Hyperbaric oxygen therapy suppresses hypoxia and reoxygenation injury to retinal pigment epithelial cells through activating peroxisome proliferator activator receptor-alpha signalling.

Retinal ischemia followed by reperfusion (IR) is a common cause of many ocular disorders, such as age-related macular degeneration (AMD), which leads to blindness in the elderly population, and proper therapies remain unavailable. Retinal pigment epithelial (RPE) cell death is a hallmark of AMD. Hyperbaric oxygen (HBO) therapy can improve IR tissue survival by inducing ischemic preconditioning responses. We conducted an in vitro study to examine the effects of HBO preconditioning on oxygen-glucose deprivation (OGD)-induced IR-injured RPE cells. RPE cells were treated with HBO (100% O2 at 3 atmospheres absolute for 90 min) once a day for three consecutive days before retinal IR onset. Compared with normal cells, the IR-injured RPE cells had lower cell viability, lower peroxisome proliferator activator receptor-alpha (PPAR-α) expression, more severe oxidation status, higher blood-retinal barrier disruption and more elevated apoptosis and autophagy rates. HBO preconditioning increased PPAR-α expression, improved cell viability, decreased oxidative stress, blood-retinal barrier disruption and cellular apoptosis and autophagy. A specific PPAR-α antagonist, GW6471, antagonized all the protective effects of HBO preconditioning in IR-injured RPE cells. Combining these observations, HBO therapy can reverse OGD-induced RPE cell injury by activating PPAR-α signalling.

Attenuation of Heat-Induced Hypothalamic Ischemia, Inflammation, and Damage by Hyperbaric Oxygen in Rats.

The present study was attempted to assess the mechanisms underlying the beneficial effects of hyperbaric oxygen (HBO2; 100% O2 at 253 kpa) in treating experimental heatstroke. Anesthetized rats were divided into five major groups: normothermic control (NC) rats treated with normobaric air (NBA; 21% O2 at 101 kpa; NC + NBA); NC rats treated with HBO2 (NC + HBO2); heatstroke (HS) rats treated with NBA (HS + NBA); HS rats treated with hyperbaric air (HBA; 21% at 253 kpa; HS + HBA); and HS rats treated with HBO2 (HS + HBO2). HS groups were exposed to heat (43°C) for exactly 68 min and then allowed to recover at 26°C. HBA or HBO2 was adopted 68 or 78 min after the start of heat exposure. Survival time values for (HS + NBA) rats, (HS + HBA) rats at 68 min, (HS + HBA) rats at 78 min, (HS + HBO2) rats at 68 min, and (HS + HBO2) rats at 78 min were found to be 90 ± 3, 133 ± 12, 109 ± 9, 240 ± 18, and 170 ± 15 min, respectively. Resuscitation with HBA or HBO2 at 68 min was superior to those treated at 78 min in prolonging the survival time values. All (HS + NBA) animals displayed hyperthermia, hypotension, and increased cellular levels of ischemia, oxidative stress and damage markers, pro-inflammatory cytokines, and an indicator of polymorphonuclear cell accumulation in their hypothalamus as compared to those of NCs. Heat-induced hyperthermia was not affected by HBA or HBO2 treatment. However, heat-induced hypotension and hypothalamic ischemia, oxidative stress, neuronal damage, and inflammation were all significantly reduced by HBA or HBO2 therapy. Compared to those of HBA therapy, HBO2 therapy had a significantly higher beneficial effect in treating heatstroke. Our results suggested that HBO2 improved heatstroke outcomes, in part, by restoring normal hypothalamic function. Delaying the onset of HBO2 therapy reduced the therapeutic efficiency.

Hypobaric hypoxia preconditioning protects against hypothalamic neuron apoptosis in heat-exposed rats by reversing hypothalamic overexpression of matrix metalloproteinase-9 and ischemia.

Background: Hypoxia-inducible factor-1α (HIF-1α), heat shock protein-72 (HSP-72), hemeoxygenase-1 (HO-1), and matrix metalloproteinase-9 (MMP-9) have been identified as potential therapeutic targets in the brain for cerebral ischemia. To elucidate their underlying mechanisms, we first aimed to ascertain whether these proteins participate in the pathogenesis of heat-induced ischemic damage to the hypothalamus of rats. Second, we investigated whether hypobaric hypoxia preconditioning (HHP) attenuates heat-induced hypothalamic ischemic/hypoxic injury by modulating these proteins in situ. Methods: Anesthetized rats treated with or without HHP were subjected to heat stress. Hypothalamic ischemic/hypoxic damage was evaluated by measuring hypothalamic levels of cerebral blood flow (CBF), partial oxygen pressure (PO2), and hypothalamic temperature via an implanted probe. Hypothalamic apoptotic neurons were counted by measuring the number of NeuN/caspase-3/DAPI triple-stained cells. Hypothalamic protein expression of HIF-1α, HSP-72, HO-1, and MMP-9 was determined biochemically. Results: Before the start of the thermal experiments, rats were subjected to 5 hours of HHP (0.66 ATA or 18.3% O2) daily for 5 consecutive days per week for 2 weeks, which led to significant loss of body weight, reduced brown adipose tissue (BAT) wet weight and decreased body temperature. The animals were then subjected to thermal studies. Twenty minutes after heat stress, heat-exposed rats not treated with HHP displayed significantly higher core and hypothalamic temperatures, hypothalamic MMP-9 levels, and numbers of hypothalamic apoptotic neurons but significantly lower mean blood pressure, hypothalamic blood flow, and PO2 values than control rats not exposed to heat. In heat-exposed rats, HHP significantly increased the hypothalamic levels of HIF-1α, HSP-72, and HO-1 but significantly alleviated body and hypothalamic hyperthermia, hypotension, hypothalamic ischemia, hypoxia, neuronal apoptosis and degeneration. Conclusions: HHP may protect against hypothalamic ischemic/hypoxic injury and overexpression of MMP-9 by upregulating the hypothalamic expression of HIF-1α, HSP-72, and HO-1 in rats subjected to heatstroke.

HSP-70-Mediated Hyperbaric Oxygen Reduces Brain and Pulmonary Edema and Cognitive Deficits in Rats in a Simulated High-Altitude Exposure.

High-mountain sickness is characterized by brain and pulmonary edema and cognitive deficits. The definition can be fulfilled by a rat model of high-altitude exposure (HAE) used in the present study. This study aimed to investigate the protective effect of hyperbaric oxygen therapy (HBO2T) and to determine the underlying mechanisms. Rats were subjected to an HAE (9.7% O2 at 0.47 absolute atmosphere of 6,000 m for 3 days). Immediately after termination of HAE, rats were treated with HBO2T (100% O2 at 2.0 absolute atmosphere for 1 hour per day for 5 consecutive days) or non-HBO2T (21% O2 at 1.0 absolute atmosphere for 1 hour per day for 5 consecutive days). As compared to non-HAE+non-HBO2T controls, the HAE+non-HBO2T rats exhibited brain edema and resulted in cognitive deficits, reduced food and water consumption, body weight loss, increased cerebral inflammation and oxidative stress, and pulmonary edema. HBO2T increased expression of both hippocampus and lung heat shock protein (HSP-70) and also reversed the HAE-induced brain and pulmonary edema, cognitive deficits, reduced food and water consumption, body weight loss, and brain inflammation and oxidative stress. Decreasing the overexpression of HSP-70 in both hippocampus and lung tissues with HSP-70 antibodies significantly attenuated the beneficial effects exerted by HBO2T in HAE rats. Our data provide in vivo evidence that HBO2T works on a remodeling of brain/lung to exert a protective effect against simulated high-mountain sickness via enhancing HSP-70 expression in HAE rats.

Heat Shock Protein 70 (HSP70) Reduces Hepatic Inflammatory and Oxidative Damage in a Rat Model of Liver Ischemia/Reperfusion Injury with Hyperbaric Oxygen Preconditioning.

BACKGROUND Several clinical conditions can cause hepatic ischemia/reperfusion (I/R) injury. This study aimed to determine the mechanism of the protective effect of hyperbaric oxygen preconditioning (HBO2P) on hepatic ischemia/reperfusion (I/R) injury in a rat model, and to investigate the effects on HBO2P and I/R injury of blocking HSP70 using antibody (Ab) pretreatment. MATERIAL AND METHODS Male Sprague-Dawley rats underwent HBO2P for 60 min at 2.0 atmosphere absolute (ATA) pressure for five consecutive days before surgical hepatic I/R injury, performed by clamping the portal vein and hepatic lobe. Four groups studied included: the non-HBO2P+ non-I/R group, which underwent sham surgery (N=10); the non-HBO2P + I/R group (N=10); the HBO2P + I/R group (N=10); and the HBO2P + HSP70-Ab + I/R group (N=10) received one dose of HSP70 antibody one day before hepatic I/R injury. Serum lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and hepatic malondialdehyde (MDA) and myeloperoxidase (MPO) were measured biochemically. Rat liver tissues were examined histologically. RESULTS In rats with hepatic I/R injury without HSP70 antibody pre-treatment, HBO2P significantly reduced hepatic injury and levels of LDH, AST, ALT, TNF-α, IL-6, MDA, and MPO levels; in comparison, the group pre-treated with an antibody to inhibit HSP70 (the HBO2P + HSP70-Ab + I/R group) showed significant reversal of the beneficial effects of HBO2P on hepatic I/R injury (p<0.05). CONCLUSIONS In a rat model of hepatic I/R injury with HBO2P, HSP70 reduced hepatic inflammatory and oxidative damage.

Human Umbilical Cord Mesenchymal Stem Cells Preserve Adult Newborn Neurons and Reduce Neurological Injury after Cerebral Ischemia by Reducing the Number of Hypertrophic Microglia/Macrophages.

Microglia are the first source of a neuroinflammatory cascade, which seems to be involved in every phase of stroke-related neuronal damage. Two weeks after transient middle cerebral artery occlusion (MCAO), vehicle-treated rats displayed higher numbers of total ionized calcium-binding adaptor molecule 1 (Iba-1)-positive cells, greater cell body areas of Iba-1-positive cells, and higher numbers of hypertrophic Iba-1-positive cells (with a cell body area over 80 µm2) in the ipsilateral ischemic brain regions including the frontal cortex, striatum, and parietal cortex. In addition, MCAO decreased the number of migrating neuroblasts (or DCX- and 5-ethynyl-2'-deoxyuridine-positive cells) in the cortex, subventricular zone, and hippocampus of the ischemic brain, followed by neurological injury (including brain infarct and neurological deficits). Intravenous administration of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs; 1 × 106 or 4 × 106) at 24 h after MCAO reduced neurological injury, decreased the number of hypertrophic microglia/macrophages, and increased the number of newborn neurons in rat brains. Thus, the accumulation of hypertrophic microglia/macrophages seems to be detrimental to neurogenesis after stroke. Treatment with hUC-MSCs preserved adult newborn neurons and reduced functional impairment after transient cerebral ischemia by reducing the number of hypertrophic microglia/macrophages.

Hyperbaric oxygen effects on neuronal apoptosis associations in a traumatic brain injury rat model.

BACKGROUND: The neuroprotective mechanisms of hyperbaric oxygen (HBO) therapy on traumatic brain injury (TBI) remain unclear, especially neuronal apoptosis associations such as the expression of tumor necrosis factor alpha (TNF-α), transforming growth-interacting factor (TGIF), and TGF-ß1 after TBI. The aim of this study was to investigate the neuroprotective effects of HBO therapy in a rat model of TBI. MATERIALS AND METHODS: The experimental rats were randomly divided into three groups as follows: TBI + normobaric air (21% O2 at one absolute atmosphere), TBI + HBO, and sham-operated normobaric air. The TBI + HBO rats received 100% O2 at 2.0 absolute atmosphere for 1 h immediately after TBI. Local and systemic TNF-α expression, neuropathology, levels of the neuronal apoptosis-associated proteins TGIF and TGF-ß1, and functional outcome were evaluated 72 h after the onset of TBI. RESULTS: Compared to the TBI control groups, the running speed of rats on the TreadScan after TBI was significantly attenuated by HBO therapy. The TBI-induced local and systemic TNF-α expression, neuronal damage score, and neuronal apoptosis were also significantly reduced by HBO therapy. Moreover, HBO treatment attenuated the expression of TGIF but increased TGF-ß1 expression in neurons. CONCLUSIONS: We concluded that treatment of TBI with HBO during the acute phase of injury can decrease local and systemic proinflammatory cytokine TNF-α production, resulting in neuroprotective effects. We also suggest that decreased levels of TGIF and increased levels of TGF-ß in the injured cortex leading to decreased neuronal apoptosis is one mechanism by which functional recovery may occur.

High-altitude pulmonary edema can be prevented by heat shock protein 70-mediated hyperbaric oxygen preconditioning.

BACKGROUND: The primary goal of this study was to test whether high-altitude exposure (HAE of 9.7% O2 at 0.47 absolute atmosphere [ATA] for 3 days) was capable of increasing lung edema, neutrophil, and hemorrhage scores as well as decreasing lung levels of both aquaporin 1 (AQP1) and AQP5 proteins and messenger RNA (mRNA) expression in rats, with a secondary goal to test whether a preinduction of heat shock protein 70 (HSP70) by hyperbaric oxygen preconditioning (HBO2P of 100% O2 at 2.0 ATA for 1 hour per day for 5 consecutive days) attenuated the HAE-induced increased lung injury scores and decreased lung AQP1 and AQP5 protein and mRNA expressions. METHODS: Rats were assigned to (1) non-HBO2P (21% O2 at 1.0 ATA) + non-HAE (21% O2 at 1.0 ATA) group; (2) non-HBO2P + HAE group; (3) HBO2P + HAE group; and HBO2P + HSP70 antibodies (Ab) + HAE group. For the HSP70 Ab group, a neutralizing HSP70 Ab was injected intravenously at 24 hours before HAE. All the physiologic and biochemical parameters were obtained at the end of HAE or the equivalent period of non-HAE. The cardiovascular and blood gas parameters were monitored for all experiments. Bronchoalveolar lavage (BAL) was performed to determine proinflammatory cytokines (interleukin 6, interleukin 1ß, and tumor necrosis factor α). Parts of the lung were excised for myeloperoxidase activity measurement, whereas the rest was collected for lung damage score assessments. AQP1 and AQP5 protein and mRAN expressions were also determined in the lung tissues. RESULTS: In the non-HBO2P + HAE group, the animals displayed higher values of lung myeloperoxidase activity, BAL proinflammatory cytokines, lung water weight, and acute lung injury scores compared with those of the non-HBO2P + non-HAE controls. In contrast, the non-HBO2P + HAE group rats had lower values of lung AQP1 and AQP5 protein and mRNA expressions, mean arterial pressure, heart rate, SO2, Paco2, HCO3, and pH compared with those of non-HBO2P + non-HAE group rats. The increased acute lung edema, neutrophil, and hemorrhage scores; increased BAL levels of proinflammatory cytokines; decreased lung AQP1 and AQP5 protein and mRNA expressions; and hypotension, bradycardia, hypoxia, and acidosis caused by HAE were all significantly attenuated by HBO2P. CONCLUSION: Our data indicate that HBO2P may attenuate high-altitude acute lung injury by a preinduction of lung HSP70 in rats.

Repetitive hyperbaric oxygen therapy provides better effects on brain inflammation and oxidative damage in rats with focal cerebral ischemia.

BACKGROUND/PURPOSE: Repetitive hyperbaric oxygen (HBO2) therapy may cause excessive generation of reactive oxygen species. This study assessed whether repetitive or 2-4-day trials of HBO2 therapy (2 treatments daily for 2-4 consecutive days) provides better effects in reducing brain inflammation and oxidative stress caused by middle cerebral artery occlusion (MCAO) in rats than did a 1-day trial of HBO2 therapy (2 treatments for 1 day). METHODS: Rats were randomly divided into four groups: sham; MCAO without HBO2 treatment; MCAO treated with 1-day trial of HBO2; and MCAO treated with 2-4-day trials of HBO2. One treatment of HBO2 (100% O2 at 253 kPa) lasted for 1 hour in a hyperbaric chamber. RESULTS: Therapy with the 2-4-day trials of HBO2 significantly and dose-dependently attenuated the MCAO-induced cerebral infarction and neurological deficits more than the 1-day trial of HBO2 therapy. The beneficial effects of repetitive HBO2 therapy were associated with: (1) reduced inflammatory status in ischemic brain tissues (evidenced by decreased levels of tumor necrosis factor-α, interleukin-1ß, and myeloperoxidase activity); (2) decreased oxidative damage in ischemic brain tissues (evidenced by decreased levels of reactive oxygen and nitrogen species, lipid peroxidation, and enzymatic pro-oxidants, but increased levels of enzymatic antioxidant defenses); and (3) increased production of an anti-inflammatory cytokine, interleukin-10. CONCLUSION: The results provide the apparently contradictory finding that heightened oxygen tension reduced oxidative stress (and inflammation), which was reflected by increased antioxidant and decreased oxidant contents under focal cerebral ischemia.

Attenuating brain inflammation, ischemia, and oxidative damage by hyperbaric oxygen in diabetic rats after heat stroke.

BACKGROUND/PURPOSE: Alternating hypothalamic-pituitary-adrenal axis mechanisms would lead to multiple organs dysfunction or failure. Herein, we attempt to assess whether hypothalamic inflammation and ischemic and oxidative damage that occurred during heatstroke (HS) can be affected by hyperbaric oxygen (HBO2) therapy in streptozotocin-induced diabetic rats. METHODS: In this study, anesthetized diabetic rats, immediately after the onset of HS, were divided into two major groups and given the normobaric air (21% O2 at 1.0 atmospheres absolute) or HBO2 (100% O2 at 2.0 atmospheres absolute). HS was induced by exposing the animals to heat stress (43°C). Another group of anesthetized diabetic rats was kept at normothermic state and used as controls. RESULTS: The survival time values for the HBO2-treated HS-diabetic rats increased form the control values of 78-82 minutes to new values of 184-208 minutes. HBO2 therapy caused a reduction of HS-induced cellular ischemia (e.g., increased cellular levels of glutamate and lactate/pyruvate ratio), hypoxia (e.g., decreased cellular levels of PO2), inflammation (e.g., increased cellular levels of interleukin-1ß, tumor necrosis factor-alpha, interleukin-6, and myeloperoxidase), and oxidative damage (e.g., increased values of nitric oxide, 2,3-dihydroxybenzoic acid, glycerol, and neuronal damage score) in the hypothalamus of the diabetic rats. CONCLUSION: Our results suggest that, in diabetic animals, HBO2 therapy may improve outcomes of HS in part by reducing heat-induced activated inflammation and ischemic and oxidative damage in the hypothalamus and other brain regions.

Microglial activation induced by traumatic brain injury is suppressed by postinjury treatment with hyperbaric oxygen therapy.

BACKGROUND: The mechanisms underlying the protective effects of hyperbaric oxygen (HBO) therapy on traumatic brain injury (TBI) are unclear. TBI initiates a neuroinflammatory cascade characterized by activation of microglia and increased production of proinflammatory cytokines. In this study, we attempted to ascertain whether the occurrence of neuroinflammation exhibited during TBI can be reduced by HBO. METHODS: TBI was produced by the fluid percussion technique in rats. HBO (100% O2 at 2.0 absolute atmospheres) was then used at 1 h (HBO I) or 8 h (HBO II) after TBI. Neurobehavior was evaluated by the inclined plane test on the 72 h after TBI and then the rats were killed. The infarction area was evaluated by Triphenyltetrazolium chloride. Immunofluorescence staining was used to evaluate neuronal apoptosis (TUNEL + NeuN), microglial cell aggregation count (OX42 + DAPI), and tumor necrosis factor-alpha (TNF-α) expression in microglia cell (OX42 + TNF-α). RESULTS: The maximum grasp angle in the inclined plane test and cerebral infarction of the rats after TBI were significantly attenuated by HBO therapy regardless of whether the rats were treated with HBO 1 or 8 h after TBI compared with the controls. TBI-induced microglial activation, TNF-α expression, and neuronal apoptosis were also significantly reduced by HBO therapy. CONCLUSIONS: Our results demonstrate that treatment of TBI during the acute phase of injury can attenuate microgliosis and proinflammatory cytokine TNF-α expression resulting in a neuroprotective effect. Even treating TBI with HBO after 8 h had a therapeutic effect.

Hypobaric hypoxia preconditioning attenuates acute lung injury during high-altitude exposure in rats via up-regulating heat-shock protein 70.

HHP (hypobaric hypoxia preconditioning) induces the overexpression of HSP70 (heat-shock protein 70), as well as tolerance to cerebral ischaemia. In the present study, we hypothesized that HHP would protect against HAE (high-altitude exposure)-induced acute lung injury and oedema via promoting the expression of HSP70 in lungs prior to the onset of HAE. At 2 weeks after the start of HHP, animals were exposed to a simulated HAE of 6000 m in a hypobaric chamber for 24 h. Immediately after being returned to ambient pressure, the non-HHP animals had higher scores of alveolar oedema, neutrophil infiltration and haemorrhage, acute pleurisy (e.g. increased exudate volume, increased numbers of polymorphonuclear cells and increased lung myeloperoxidase activity), increased pro-inflammatory cytokines [e.g. TNF-α (tumour necrosis factor-α), IL (interleukin)-1ß and IL-6], and increased cellular ischaemia (i.e. glutamate and lactate/pyruvate ratio) and oxidative damage [glycerol, NOx (combined nitrate+nitrite) and 2,3-dihydroxybenzoic acid] markers in the BALF (bronchoalveolar fluid). HHP, in addition to inducing overexpression of HSP70 in the lungs, significantly attenuated HAE-induced pulmonary oedema, inflammation, and ischaemic and oxidative damage in the lungs. The beneficial effects of HHP in preventing the occurrence of HAE-induced pulmonary oedema, inflammation, and ischaemic and oxidative damage was reduced significantly by pretreatment with a neutralizing anti-HSP70 antibody. In conclusion, HHP may attenuate the occurrence of pulmonary oedema, inflammation, and ischaemic and oxidative damage caused by HAE in part via up-regulating HSP70 in the lungs.

Reducing pulmonary injury by hyperbaric oxygen preconditioning during simulated high altitude exposure in rats.

BACKGROUND: Hyperbaric oxygen preconditioning (HBO2P + HAE) has been found to be beneficial in preventing the occurrence of ischemic damage to brain, spinal cord, heart, and liver in several disease models. In addition, pulmonary inflammation and edema are associated with a marked reduction in the expression levels of both aquaporin (AQP) 1 and AQP5 in the lung. Here, the aims of this study are first to ascertain whether acute lung injury can be induced by simulated high altitude in rats and second to assess whether HBO2P + HAE is able to prevent the occurrence of the proposed high altitude-induced ALI. METHODS: Rats were randomly divided into the following three groups: the normobaric air (NBA; 21% O2 at 1 ATA) group, the HBO2P + high altitude exposure (HAE) group, and the NBA + HAE group. In HBO2P + HAE group, animals received 100% O2 at 2.0 ATA for 1 hour per day, for five consecutive days. In HAE groups, animals were exposed to a simulated HAE of 6,000 m in a hypobaric chamber for 24 hours. Right after being taken out to the ambient, animals were anesthetized generally and killed and thoroughly exsanguinated before their lungs were excised en bloc. The lungs were used for both histologic and molecular evaluation and analysis. RESULTS: In NBA + HAE group, the animals displayed higher scores of alveolar edema, neutrophil infiltration, and hemorrhage compared with those of NBA controls. In contrast, the levels of both AQP1 and AQP5 proteins and mRNA expression in the lung in the NBA + HAE group were significantly lower than those of NBA controls. However, the increased lung injury scores and the decreased levels of both AQP1 and AQP5 proteins and mRNA expression in the lung caused by HAE was significantly reduced by HBO2P + HAE. CONCLUSIONS: Our results suggest that high altitude pulmonary injury may be prevented by HBO2P + HAE in rats.

Reduction of ischemic and oxidative damage to the hypothalamus by hyperbaric oxygen in heatstroke mice.

The aims of the present paper were to ascertain whether the heat-induced ischemia and oxidative damage to the hypothalamus and lethality in mice could be ameliorated by hyperbaric oxygen therapy. When normobaric air-treated mice underwent heat treatment, the fractional survival and core temperature at 4 hours after heat stress were found to be 0 of 12 and 34 degrees C +/- 0.3 degrees C, respectively. In hyperbaric oxygen-treated mice, when exposed to the same treatment, both fractional survival and core temperature values were significantly increased to new values of 12/12 and 37.3 degrees C +/- 0.3 degrees C, respectively. Compared to normobaric air-treated heatstroke mice, hyperbaric oxygen-treated mice displayed lower hypothalamic values of cellular ischemia and damage markers, prooxidant enzymes, proinflammatory cytokines, inducible nitric oxide synthase-dependent nitric oxide, and neuronal damage score. The data indicate that hyperbaric oxygen may improve outcomes of heatstroke by normalization of hypothalamic and thermoregulatory function in mice.

Attenuating experimental spinal cord injury by hyperbaric oxygen: stimulating production of vasculoendothelial and glial cell line-derived neurotrophic growth factors and interleukin-10.

The present study was carried out to further examine the mechanisms underlying the beneficial effects of hyperbaric oxygen (HBO(2)) on experimental spinal cord injury (SCI). Rats were divided into three major groups: (1) sham operation (laminectomy only); (2) laminectomy + SCI + normobaric air (NBA; 21% oxygen at 1 ATA); and (3) laminectomy + SCI + HBO(2) (100% oxygen at 2.5 ATA for 2 h). Spinal cord injury was induced by compressing the spinal cord for 1 min with an aneurysm clip calibrated to a closing pressure of 55 g. HBO(2) therapy was begun immediately after SCI. Behavioral tests of hindlimb motor function as measured by the Basso, Beattie, and Bresnahan (BBB) locomotor scale was conducted on days 1-7 post-SCI. The triphenyltetrazolium chloride staining assay and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling assay were also conducted after SCI to evaluate spinal cord infarction and apoptosis, respectively. Cells positive for glial cell line-derived neurotrophic nerve growth factor (GDNF) and vascular endothelial growth factor (VEGF) and cytokines in the injured spinal cord were assayed by immunofluorescence and commercial kits, respectively. It was found that HBO(2) therapy significantly attenuated SCI-induced hindlimb dysfunction, and spinal cord infarction and apoptosis, as well as overproduction of spinal cord interleukin-1beta and tumor necrosis factor-alpha. In contrast, the numbers of both GDNF-positive and VEGF-positive cells and production of spinal cord interleukin-10 after SCI were all significantly increased by HBO(2). These data suggest that HBO(2) may attenuate experimental SCI by stimulating production of GDNF, VEGF, and interleukin-10.

A hyperbaric oxygen therapy approach to heat stroke with multiple organ dysfunction.

Here in we report the case of a patient who displayed a classic heat stroke with multiple organ dysfunction and hypercoagulable state resistant to conventional whole body cooling and antipyretic therapy, and necessitating the use of hyperbaric oxygen therapy (HBOT) to rescue him from death. A 49-year-old male laborer, suffering from heat stroke syndromes (e.g., hyperpyrexia, seizure and coma, and hypotension), was admitted to an emergency unit of a medical center hospital. The patient displayed multiple organ dysfunction with rhabdomyolysis, hepatic, renal, respiratory, and cerebral dysfunction, and disseminated intravascular coagulation (DIC). Both hyperpyrexia and multiple organ dysfunction were resistant to conventional treatment measures. HBOT was adopted to rescue the patient from heat stroke-induced death. Before HBOT, analyses of serum revealed hypercoagulable state or DIC as well as signs of rhabdomyolysis, and renal and hepatic failure. In addition, pulmonary edema, coma, hypotension, and hyperpyrexia occurred. HBOT was used successfully to combat these syndromes and to rescue the patient from heat stroke death. This case suggests that HBOT is useful for treatment of heat stroke with multiple organ dysfunction.

Hyperbaric oxygen causes both antiinflammation and antipyresis in rabbits.

Current study was attempted to assess whether hyperbaric oxygen pretreatment or treatment exerts its antipyresis by reducing circulating interleukin-6 and hypothalamic glutamate, hydroxyl radicals and prostaglandin-E(2) in rabbits. It was found that systemic administration of lipopolysaccharide induced increased levels of both core temperature and hypothalamic levels of glutamate, hydroxyl radicals, and prostaglandin E(2) accompanied by increased plasma levels of interleukin-6. The rise in both the core temperature and hypothalamic glutamate, hydroxyl radicals and prostaglandin-E(2) could also be induced by intracerebroventricular injection of interleukin-6. Pretreatment or treatment with hyperbaric oxygen significantly reduced the lipopolysaccharide-induced overproduction of circulating interleukin-6, and hypothalamic glutamate, prostaglandin E(2), and hydroxyl radicals. The febrile response caused by central administration of interleukin-6 could also be suppressed by hyperbaric oxygen pretreatment or treatment. Simultaneous administration of an anti-oxidant (e.g., N-acetyl-L-cysteine) significantly enhanced the antipyretic effects exerted by hyperbaric oxygen treatment. These results indicate that hyperbaric oxygen pretreatment or treatment may exert its antipyresis by inhibiting the glutamate-hydroxyl radicals-prostaglandin-E(2) pathways in the hypothalamus and circulating interleukin-6 accumulation during lipopolysaccharide-fever.

Curcumin inhibits the increase of glutamate, hydroxyl radicals and PGE2 in the hypothalamus and reduces fever during LPS-induced systemic inflammation in rabbits.

Evidence has accumulated to suggest that systemic administration of lipopolysaccharide (LPS), in addition to elevating tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) as well as fever, induces overproduction of glutamate, hydroxyl radicals and prostaglandin E(2) (PGE(2)) in the rabbit's hypothalamus. Current study was attempted to assess whether Curcumin exerts its antipyresis by reducing circulating pro-inflammatory cytokines and hypothalamic glutamate, hydroxyl radicals and PGE(2) in rabbits. The microdialysis probes were stereotaxically and chronically implanted into the preoptic anterior hypothalamus of rabbit brain for determination of glutamate, hydroxyl radicals, and PGE(2) in situ. It was found that systemic administration of LPS (2 microg/kg) induced increased levels of both core temperature and hypothalamic levels of both glutamate and hydroxyl radicals accompanied by increased plasma levels of TNF-alpha, IL-1beta, and IL-6. The rise in both the core temperature and hypothalamic glutamate and hydroxyl radicals could also be induced by direct injection of TNF-alpha, IL-1beta, or IL-6 into the lateral ventricle of rabbit brain. Pretreatment with Curcumin (5-40 mg/kg, i.p.) 1 h before an i.v. dose of LPS significantly reduced the LPS-induced overproduction of circulating TNF-alpha, IL-1beta, and IL-6, and brain glutamate, PGE(2), and hydroxyl radicals. Both the febrile response and overproduction of both glutamate and hydroxyl radicals in the hypothalamus caused by central administration of TNF-alpha, IL-1beta, or IL-6 could be suppressed by Curcumin. These results indicate that systemic injection of Curcumin may exert its antipyresis by inhibiting the glutamate-hydroxyl radicals-PGE(2) pathways in the hypothalamus and circulating TNF-alpha, IL-1beta, and IL-6 accumulation during LPS fever.

Prevention and suppression of pyrogenic fever in rabbits by hyperbaric oxygen.

Current investigation was to determine whether hyperbaric oxygen had an effect on the febrile responses to systemic administration of lipopolysaccharide. An intravenous dose of lipopolysaccharide (2 microg/kg) caused an increase in core temperature accompanied by both plasma tumor necrosis factor-alpha and hypothalamic prostaglandin E(2) overproduction in rabbits. Administering hyperbaric oxygen (100% at 253 kPa) but not normobaric oxygen (100% at 101 kPa), once a day for consecutive 7 days prior to or 1 h after injecting lipopolysaccharide significantly reduced the lipopolysaccharide-induced elevation of both core temperature and circulating tumor necrosis factor-alpha. As compared to those of the simultaneous administration of normobaric air and lipopolysaccharide, administering hyperbaric oxygen or air plus lipopolysaccharide simultaneously had lesser febrile effects in terms of core temperature elevation, tumor necrosis factor-alpha overproduction and hypothalamic prostaglandin E(2) accumulation. However, the febrile responses produced by simultaneous application of normobaric oxygen plus lipopolysaccharide were not significantly different from those of normobaric air plus lipopolysaccharide. The results indicate that hyperbaric oxygen, and to some extent hyperbaric air, may cause prevention and suppression of pyrogenic fever by reducing overproduction of both circulating tumor necrosis factor-alpha and hypothalamic prostaglandin E(2).