Hyperoxia Preconditioning Research Articles

Time course of neuroprotection induced by in vivo normobaric hyperoxia preconditioning and angiogenesis factors.

Objective(s):Every year, a large number of people lose their lives due to stroke. Stroke is the second leading cause of death worldwide. Surprisingly, recent studies have shown that preconditioning with hyperoxia (HO) increases tissue tolerance to ischemia, ultimately reducing damages caused by stroke. Addressed in this study are beneficial contributions from HO preconditioning into reduced harm to be incurred by the attack, as well as its effect on the expression levels of vascular endothelial growth factor (VEGF) and endostatin.Materials and Methods:A set of experiments was conducted where a number of rats were divided into three groups. The animals in the first group received 90% oxygen for 4 hr a day, for 6 days. The second group was housed in room air and the third group was a sham (surgical stress). After 60 min of ischemia, 24 hr blood flow, neurological deficit score (NDS) and infarct volume (IV) in the group MCAO (Middle Cerebral Artery Occlusion) were investigated. Immediately following a 48 hr HO pre-treatment, sampling was performed to measure the expression levels of VEGF and endostatin.Results:Preconditioning with alternating HO led to reduced infarct volume and NDS. Moreover, pre-treatment with HO resulted in increased VEGF expression while decreasing endostatin.Conclusion:Although further studies are deemed necessary to clarify the mechanisms of ischemic tolerance, apparently, somewhat intermittent hyperoxia can be associated with positive impacts by increasing VEGF and decreasing expression of endostatin.

Hyperbaric oxygen and hyperbaric air preconditioning induces ischemic tolerance to transient forebrain ischemia in the gerbil

Ischemic preconditioning with sublethal stress triggers defensive mechanisms against ischemic brain damage; however, such manipulations are potentially dangerous and, therefore, safe stimuli have been sought. Hyperoxia preconditioning by administration of hyperbaric (HBO) or normobaric oxygen (NBO) may have neuroprotective potential. The aim of this study was to determine whether preconditioning with HBO and air (HBA) applied at 2.5 absolute pressure (ATA) or NBO preconditioning induces ischemic tolerance in the brain of gerbils subjected to 3min transient cerebral ischemia. Neuronal cell survival, changes in brain temperature, the generation of factors involved in neurodegeneration and basic behavior in nest building were all tested. Hyperoxic preconditioning prevented ischemia-induced neuronal cell loss, reduced the number of TUNEL positive cells in the CA1 region of the hippocampus and improved the nest building process compared to untreated ischemic animals. Preconditioning also suppressed the production of reactive oxygen species and increased Bax expression normally observed after an ischemic episode. Only HBO preconditioning inhibited ischemia-evoked increases in brain temperature. Our results show that hyperoxic preconditioning results in induction of ischemic tolerance and prevents ischemia-induced neuronal damage in the gerbil brain. Pressurized air preconditioning was as effective as HBO or NBO preconditioning in providing neuroprotection. The observed neuroprotection probably results from mild oxidative stress evoked by increased brain tissue oxidation and activation of antioxidant and antiapoptotic defenses.

Normobaric Hyperoxia Preconditioning Induces Changes in the Brain Lipidome.

Recent investigations have demonstrated that normobaric hyperoxia induces neuroprotection against ischemic injury. The aim of study was to determine the survey of HO (hyperoxia) preconditioning on brain lipidome.The animals were assigned into three groups, the first experimental group was exposed to 95% inspired HO for 4 h /day for six consecutive days. The second experimental group considered as the control group and was exposed to 21% oxygen as room air (RA) in the same chamber. The third group acted as sham, which was under the stress of surgery condition without ischemia. The first two groups were divided into 2 subgroups, intact (without any surgery) and middle cerebral artery occlusion- operated (MCAO). Twenty-four hours after exposure to hyperoxia, MCAO subgroups were subjected to 60 min of right middle cerebral artery occlussion. After 24 h reperfusion, infarct volume (IV) and neurological deficit score (NDS) were assessed in MCAO subgroup. Brain lipidomics were measured in the intact subgroup. Preconditioning with HO significantly reduced NDS and IV and elevated the level of phosphatidylethanolamine (PE), sphingomyelin (SM), cholesterol ester (CE), cholesterol (Chol), phosphatidylcholine (PC), triglyceride (TG) and cerebroside (CB) in the brain as compared with the control (sham and RA). HO preconditioning, significantly decreased the brain ceramide (Cer) and lyso- phosphatidylcholine (Lyso-PC or LPC) levels. Preconditioning with HO decreases brain ischemia injury via changes in brain lipidomics and significantly decreases the brain ceramides (CER).Although more studies are required to explain the mechanisms of time course of neuroprotection, HO preconditioning partly decreases brain ischemia injury via changes in brain lipidome.

Hyperoxia-induced preconditioning against renal ischemic injury is mediated by reactive oxygen species but not related to heat shock proteins 70 and 32

Pre-exposure of rats to normobaric hyperoxia (O2 ≥ 95%) may induce late preconditioning against renal ischemia-reperfusion (IR) injury. In this study we investigated probable mechanisms of IR injury such as the role of reactive oxygen species (ROS), renal antioxidant agents, and heat shock proteins (HSP) 32 and 70 during delayed hyperoxia-preconditioning (HO). Fifty-two rats were divided into 7 groups: (A) IR, (B) HO + IR, (C) mercaptopropionyl glycine (MPG) + HO + IR, (D) MPG + IR, (E) HO + sham, (F) MPG + sham, and (G) sham. Rats in the following study groups (group B, C and E) were kept in a normobaric hyperoxic environment for 4 h/day for 6 consecutive days, after which they were subjected to 40 minutes of ischemia; animals in the control group (group A, D, F, and G) were kept in a normoxic cage. At the end of the preconditioning period, 24 hours of reperfusion was performed. Renal function was assessed by measuring serum creatinine (Cr), blood urea nitrogen (BUN), and creatinine clearance (CLCr). Induction of the antioxidant system was evaluated by measuring renal catalase (CAT) and superoxide dismutase (SOD) activities and glutathione (GSH) and malondialdehyde (MDA) content. The role of ROS was investigated by use of MPG (a ROS scavenger). HSP32 & 70 mRNA and protein also were determined. The hyperoxia-preconditioned IR group (B) had a lower plasma Cr and BUN and greater CLCr compared with the IR group (A) (P ≤ .016). Administration of MPG led to an increase in plasma Cr and BUN and a decrease in CLCr in group C compared with the hyperoxia-preconditioned group B (P ≤ .004). The hyperoxia-preconditioned IR group had a greater CAT activity and GSH level compared with the IR group A (P ≤ .007), whereas the administration of MPG did not change the GSH level but led to a decrease in CAT activity in group D compared with group B (P < .001). SOD activity did not change in hyperoxia-preconditioned ischemic rats compared with ischemic rats. Hyperoxia preconditioning and MPG administration in ischemic animals did not result in any considerable change in MDA level compared with the IR group A. Also, there were no clinically relevant differences in HSP32 & 70 mRNA and protein between all groups. The present study demonstrates that repeated pre-exposure to hyperoxia can decrease subsequent renal IR damage in this rat model of renal ischemia. Free radical production after hyperoxia appears to play a pivotal role in the hyperoxia-induced renal protection independent of HSP level. Antioxidant enzyme activities and especially catalase seem to be implicated in this renal protective mechanism.

Normobaric hyperoxia (HO) preconditioning induces durable and effective neuroprotection against cerebral ischemia and mGluRII expression

Preconditioning/ischemic tolerance of brain refers to a natural adaptive response induced by sublethal insults to increase brain resistance after stroke. Molecular studies can contribute to clarify precise mechanism(s) of this neuroprotective phenomenon. In this study, we attempted to determine durability of neuroprotection exerted by normobaric hyperoxia (HO) and its effects on mGluRII expression. Rats were divided into five groups (hyperoxia-intact, hyperoxia-MCAO, room air-intact, room air-MCAO and room air-sham). Hyperoxia groups consist of four subgroups (2HO, 5HO, 10HO and 15HO). It means that respectively 2, 5, 10 or 15 days after pretreatment (exposure to 95% inspired O2 for 4h/day and 6 consecutive days) animals were subjected to MCAO surgery (hyperoxia-MCAO group) or that decapitated as intact (hyperoxia-intact). Room air groups were considered as control and exposed to 21% oxygen. MCAO groups after the time specified in each group were subjected to 60minutes of right middle cerebral artery occlusion (MCAO). 24hours after reperfusion, neurologic deficit score (NDS) and brain infarct volume (IV) were evaluated in MCAO-operated groups. Sham operated and intact groups were used to assess expression of mGluR2/3 and glutathione (GSH) levels of core, penumbra and subcortex regions. Preconditioning with HO transiently decreased NDS and IV, and increased expression of mGluR2/3 in core, penumbra, and subcortex. These effects of hyperoxia disappeared gradually during15 days after pretreatment. Although additional studies will be required to further elucidate precise mechanism(s) in ischemic tolerance, it seems that likely part of protective effect of intermittent HO is associated with upregulation of mGluR2/3.

Ischemic Tolerance Induced by Normobaric Hyperoxia and Evaluation of Group I and II Metabotropic Glutamate Receptors

Preconditioning-induced ischemic tolerance is one of the most important mechanisms, responsible for the increased brain resistance after stroke. Recent studies over the past years have provided interesting insights into the molecular mechanisms of this neuroprotective phenomenon. In this research, we attempted to see changes in the expression of group I and II metabotropic glutamate receptors (mGluR I and II) following intermittent hyperoxia preconditioning. Rats were divided into five groups (hyperoxia-intact, hyperoxia-MCAO, room air-intact, room air- MCAO, room air-sham). Hyperoxia groups were exposed to 95% inspired O2 for 4 h/day and 6 consecutive days. Oxygen level in room air groups was %21. 48 hours after pretreatment, MCAO-operated groups were subjected to focal cerebral ischemia for 60 min. 24 hours after reperfusion, neurologic deficit score (NDS) and brain infarct volume (IV) were evaluated in MCAO-operated subgroups. Sham-operated and intact groups were used to assess expression of group I and II mGluR and glutathione (GSH) levels of core, penumbra and subcortex regions. The results of this study showed that preconditioning with intermittent HO decreased NDS and IV, increased GSH levels in subcortex, and upregulated mGluRs I and II significantly. Although additional studies will be required to further elucidate precise mechanism(s) of ischemic tolerance, it seems that intermittent HO may exert its protective effects in part through upregulation of mGluR I and II.

Ischemic Tolerance Induced by Normobaric Hyperoxia and Evaluation of Group I and II Metabotropic Glutamate Receptors

Preconditioning-induced ischemic tolerance is one of the most important mechanisms, responsible for the increased brain resistance after stroke. Recent studies over the past years have provided interesting insights into the molecular mechanisms of this neuroprotective phenomenon. In this research, we attempted to see changes in the expression of group I and II metabotropic glutamate receptors (mGluR I and II) following intermittent hyperoxia preconditioning. Rats were divided into five groups (hyperoxia-intact, hyperoxia-MCAO, room air-intact, room air- MCAO, room air-sham). Hyperoxia groups were exposed to 95% inspired O2 for 4 h/day and 6 consecutive days. Oxygen level in room air groups was %21. 48 hours after pretreatment, MCAO-operated groups were subjected to focal cerebral ischemia for 60 min. 24 hours after reperfusion, neurologic deficit score (NDS) and brain infarct volume (IV) were evaluated in MCAO-operated subgroups. Sham-operated and intact groups were used to assess expression of group I and II mGluR and glutathione (GSH) levels of core, penumbra and subcortex regions. The results of this study showed that preconditioning with intermittent HO decreased NDS and IV, increased GSH levels in subcortex, and upregulated mGluRs I and II significantly. Although additional studies will be required to further elucidate precise mechanism(s) of ischemic tolerance, it seems that intermittent HO may exert its protective effects in part through upregulation of mGluR I and II. Keywords: Brain Ischemia, Glutathione levels, Hyperoxia preconditioning, Ischemic tolerance, Metabotropic glutamate receptors, Normobaric hyperoxia

Prolonged hyperoxia preconditioning attenuates behavioral symptoms of 6-hydroxydopamine-induced Parkinsonism

Objectives: Several lines of evidences show that hyperoxia preconditioning provides neuronal protection against central nervous system ischemic damages. Common pathways including mitochondrial dysfunction, apoptosis, and caspase activation are involved in acute neurodegeneration (e.g. after cerebral ischemia) and chronic neurodegeneration (e.g. neuronal death in Parkinson’s disease). The aim of the present research was to study the effect of hyperoxia preconditioning on 6-hydroxydopamine (6-OHDA)-induced Parkinsonism.Methods: Male Wistar rats were first subjected to either air with high oxygen concentration (>90%) or atmospheric air for prolonged (24 hours) or intermittent (six consecutive days, 4 hours each day) periods and then 6-OHDA was injected into their left striatums by stereotaxic surgery. Development and severity of the 6-OHDA-induced Parkinsonism was assessed using apomorphine-induced rotational test, elevated body swing test, and rotarod test within 2–5 weeks after the surgery.Results: Significant data obtained in rats treated with prolonged hyperoxia, but not the intermittent hyperoxia. In these rats, the number of apomorphine-induced rotations was ∼60% lower than that in control and sham groups. Rats belonging to the prolonged hyperoxia group also showed considerably better motor performance and learning pattern in rotarod test. These results were confirmed by the data obtained in the elevated body swing test.Discussion: Our findings show that the prolonged hyperoxia preconditioning attenuates the behavioral symptoms of 6-OHDA-induced Parkinsonism. Considering the well-known correlation between dopaminergic neuronal death in the substantia nigra and the behavioral symptoms of 6-OHDA-induced Parkinsonism, it could be speculated that the prolonged hyperoxia preconditioning induces the mechanisms that provide dopaminergic neuroprotection against Parkinsonism-induced toxins.

Hyperoxia preconditioning: the next frontier in neurology?

Oxygen is indispensable for all aerobic organisms and has become one of the most widely used therapeutic agents. Currently, oxygen not only is applied in the treatment of diseases, but becomes a modality for the prevention of some diseases. Hyperoxia preconditioning with normobaric or hyperbaric oxygen has been found to be protective in some diseases in several animal models and clinical trials. Currently, investigators pay increasing attention to the application of hyperoxia preconditioning in the prevention of common neurological diseases, and encouraging effectiveness has been achieved. In the present short review, we briefly described the development, application and mechanisms of hyperoxia preconditioning in the neurology, and the issues in future application of hyperoxia preconditioning were also proposed.

Neuroprotection Caused by Hyperoxia Preconditioning in Animal Stroke Models

Ischemic tolerance induced by hyperoxia (HO) can protect against brain injury and neurodegenerative diseases. Although multiple studies demonstrate neuroprotection by HO, the exact mechanism(s) of HO neuroprotection has not been elucidated. Here, I first review related mechanisms of brain ischemia and then data evaluating the neuroprotective effects of HO in focal and global ischemic animal models. I clearly establish that the cerebrovascular, extracellular matrix, plasma membrane, endoplasmic reticulum, mitochondrial, and lysosomal reactions are critical in neuroprotection induced by HO in focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke. Neuroprotection induced by HO exhibits specific adaptation responses that involve a number of cellular and biochemical alterations, including metabolic homeostasis and reprogramming of gene expression. The changes in the metabolic pathways are generally short lived and reversible, while the consequences of gene expression are a long-term process and may lead to the permanent alteration in the pattern of gene expression. The neuroprotection provided by HO may have important clinical implications. Therefore, it is important to assess the benefits and risks of HO therapy in noninfarcted tissue.

In vivo normobaric hyperoxia preconditioning induces different degrees of antioxidant enzymes activities in rat brain tissue

Recent studies suggest that intermittent and prolonged normobaric hyperoxia results in ischemic tolerance to reduce ischemia brain injury. In this research attempts were made to see the changes in antioxidant enzyme activities following prolonged and intermittent normobaric hyperoxia preconditioning. Rats were divided into four experimental groups, each of 21 animals. The first two were exposed to 95% inspired normobaric hyperoxia for 4 h/day for 6 consecutive days (intermittent normobaric hyperoxia) or for 24 h continuous (prolonged normobaric hyperoxia). The second two groups acted as controls, and were exposed to 21% oxygen in the same chamber. Each main group was subdivided to middle cerebral artery occlusion-operated, sham-operated (without middle cerebral artery occlusion), and intact (without any surgery) subgroups. After 24 h, middle cerebral artery occlusion-operated subgroups were subjected to 60 min of right middle cerebral artery occlusion. After 24 h reperfusion, neurologic deficit score, infarct volume were measured in middle cerebral artery occlusion-operated subgroups. Antioxidant enzyme activities were assessed in sham-operated and intact subgroups. Preconditioning with prolonged and intermittent normobaric hyperoxia decreased neurologic deficit score and infarct volume, and increased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) significantly. Although further studies are needed to clarify the mechanisms of ischemic tolerance, the intermittent and prolonged normobaric hyperoxia seems to partly exert their effects via increase antioxidant enzymes activities.

Delayed Cardioprotective Effects of Hyperoxia Preconditioning Prolonged by Intermittent Exposure

In our previous study, it was indicated that pre-exposing rats to normobaric hyperoxia could induce a late preconditioning against infarction and arrhythmia. In this study, attempts were made to know whether the intermittent pre-exposure to the same environment could prolong the late phase of hyperoxia preconditioning. In the first series of experiments, rats were divided into five groups; group 1 was pre-exposed to normal air (NOR) and the other groups to hyperoxic air (O(2)>95%, 120 min once a d) 12, 24, 48, and 72 h (H12, H24, H48, and H72 groups) before 30 min ischemia. In the second series of experiments, rats were pre-exposed to intermittent hyperoxic air (1, 2, or 3 consecutive d) at different times before being subjected to ischemia (H48, H2-48, H2-72, H3-72, and H3-96 groups). The infarct size was measured by triphenyltetrazolium chloride staining, and lead II of electrocardiogram recorded to monitor ischemic-induced arrhythmia. Compared with NOR group, the infarct size and incidence of arrhythmia were reduced significantly in H24 and H48 groups. When the exposure periods were enhanced to 2 d, the infarct size did not decrease significantly, but the incidence of arrhythmia reduced. When the pre-exposure times were enhanced to 3 d, both the infarct size and incidence of arrhythmia decreased significantly in H3-72 group, but not in H3-96 group. These results show that the late phase of hyperoxia preconditioning may last for more than 48 h and prolong by intermittent per-exposure to the same environment.

Normobaric hyperoxia induces ischemic tolerance and upregulation of glutamate transporters in the rat brain and serum TNF-α level

Recent studies suggest that intermittent and prolonged normobaric hyperoxia (HO) results in ischemic tolerance to reduce ischemic brain injury. In this research, we attempted to see changes in excitatory amino acid transporters (EAATs) and TNF-α levels following prolonged and intermittent hyperoxia preconditioning. Rats were divided into four experimental groups, each of 21 animals. The first two were exposed to 95% inspired HO for 4 h/day for 6 consecutive days (intermittent HO, InHO) or for 24 continuous hours (prolonged HO, PrHO). The second two groups acted as controls, and were exposed to 21% oxygen in the same chamber. Each main group was subdivided to middle cerebral artery occlusion (MCAO-operated), sham-operated (without MCAO), and intact (without any surgery) subgroups. After 24 h from pretreatment, MCAO-operated subgroups were subjected to 60 min of right MCAO. After 24 h reperfusion, neurologic deficit score (NDS) and infarct volume were measured in MCAO-operated subgroups. EAATs expression and serum TNF-α levels were assessed in sham-operated and intact subgroups. Preconditioning with prolonged and intermittent HO decreased NDS and upregulated EAAT1, EAAT2, and EAAT3 and increased serum TNF-α levels significantly. Although further studies are needed to clarify the mechanisms of ischemic tolerance, the intermittent and prolonged HO seems to partly exert their effects via increase serum TNF-α levels and upregulation of EAATs.