% and 44%, and remained constant throughout the perfusion. Glucose utilization increased 2 fold, endogenous glycogen fell by 50% and lactate + pyruvate production increased 3 fold, showing a stimulation of glycolysis. Oleate uptake decreased by 28%, while triglycerides content remained higher. The ATP/ADP ratio decreased by 24%. Conversely to oleate, IHA uptake was not significantly modified, but its intracellular fate showed a higher radioactivity in all lipid fractions: polar lipids, diglycerides, free FAs and triglycerides. beta oxidation of IHA, evidenced by iodide production, decreased by 39%. The external detection of cardiac radioactivity allowed us to obtain time-activity curves that were analyzed with a 4-compartment mathematical model. The data evidenced an esterification ratio significantly higher in hypoxia. The metabolism of IHA as estimated by the intracellular analysis or, in a non-invasive way, by external detection, was similar to the metabolism of oleate. Thus, lipid metabolism, in hypoxia, can be explored by external detection with IHA.

An experimental model of hypoxia on isolated rat heart, in a recirculating system: Study of fatty acid metabolism with an iodinated fatty acid

An experimental model of hypoxia on isolated rat heart, in a recirculating system: Study of fatty acid metabolism with an iodinated fatty acid

Alterations in Jejunal Transport and (Na+-K+)-ATPase in an Experimental Model of Hypoxia in Rats

Hypoxia was induced by exposing rats to an atmosphere of 93% N2, 7% O2 for 4-48 hr. The animals became hypoxic as indicated by a decreased blood PaO2 (mean +/- SEM: 48 +/- 10 mm Hg). Hypoxia was accompanied by metabolic acidosis (pH 7.22 +/- 0.02) and decreased serum bicarbonate levels (9.0 +/- 4.0 meq/liter). Hypoxic rats also showed evidence of tissue hypoxia; liver tryptophan oxygenase levels were increased to 21 +/- 2 nmole/min/mg protein. In the hypoxic animals there was decreased jejunal mucosal (Na+-K+)-ATPase activity and an inhibition of active intestinal transport of sodium, glucose, 3-O-methylglucose, galactose, tyrosine, phenylalanine, and glycine as determined by in vivo perfusion studies. Jejunal fructose transport, which has a large passive component, was unaffected by hypoxia. The electrolyte, carbohydrate, and amino acid transport alterations produced by hypoxia were seen in the absence of an effect on jejunal cell number, DNA synthesis, or cell turnover. There was also no evidence of histological or ultrastructural damage. Furthermore, studies with a luminal macromolecular tracer, horseradish peroxidase, indicated that the jejunal lumen-to-blood barrier to macromolecules was also unaltered in these hypoxic animals. In vitro local oxygenation of the jejunum, by bubbling of 95% O2:5% CO2, markedly improved sodium and glucose (but not 3-O-methylglucose) absorption in hypoxic rats and control rats. The (Na+-K+)-ATPase activity of the jejunal mucosa of hypoxic rats was significantly enhanced by the local bubbling of 95% O2:5% CO2. Overall, our data indicate that during relatively mild conditions of hypoxia there is an inhibition of jejunal (Na+-K+)-ATPase activity and related transport processes that is prevented by in situ oxygenation.

Ischemic brain injury and cell calcium: Morphologic and therapeutic aspects

Histopathological data obtained from different experimental models of hypoxia and ischemia were evaluated in order to extend current knowledge of mechanisms responsible for delayed neuronal cell death. Special attention is given to the distribution of calcium (Ca2+) in vulnerable areas during the postischemic period. Between an initial defensive Ca2+ sequestration, which is completely reversible, and final toxic Ca2+ overload, which is associated with irreversible neuronal necrosis, important Ca2+ shifts could be demonstrated cytochemically. Such shifts occur mainly at excitatory presynaptic sites and seem to precede structural ischemic cell change in postsynaptic areas. Recent results obtained with some Ca2+ entry blockers indicate that prophylactic treatment and postischemic intervention prevent cytosolic Ca2+ overload and reduce delayed brain injury.