The neuroprotective effects of oxygen therapy in Alzheimer’s disease: a narrative review

Respiratory insufficiency is the leading cause of morbidity and mortality following cervical spinal cord injury (SCI). Diaphragm atrophy following SCI occurs as a result of damage to respiratory neural circuitry, which leads to impaired muscle contractility. Disruption of redox balance occurs after SCI and increased mitochondrial reactive oxygen species production is an upstream trigger for diaphragm muscle atrophy and weakness. Recently, we demonstrated that increased antioxidant capacity in response to hyperbaric oxygen (HBO) therapy may play a role in preserving mitochondrial redox homeostasis following SCI. However, a precise understanding of the mechanisms by which HBO therapy can prevent diaphragm dysfunction is lacking. In this regard, evidence indicates that the secretion of neurotrophic factors, such as brain derived neurotrophic factor (BDNF), may also contribute to enhanced functional recovery when HBO therapy is initiated acutely following cervical SCI. Through activation of the 5′ adenosine monophosphate‐activated protein kinase (AMPK) and serine‐threonine protein kinase (AKT) signaling via the phosphorylation of its receptor tropomyosin receptor kinase B (TrKb), BDNF expression has been shown to modulate mitochondrial biogenesis and skeletal muscle proteolysis. Therefore, we tested the hypothesis that 10 days of HBO therapy initiated in the acute phase following cervical SCI can increase diaphragm mitochondrial biogenesis and prevent diaphragm proteolytic signaling by activating BDNF/TrkB signaling. To test this, adult male Sprague‐Dawley rats were separated into three groups (n=8/group): (1) non‐injured, room air exposure (CON); (2) lateral‐cervical spinal cord contusion, room air exposure (SCI); and (3) lateral‐cervical spinal cord contusion, HBO therapy (SCI+HBO). Animals in the SCI and SCI+HBO groups were anesthetized, and following laminectomy at the C3–C4 level, a lateral‐cervical spinal contusion was made using a mechanical impactor. HBO therapy consisted of 10 days of exposure starting on the day of SCI, using a 40 L chamber flushed with 100% O2 and pressurized to 3 ATA. Our results indicate that HBO therapy delivered in the acute phase of SCI positively affected BDNF/TrkB signaling. Specifically, diaphragm protein expression of BDNF, p‐AKT/AKT and p‐AMPK/AMPK were increased after 10 days of HBO therapy compared to CON animals (p<0.05). Additionally, HBO therapy prevented the SCI‐induced reduction in diaphragm peroxisome proliferator‐activated receptor‐gamma coactivator (PGC1‐α) protein expression (p<0.05), as well as the caspase‐3‐specific cleavage of α‐II‐spectrin observed in the SCI group (p<0.05). In summary, these findings demonstrate that HBO therapy can induce BDNF signaling and highlight an additional mechanism for the protective effects of HBO therapy to preserve diaphragm muscle function following SCI.

Migraine and cluster headaches are severe and disabling. Migraine affects up to 18% of women, while cluster headaches are much less common (0.2% of the population). A number of acute and prophylactic therapies are available. Hyperbaric oxygen therapy (HBOT) is the therapeutic administration of 100% oxygen at environmental pressures greater than one atmosphere, while normobaric oxygen therapy (NBOT) is oxygen administered at one atmosphere. This is an updated version of the original Cochrane review published in Issue 3, 2008 under the title 'Normobaric and hyperbaric oxygen for migraine and cluster headache'. To examine the efficacy and safety of normobaric oxygen therapy (NBOT) and hyperbaric oxygen therapy (HBOT) in the treatment and prevention of migraine and cluster headache. We updated searches of the following databases up to 15 June 2015: CENTRAL (the Cochrane Library), MEDLINE, EMBASE, and CINAHL. For the original review we searched the following databases up to May 2008: CENTRAL, MEDLINE, EMBASE, CINAHL, DORCTIHM, and reference lists from relevant articles. We handsearched relevant journals and contacted researchers to identify trials. Randomised controlled trials comparing HBOT or NBOT with one another, other active therapies, placebo (sham) interventions, or no treatment in participants with migraine or cluster headache. Three review authors independently extracted data and assessed the quality of the evidence using the GRADE approach. In this update, we included 11 trials with 209 participants. Five trials (103 participants) compared HBOT versus sham therapy for acute migraine, three trials compared NBOT to sham therapy or ergotamine tartrate for cluster headache (145 participants), two trials evaluated HBOT for cluster headache (29 participants), and one trial (56 participants) compared NBOT to sham for a mixed group of headache. The risk of bias varied considerably across these trials but in general trial quality was poor to moderate. One trial may not have been truly randomised and two included studies were reported as abstracts only. Seven trials did not indicate allocation concealment or randomisation method. Notably, 10 of the 11 trials used a sham comparator therapy and masked the outcome assessor to allocation.We pooled data from three trials, which suggested that HBOT was effective in relieving migraine headaches compared to sham therapy (risk ratio (RR) 6.21, 95% CI 2.41 to 16.00; 58 participants, three trials). The quality of evidence was low, having been downgraded for small crossover studies with incomplete reporting. There was no evidence that HBOT could prevent migraine episodes, reduce the incidence of nausea and vomiting, or reduce the requirement for rescue medication. There was no evidence that HBOT was effective for the termination of cluster headache (RR 11.38, 95% CI 0.77 to 167.85; P = 0.08) (one trial), but this trial had low power.NBOT was effective in terminating cluster headache compared to sham in a single small study (RR 7.88, 95% CI 1.13 to 54.66), but not superior to ergotamine administration in another small trial (RR 1.17, 95% CI 0.94 to 1.46; P = 0.16). A third trial reported a statistically significant difference in the proportion of attacks successfully treated with oxygen (117 of 150 attacks were successfully treated with NBOT (78%) versus 30 of 148 attacks treated with NBOT (20%)). The proportion of responders was consistent across these three trials, and suggested more than 75% of headaches were likely to respond to NBOT.No serious adverse events during HBOT or NBOT were reported. Since the last version of this review, two new included studies have provided additional information to change the conclusions. There was some evidence that HBOT was effective for the termination of acute migraine in an unselected population, and some evidence that NBOT was similarly effective in cluster headache. Given the cost and poor availability of HBOT, more research should be done on patients unresponsive to standard therapy. NBOT is cheap, safe, and easy to apply, so will probably continue to be used despite the limited evidence in this review.

To present recovery from vision loss due to CO poisoning with Hyperbaric Oxygen (HBO) therapy in two patients. Two female patients developed visual deterioration after carbon monoxide (CO) poisoning and were treated with hyperbaric oxygen therapy (HBO). Clinical examination, including visual acuity assessment, visual field examination and visual evoked potentials (VEPs) before and after the HBO therapy were performed. In Case 1 the visual loss started on the third day with visual acuity at the level of perception of hand movements at 10 cm in the right eye and finger count at 10 cm in the left eye. The visual evoked potentials (VEPs) had low amplitudes and prolonged (128 msec bilaterally) latencies (implicit times). After 48 sessions and 52 days of HBO therapy, the visual acuity became 0.2 in the right eye and 0.15 in the left eye. Visual field examination revealed homonymous right lower quadrant anopsia. The VEPs also improved. In Case 2 the visual acuity was 0.2 in the right eye and 0.1 in the left eye on the 6th day following the accident when the patient was admitted for treatment. The VEP latencies were within normal limits. After 36 days and 35 sessions of HBO therapy, the visual acuity became 0.7 on both eyes. The visual fields completely normalised. The VEP latencies in this case also became shorter. It appears that the adverse effects of CO poisoning continue to progress during the late period and we believe that HBO treatment in this period may still be effective and will prevent some of the neurological sequelae such as visual loss from becoming permanent. Clinical, neurological, neuropsychological, visual outcome seems to be favourable even if HBO treatment started as late as 6 or 8 days after the exposure to CO.

Migraine and cluster headaches are severe and disabling. Migraine affects up to 18% of women, while cluster headaches are much less common (0.2% of the population). A number of acute and prophylactic therapies are available. Hyperbaric oxygen therapy (HBOT) is the therapeutic administration of 100% oxygen at environmental pressures greater than one atmosphere, while normobaric oxygen therapy (NBOT) is oxygen administered at one atmosphere. To assess the safety and effectiveness of HBOT and NBOT for treating and preventing migraine and cluster headaches. We searched the following in May 2008: CENTRAL, MEDLINE, EMBASE, CINAHL, DORCTIHM and reference lists from relevant articles. Relevant journals were hand searched and researchers contacted. Randomised trials comparing HBOT or NBOT with one another, other active therapies, placebo (sham) interventions or no treatment in patients with migraine or cluster headache. Three reviewers independently evaluated study quality and extracted data. Nine small trials involving 201 participants were included. Five trials compared HBOT versus sham therapy for acute migraine, two compared HBOT to sham therapy for cluster headache and two evaluated NBOT for cluster headache. Pooling of data from three trials suggested that HBOT was effective in relieving migraine headaches compared to sham therapy (relative risk (RR) 5.97, 95% confidence interval (CI) 1.46 to 24.38, P = 0.01). There was no evidence that HBOT could prevent migraine episodes, reduce the incidence of nausea and vomiting or reduce the requirement for rescue medication. There was a trend to better outcome in a single trial evaluating HBOT for the termination of cluster headache (RR 11.38, 95% CI 0.77 to 167.85, P = 0.08), but this trial had low power.NBOT was effective in terminating cluster headache compared to sham in a single small study (RR 7.88, 95% CI 1.13 to 54.66, P = 0.04), but not superior to ergotamine administration in another small trial (RR 1.17, 95% CI 0.94 to 1.46, P = 0.16). Seventy-six per cent of patients responded to NBOT in these two trials. No serious adverse effects of HBOT or NBOT were reported. There was some evidence that HBOT was effective for the termination of acute migraine in an unselected population, and weak evidence that NBOT was similarly effective in cluster headache. Given the cost and poor availability of HBOT, more research should be done on patients unresponsive to standard therapy. NBOT is cheap, safe and easy to apply, so will probably continue to be used despite the limited evidence in this review.

Objective To explore the relationship between the proliferation of neural stem cells (NSCs)and the expression of β-catenin protein in neonate rats with hypoxic ischemic brain damage (HIBD) after hyperbaric oxygen (HBO) therapy. Methods One hundred and eighty Sprague-Dawley rats aged 7 days were randomly divided into a normal control group (CON) , a HIBD model group and a HBO treatment group. The HIBD model was induced using Rice's method. Beginning 3h after the HIBD, HBO was administered to the HBO treatment group at 2 atmospheres for 60 min, once daily for 7 days. The HIBD model group was not given any treatment. The expression of nestin/β-catenin protein in the subventricular zone of the ischemic brain was double-stained for immunofluorescence and analyzed by confocal scanning microscopy dynamically at 3 hours, 21 hours, and then on the 3rd, 5th, 7th and 14th day of HBO therapy. The expression of whole cell β-catenin and nuclear β-catenin protein in the left brain were also examined by Western blotting at these 6 time points. Linear correlation was used to analyze the correlation between β-catenin and nestin protein. Results The expression of β-catenin protein in NSCs increased initially at the 21st hour after HBO therapy in the model group and the HBO group as compared with the normal control group.β-catenin protein in the model group reached a higher level, though there was no significant difference between model group and the HBO group. At the 5th day of HBO therapy β-catenin protein in the HBO group had reached a significantly higher level than in the model group. At the 14th day the average expression of β-catenin in the HBO group began to decrease. The expression of nestin protein began to increase 21 hours after HBO therapy began, and it peaked at the 7th day of HBO therapy and then decreased. In the HBO group the increase in nestin protein was linearly correlated with that of β-catenin protein. The whole cell β-catenin protein and β-catenin nucleic protein readings increased initially by the 21st hour of HBO therapy and by the 5th day were significantly higher than the levels in the model group. Conclusion HBO treatment is capable of stimulating the proliferation of NSCs in HIBD neonate rats.The proliferation of NSCs is correlated with the activation of β-catenin protein. Key words: Hyperbaric oxygen; Hypoxic-ischemic brain damage; Neural stem cells; β-catenin

Objective To explore changes in cognitive and memory function in the Alzheimer's disease (AD) model rats, and also its association with the changes in the expressions of brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB) and synaptophysin in hippocampus, following HBO treatment. Methods The rats were randomly divided into 4 groups: the normal control group, the sham surgical group (5μl of saline were injected into bilateral hippocampus), the model control group (5μl of Aβ25-35 were injected into bilateral hippocampus) and the HBO treatment group (5μl of Aβ25-35 were injected into bilateral hippocampus and treated with HBO), each consisting of 10 animals. During the experiment, the rats were fed with conventional clean food and were kept in a space with constant temperature. Two weeks after injection with Aβ25-35, the rats were treated with HBO. Following completion of treatment, the rats of all the groups had the Morris water maze tests, i.e. navigational experiment and space exploration experiment, to detect changes in cognitive and spatial memory. Then, the expression levels of BDNF, TrkB and synaptophys in hippocampus were detected by Western Blot and immunohistochemistry. Results The results of the Morris water maze tests indicated that the number of running across the platform for the rats in the HBO group was 3.3 and the percentage of swimming in the original quadrant accounted for 30%, and statistical significance could be seen when comparisons were made (P<0.05). It was suggested that HBO could significantly improve spatial memory of the AD model rats, and at the same time it could enhance the expressions of BDNF, TrkB and synaptophysin in hippocampus. Statistical significance could be noted when it was compared with the model control group (P<0.05). Conclusions HBO might increase the expression levels of BDNF, TrkB and synaptophysin, which were closely associated with memory, thus improving the cognitive function and spatial memory of the AD model rats. Key words: Hyperbaric oxygen; Alzheimer's disease; Brain-derived neurotrophic factor; Tyrosine kinase receptor B; Synaptophysin

Mutations in the presenilin 1 (PS1) gene are responsible for the early onset of familial Alzheimer disease (FAD). Accumulating evidence shows that PS1 is involved in gamma-secretase activity and that FAD-associated mutations of PS1 commonly accelerate Abeta(1-42) production, which causes Alzheimer disease (AD). Recent studies suggest, however, that PS1 is involved not only in Abeta production but also in other processes that lead to neurodegeneration. To better understand the causes of neurodegeneration linked to the PS1 mutation, we analyzed the development of tau pathology, another key feature of AD, in PS1 knock-in mice. Hippocampal samples taken from FAD mutant (I213T) PS1 knock-in mice contained hyperphosphorylated tau that reacted with various phosphodependent tau antibodies and with Alz50, which recognizes the conformational change of PHF tau. Some neurons exhibited Congo red birefringence and Thioflavin T reactivity, both of which are histological criteria for neurofibrillary tangles (NFTs). Biochemical analysis of the samples revealed SDS-insoluble tau, which under electron microscopy examination, resembled tau fibrils. These results indicate that our mutant PS1 knock-in mice exhibited NFT-like tau pathology in the absence of Abeta deposition, suggesting that PS1 mutations contribute to the onset of AD not only by enhancing Abeta(1-42) production but by also accelerating the formation and accumulation of filamentous tau.

Conclusion: The excellent tolerability of intratympanic (IT) steroid offers the possibility to use a high dose, which would appear to be more effective than intravenous (IV) steroid treatment, when both are associated with hyperbaric oxygen (HBO) therapy. Objective: The purpose of the study was to assess for the first time the efficacy of the association of IT steroid and HBO therapy in patients presenting idiopathic sudden sensorineural hearing loss (ISSNHL), comparing this protocol with another consisting of IV steroid administration and HBO therapy. Methods: A total of 48 patients presenting ISSNHL were recruited. Patients were divided into two categories: the severe ISSNHL group with a pure-tone average (PTA) between 70 and 90 dB, and the profound ISSNHL group with a PTA >90 dB. The first protocol consisted of 10 days of HBO therapy together with IV methylprednisolone 1 mg/kg body weight for 7 days; the second protocol consisted of HBO therapy for 10 days, associated with an IT injection of prednisolone at a dose of 62.5 mg/ml, once a day for 3 consecutive days, performed 2 h before the HBO therapy. Results: The overall success rate was superior in the group submitted to IT steroid and HBO therapy. Nevertheless, these clinical results were not statistically significant.

Effects of hyperbaric oxygen therapy on caustic esophageal injury in rats

Effect of Perioperative Hyperbaric Oxygen on Bruising in Face-lifts

Cervical spinal cord injury can cause significant respiratory dysfunction and in severe cases necessitates mechanical ventilation. Accumulating evidence indicates that hyperbaric oxygen (HBO) therapy, initiated shortly after spinal cord injury (SCI), can mitigate spinal cord pathology. Further, a recent study from our group demonstrated that HBO therapy can attenuate diaphragm atrophy after SCI. The primary purpose of the present investigation was to evaluate diaphragm electromyogram (EMG) activity during HBO therapy in rats with cervical SCI. HBO therapy has not been widely adopted after SCI, and if HBO is to be translated to human use, we reasoned that it is important to determine how breathing is impacted during HBO exposure. Adult female Sprague‐Dawley rats were implanted with chronic indwelling EMG electrodes in the mid‐costal diaphragm two weeks prior to SCI. Following hemicontusion injury of the C4 spinal cord, one experimental group was treated with HBO (n=3), and another group was left untreated (n=3). The HBO treatment consisted of a one hour exposure to 100% O2 at 3 atmospheres (ATA). In all experiments, diaphragm EMG activity was recorded in freely moving rats, without anesthesia. Recordings were made for 10 minutes prior to treatment, throughout the HBO exposure, and for 10 minutes after. Diaphragm EMG recordings in the normobaric normoxia control group conditions were completed for the same duration of time as the treated group. Daily HBO treatment and EMG recordings were done until 10‐days post‐SCI. Peak diaphragm EMG burst amplitude was quantified before SCI, over the 10 days of treatment, and at 1 and 2 weeks post‐treatment. Prior to SCI, body weight was similar between groups (control: 227±4 g; HBO: 228±3 g). All rats with tolerated HBO treatment with no evidence of adverse events or impact on weight gain over the 10 day period (10 day body weight: control: 198 ± 14 g; HBO: 197 ± 13 g). The acute HBO exposure caused an increase in the area under the curve of the rectified and integrated inspiratory burst amplitude of the diaphragm recording made ipsilateral to the lesion. This increase averaged 126 ± 18% of baseline across the 10 HBO treatments. The ipsilateral EMG burst amplitude also remained elevated at 10 min post‐HBO exposure (115 ± 32%) compared to pre HBO exposure. At the conclusion of the 10 day treatment paradigm, ipsilateral diaphragm EMG output during quiet breathing was elevated in HBO (156 ± 50% of post‐injury baseline) as compared to the control group (111 ± 6% of baseline). However the ipsilateral diaphragm EMG burst amplitude of the two groups were similar when evaluated 2 weeks after the daily HBO sessions concluded. This ongoing study indicates that acute exposure to HBO therapy is associated with an increase in diaphragm EMG activity, and 10 days of HBO therapy accelerates the recovery of diaphragm activation following cervical contusion injury.

Conclusion. The average recovery of hearing and cessation of tinnitus was significantly better after hyperbaric oxygen therapy (HBOT) than after normobaric oxygen therapy (NBOT). HBOT can be valuable adjuvant therapy for patients with acute acoustic trauma (AAT). Objectives. AAT was one of the early indications for the use of HBOT. The rationale of administering oxygen to patients with AAT is based on experimental studies showing that noise exposure results in cochlear hypoxia, which could be compensated by HBOT. The aim of this study was to investigate the efficacy of HBOT in patients with AAT. Patients and methods. We compared the recovery from hearing impairment and tinnitus in 60 ears treated with HBOT with 60 ears treated with NBOT. The HBOT was given daily for 1–8 days. There were no significant differences in clinical or audiological data between HBOT and NBOT groups. Results. The average recovery of hearing both at high and speech frequencies was significantly better and tinnitus persisted less commonly after the HBOT than after the NBOT. Normal hearing at the end of the follow-up period was regained in 42 ears in the HBOT group and in 24 ears in the NBOT group (p<0.01).

Carbon monoxide (CO) poisoning is an important cause of mortality and late neurological sequelae such as memory loss, personality changes, psychosis, dementia, and so on. The benefits of hyperbaric oxygen (HBO) therapy are still discussed, but the majority of trials recommend it in severe cases with coma and/or hemodynamic instability, irrespective of carboxyhemoglobin (COHb) level, to prevent permanent neurological deficits. We present a 35-yr-old woman who underwent accidental CO poisoning. Although breathing 100% oxygen by mask during transfer to the hospital, she was in deep coma, hypotensive, cyanotic, and hypoxic (arterial pO2 7,41 kPa, HbO2 87.8%), with serum COHb 26.7% on hospital admission. Orotracheal intubation, mechanical ventilation, iv fluids, dobutamin, and norepinephrine were administered. COHb level decreased to 17.2% within 1 h. To prevent severe neurological sequelae, the patient was transferred as soon as possible to an HBO center 60 km distant to perform HBO therapy twice at 3.0 and once at 2.2 atm within 24 h. After the second HBO session, the patient regained consciousness, and respiratory failure and shock resolved. She was transferred to our hospital and discharged few weeks later with discrete paresis of peripheral nerves, discrete ischemic brain lesions on computed tomography (CT) scan, and moderately abnormal electroencephalogram (EEG) without cognitive disturbances. She was able to resume her daily activities. We conclude that in severe CO poisoning, normobaric oxygen therapy and resuscitation by fluids, inotropic agents, and catecholamines is essential for survival, but additional HBO therapy seems to prevent major neurological sequelae.

Thiol/disulfide homeostasis in patients treated with normobaric or hyperbaric oxygen for carbon monoxide poisoning

To present recovery from vision loss due to CO poisoning with Hyperbaric Oxygen (HBO) therapy in two patients. Two female patients developed visual deterioration after carbon monoxide (CO) poisoning and were treated with hyperbaric oxygen therapy (HBO). Clinical examination, including visual acuity assessment, visual field examination and visual evoked potentials (VEPs) before and after the HBO therapy were performed. In Case 1 the visual loss started on the third day with visual acuity at the level of perception of hand movements at 10 cm in the right eye and finger count at 10 cm in the left eye. The visual evoked potentials (VEPs) had low amplitudes and prolonged (128 msec bilaterally) latencies (implicit times). After 48 sessions and 52 days of HBO therapy, the visual acuity became 0.2 in the right eye and 0.15 in the left eye. Visual field examination revealed homonymous right lower quadrant anopsia. The VEPs also improved. In Case 2 the visual acuity was 0.2 in the right eye and 0.1 in the left eye on the 6th day following the accident when the patient was admitted for treatment. The VEP latencies were within normal limits. After 36 days and 35 sessions of HBO therapy, the visual acuity became 0.7 on both eyes. The visual fields completely normalised. The VEP latencies in this case also became shorter. It appears that the adverse effects of CO poisoning continue to progress during the late period and we believe that HBO treatment in this period may still be effective and will prevent some of the neurological sequelae such as visual loss from becoming permanent. Clinical, neurological, neuropsychological, visual outcome seems to be favourable even if HBO treatment started as late as 6 or 8 days after the exposure to CO.