GeroScience (2023) 45:747–756

https://doi.org/10.1007/s11357-022-00707-z

REVIEW

The potential of hyperbaric oxygen as a therapy

for neurodegenerative diseases
Paapa Mensah‑Kane · Nathalie Sumien

Received: 25 August 2022 / Accepted: 3 December 2022 / Published online: 16 December 2022
© The Author(s), under exclusive licence to American Aging Association 2022

Abstract The World Health Organization estimates Keywords Hyperbaric oxygen · Epigenetics ·
that by the year 2040, neurodegenerative diseases Neurodegenerative diseases · Alzheimer’s disease ·
will be the second leading cause of death in devel- Parkinson’s disease · Oxidative stress · Inflammation ·
oped countries, overtaking cancer-related deaths Neurodegeneration
and exceeded only by cardiovascular disease–related
death. The search for interventions has therefore
become paramount to alleviate some of this burden. Introduction
Based on pathways affected in neurodegenerative dis-
eases, hyperbaric oxygen treatment (HBOT) could Neurodegenerative diseases (NDD) can be charac-
be a good candidate. This therapy has been used for terized by a continuous or progressive loss of a spe-
the past 50 years for conditions such as decompres- cific vulnerable neuronal population in the brain or
sion sickness and wound healing and has been shown spinal cord [1]. The classification of NDD can be
to have promising effects in conditions associated based on the anatomical spread of neurodegenera-
with neurodegeneration and functional impairments. tion (e.g., extrapyramidal disorders, frontotemporal
The goal of this review was to explore the history degenerations, or spinocerebellar degenerations),
of hyperbaric oxygen therapy, its uses, and benefits, the primary molecular abnormality (e.g., amyloid-β,
and to evaluate its effectiveness as an intervention prion protein, tau, α-synuclein), or the main clini-
in treating neurodegenerative diseases. Additionally, cal features (e.g., parkinsonism, motor neuron dis-
we examined common mechanisms underlying the order, or dementia) [1, 2]. Despite these differential
effects of HBOT in different neurodegenerative dis- classifications and symptoms presentations, NDDs,
eases, with a special emphasis on epigenetics. including disorders such as Parkinson’s disease
(PD), amyotrophic lateral sclerosis (ALS), and Alz-
heimer’s disease (AD), share certain processes that
lead to the dysfunction and eventual death of neu-
rons. Some of the major common factors involved
in NDDs are oxidative stress, programmed cell
death, neuroinflammation, mitochondrial dysfunc-
P. Mensah‑Kane · N. Sumien (*) tion, epigenetic modifications, proteotoxic stress,
Department of Pharmacology and Neuroscience, and impairment of its associated ubiquitin/protea-
University of North Texas Health Science Center,
somal and autophagosomal systems [2]. Because of
Fort Worth, TX, USA
e-mail: [email protected]

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these commonalities, it is not surprising to observe Hyperbaric oxygen therapy (HBOT)

an overlap of symptomology in these diseases [1].
Millions of individuals are affected by NDDs Normoxic conditions (20.8% oxygen) are neces-
worldwide, so much so that by 2040, the World sary to maintain effective metabolism, and any slight
Health Organization estimates that NDDs will be deviation from this concentration can lead to major
the second leading cause of death in developed physiological alterations [10]. Hypoxic conditions are
countries [3]. Treatments are available to relieve and sensed by chemoreceptors leading to altered cellular
manage symptoms of particular diseases [4]; how- response. Generally, mitochondria signal the onset
ever, effective therapies to slow down the progress of hypoxia by generating reactive oxygen species via
or cure these diseases are still lacking. Recent stud- the electron transport chain. The reactive oxygen spe-
ies show a paradigm shift from just symptomatic cies, once released into the intermembrane space of
management to prevention of further deterioration the mitochondria, activate enzymes, transcription fac-
mainly by cytoprotective mechanisms. Substantial tors, and post‐translational responses [11]. The focus
evidence points to oxidative stress and inflamma- of this review is on hyperbaric oxygen, which relates
tion playing a fundamental role in neurodegenera- to exposure to 100% oxygen while in a pressur-
tion. Thus, these mechanisms have become targets ized chamber. The pressure needs to be higher than
for cytoprotection [4]. Hyperbaric oxygen therapy 1 atmosphere absolute (ATA) which is considered
(HBOT) has been used over the past 50 years for a sea level [12]. Hyperbaric oxygen treatment usually
variety of conditions such as decompression sick- entails increasing the pressure to 2.0–2.5 ATA for a
ness, wound healing, and in conditions where oxy- duration of 90–120 min, with a number of therapeu-
gen levels are compromised [5]. HBOT reduces tic sessions depending on the conditions being treated
neuroinflammation in severe brain dysfunctions and [13]. The air pressure increase leads to improve oxy-
has the capacity to down-regulate proinflammatory gen cellular delivery [10]. Oxygen increases and in
cytokines (IL-1β, IL-12, TNFα, and IFNγ) while turn stimulates stem-cell proliferation and certain
upregulating an anti-inflammatory cytokine (IL-10) growth factors that mediate the healing process [10].
making it potentially cytoprotective [6]. Recently, However, an increase in oxygen may lead to excess
basic and clinical research has shown the potential oxidative stress which could lead to damages of mac-
of HBOT to treat neurodegenerative diseases [7–9]. romolecules like deoxyribonucleic acid, proteins, and
The goal of this narrative review is to provide a his- lipids [14], which was the main reason for prior reluc-
torical context on the use of HBOT, to consider its tance in using HBOT as a therapeutic tool.
efficacy in treating NDDs in preclinical and clinical
settings, and to highlight the mechanisms underly- Historical perspective
ing its beneficial effects with a fresh perspective on
the role of epigenetics. The history of HBOT is closely related to that of div-
ing medicine, with origins dating back to the 1500 s
when Leonardo Da Vinci made drawings of diving
Search appliances [15]. It was not until 1662, however, that
hyperbaric therapy was first documented when Hen-
The literature search was conducted using PubMed shaw, a British physician, built an airtight chamber
from 1968 to 2022, using the following keywords: called a “Domicilium” that could simulate various
“Hyperbaric oxygen therapy,” “Hyperbaric oxygen,” climate and pressure conditions [15]. In 1834, Junrod
“neurodegenerative disease,” “Alzheimer’s disease,” treated pulmonary problems with a hyperbaric cham-
“Parkinson’s Disease,” and “Amyotrophic lateral scle- ber in France [15]. Over time, hyperbaric chambers
rosis.” Articles written in English that were full text became more present and were available in most cit-
were included in the review. Articles that had a direct ies of Europe. However, the challenge was that there
relation with hyperbaric oxygen and neurodegen- was no scientific rationale for the use of HBOT and
erative diseases were reviewed. As the articles were no standardized prescription across physicians [16].
evaluated, some of the references made were further In 1775, the discovery of oxygen led to its use in
explored and added to this review. lieu of compressed gases, yet it was short-lived as

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Lavoisier and Seguin reported the harmful effects of effects of HBOT are usually dependent on pressure
concentrated oxygen in 1789 [16]. Subsequently, Bert and time exposure [12]. Generally, side effects, such
suggested the use of normobaric instead of hyperbaric as headache, claustrophobia, and reversible myopia,
oxygen for decompression sickness [16]. Behnke and are tolerable and easily reversed when the therapy is
Shaw were the first to utilize HBOT for decompres- halted [21]. Interestingly, HBOT has been used as a
sion sickness treatment in 1937 based on the model tool to induce oxidative stress in screening potential
devised by Drager, who first explored the possibility antioxidants, using high pressure for long periods of
of treating this condition with oxygen under pressure time (above 4 ATA and for a period exceeding 3 h)
[16]. [12, 17].

Hyperbaric oxygen therapy indications and caveats

Hyperbaric oxygen and neurodegenerative
The initial uses of HBOT were based on the pressure- diseases
dependent effervescent reducing action (Boyle-Mar-
riott law) and the hyperoxygenation of tissues [17]. Rationale for the use of HBOT in neurodegenerative
Pathologies with known benefits from the hyperoxic diseases
state created by HBOT are necrotizing tissues, radia-
tion injury, wounds and burns, compartment syn- Diseases associated with a reduced loss of oxygen
dromes, and gas gangrene [18], and several others supply predispose the individual to neurodegenera-
as listed by the Undersea and Hyperbaric Medical tion [22] suggesting a major role of hypoxia in NDDs.
Society [19]. The other mechanism (bubble-reducing Hypoxia-inducible factor-1 (HIF-1), a transcriptional
effect) has been associated with another set of indica- factor fundamental to cellular and tissue adaption to
tions that benefits from HBOT such as decompression low oxygen tension, has been implicated in a host
sickness and air/gas embolism [19]. In fact, HBOT of NDDs including Alzheimer’s (AD), Parkinson’s
remains the only treatment available for decompres- (PD), Huntington’s diseases (HD), and amyotrophic
sion sickness, a result of nitrogen forming gas bub- lateral sclerosis (ALS) and has become a potential
bles in tissues and blood due to a partial increase in medicinal target [21, 23]. The incidence of AD, for
nitrogen’s pressure from divers rising too quickly instance, is greatly increased following conditions
to the water surface [20]. Another major issue that associated with hypoxia such as stroke and cerebral
HBOT is used for as a life-saving treatment is carbon ischemia [24, 25]. Furthermore, cerebral hypoperfu-
monoxide poison. Typically, carbon monoxide has an sion which gives rise to cerebral hypoxia has been
affinity for hemoglobin 240 times higher than that of observed in the early stages of AD, with strong cor-
oxygen. Hence, the ability of the blood to carry oxy- relations to both worsening of function and structural
gen is decreased in the presence of carbon monoxide. components implicated in AD [26–28]. Hypoxia is
Hyperbaric oxygen supplies the tissue with oxygen by known to drive hyperphosphorylation of tau, dys-
enhancing its dissolution in the plasma, and by free- function of the blood–brain barrier, accumulation of
ing hemoglobin from carbon monoxide [20]. Note- β-amyloid (Aβ), and degeneration of neurons [29]. In
worthy, for certain conditions, HBOT is used as an the case of Parkinson’s disease (PD), hypoxic brain
adjunctive treatment and has demonstrated improve- injury enhances α-synuclein (α-syn) expression and
ments in a variety of inflammatory or infectious dis- aggregation which is a pathological hallmark of PD
ease models such as colitis, sepsis, and others [17]. [22]. It has been postulated that hypoxia through
Based on the anti-inflammatory and oxygenation HIF-1α in dopaminergic cells upregulates ATP13A2
mechanisms of HBOT, there is some potential for it (PARK9), a transcription factor with mutations that
to be a therapy used in neurodegenerative diseases, have been found in postmortem PD [22]. Occupa-
which we will discuss further below. tions that could cause hypoxic conditions, like being
It is important to note that the use of hyperbaric a firefighter, double the risk to develop amyotrophic
oxygen therapy must not exceed a pressure of 3 ATA lateral sclerosis (ALS). In fact, hypoxia is not only
and not be administered for more than 2 h at a time, one of the causing factors of ALS but also drives the
as this typically results in toxicity [17]. The side progression of it [22]. Neurotoxicity and cell death

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induced by hypoxia involve a complex plethora of magnetic resonance imaging [34]. Also, elderly
factors that tend to be interrelated. They include mito- patients who had significant memory loss exhibited
chondrial dysregulation, oxidative stress, inflamma- improved cognition and increased cerebral blood flow
tion, metal homeostasis, apoptosis, synaptic trans- after exposure to HBOT [35]. In a pre-clinical model
mission, and autophagy, all contributing to neuronal of aging (D-gal-induced aging) in rats [36] and mice
death [22]. Another factor affecting the development [37, 38] as well as in a model of aging and obesity
of dementia and age-related cognitive declines is [36], HBOT prevented cognitive impairments and
the cerebromicrovasculature, as impaired microcir- hippocampal-dependent pathologies via augmenta-
culation has been associated with vascular cognitive tion of cholinergic pathways, anti-apoptotic effects
impairments [30]. Since the fundamental problem in [37], and reduction in oxidative damage and inflam-
the above-described conditions is a dearth of oxygen, matory responses [36, 37].
the theoretical approach to address this problem is to
augment oxygen in the system; therefore, HBOT may Clinical studies of HBOT in neurodegenerative
be a viable tool in their management [30, 31]. diseases
As age is a major risk factor for the development of
several neurodegenerative diseases [32], it is impor- Several clinical studies have been conducted to evalu-
tant to discuss the effect of HBOT on the neurobiol- ate the influence of HBOT on neurodegenerative dis-
ogy of aging. HBOT improved age-related cognitive eases, and of other neurological conditions like stroke
deficits in healthy elderly subjects [33]. In that study, and traumatic brain injury which predisposes patients
male patients with a mean age of 68 years exhibit- to developing neurodegenerative diseases like AD
ing clinical manifestations of intellectual deteriora- (Table 1). In a randomized prospective crossover
tion were assessed after 30 intermittent exposures to control trial of mild traumatic brain injury (mTBI),
100% oxygen at 2.5 ATA. Psychological tests of cog- 56 patients were enrolled and the treated group was
nitive functioning showed highly significant gains in exposed to 40 HBOT sessions (60 min a day at a
treated subjects as compared to control levels [33]. pressure of 1.5 ATA) [39]. The Mindstreams battery
In a recent randomized control clinical trial, healthy test for evaluating cognition, EQ-5D for quality of
adults aged above 64 years were either exposed to life, and SPECT imaging for assessing brain activity
HBOT or no treatment for 3 months. HBOT induced were carried out. Treatment with hyperbaric oxygen
cognitive improvement in these healthy aging adults improved cognitive function and quality of life signif-
through mechanisms involving regional changes in icantly and treated patients also exhibited increased
cerebral blood flow (CBF) measured by perfusion brain activity [39]. In another study, the same research

Table 1  Summary of clinical outcomes of HBOT on brain function and other markers in neurodegenerative diseases
Disease Authors HBOT Findings

Mild traumatic brain injury Boussi-gross et al., 2013 40 sessions at 1.5 ATA, 5 days/ Increased brain activity (SPECT,
week, 60 min/day cognition, and quality of life)
Stroke Boussi-gross et al., 2015 40–60 sessions at 2 ATA, 5 days/ Reduction in memory impairments
week, 90 min/day
Alzheimer’s disease Harch and Fogarty 2018 40 sessions at 1.15 ATA, 5 days/ Increase in energy, brain metabolism
week, 50 min/day and cognition
Alzheimer’s disease Chen et al., 2020 20 sessions at 1.18 ATA, 7 days/ Improved cognitive function
week, 40 min/day (Montreal cognitive assessment,
mini-mental state examination, and
activities of daily living scale)
Parkinson’s disease Xu et al., 2018 30 days at 2 ATA, 2 sessions of Improved non-motor symptoms of
40 min/day separated by 10-min severe depression and anxiety
interval
Amyotrophic lateral sclerosis Steele et al., 2004 20 sessions at 2 ATA, 5 days/week, Decreased fatigue and increased
60 min/day muscle strength

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group using the same HBOT protocol determined that symptoms of severe depression and anxiety [43].
the treatment led to a reduction in memory impair- Phase I clinical trial involving 5 ALS patients treated
ment in post-stroke patients [40]. In a case study, a with hyperbaric oxygen at 2 atmospheres pressure for
58-year-old woman, diagnosed with rapid progression 60 min daily for 5 days a week for 4 weeks resulted in
AD, was exposed to HBOT for 8 weeks at 1.15 atmos- decreased fatigue and increased muscle strength [44].
phere absolute with 50-min total treatment time, once
per day, 5 days per week [41]. The patient became Pre‑clinical studies of HBOT in neurodegenerative
more energetic and her capacity to carry out tasks like diseases
drawing of clock and daily living was improved after
the 21st day of HBOT. PET imaging showed a corre- There are several pre-clinical studies also suggest-
sponding regional and global increase in brain metab- ing a beneficial role of HBOT in a variety of animal
olism [41]. In a larger clinical study including control models (Table 2). In a mouse model of AD (3 × Tg),
AD patients, AD patients, and amnestic mild cogni- HBOT improved cognition while reducing inflam-
tive impairment (aMCI), psychiatric assessments mation, plaque burden, and Tau phosphorylation [9].
including Montreal cognitive assessment (MoCA), In that study, male 3 × Tg mice aged 17 months were
mini-mental state examination (MMSE), and activi- used with 14-month-old C57BL/6 male mice as con-
ties of daily living (ADL) scale before and at different trols. The treatment with HBO consisted of 2 ATA for
months after treatment were carried out. Treatment an hour daily for 14 consecutive days and resulted in
involved exposing AD and aMCI patients to 40 min diminished neuroinflammatory processes by reducing
of oxygen at a pressure of 0.12 Megapascal (MPa) microgliosis, astrogliosis, and the secretion of pro-
(equivalent of 1.18 ATA) separated by 20-min inter- inflammatory cytokines while improving cognition
vals. HBOT improved cognitive function significantly in the process [9]. In another study, HBOT improved
assessed by MMSE and MoCA in AD patients after cognition in a mouse model of AD (5 × FAD) and
a month follow-up. MMSE score was also improved improved cerebral blood flow [35]. A combination of
by treatment at 3 months while MoCA score saw HBOT and Ginkgo biloba extract has also been found
improvement at both 1- and 3-month follow-ups in to ameliorate cognitive and memory impairment in
aMCI patients [42]. Another case study reported an AD model of rat induced by injecting Aβ 25–35
that HBOT treatment given to Parkinson’s disease [45], through inhibiting oxidative stress by block-
patient over a period of 30 days improved non-motor ing mitochondria-mediated apoptosis signaling [46],

Table 2  Summary of pre-clinical outcomes of HBOT on brain function and other markers in neurodegenerative diseases
Disease Authors HBOT Findings

Alzheimer’s disease-3 × Tg mice Shapira et al., 2018 14 sessions at 2 ATA, 7 days/week, Improved cognition, while reducing
60 min/day inflammation, plaque burden and
Tau phosphorylation
Alzheimer’s disease-5 × FAD Shapira et al., 2021 20 sessions at 2 ATA, 5 days/week, Improved cognition and improved
mice 60 min/day cerebral blood flow
Alzheimer’s disease-Aβ 25–35 Zhang et al., 2015 20 sessions at 2 ATA, (consisted of Improved cognitive and memory
injected rats two courses of 10 days with an impairment in combination with
interval of 3 days between two Ginkgo biloba
courses), 60 min/day
Parkinson’s disease-6-OHDA Pan et al., 2015 14 sessions at 2.4 ATA, 7 days/ Reduced apomorphine-induced turn-
rats week, 60 min/day ing and neuroprotection of substan-
tia nigra’s dopaminergic neurons
Parkinson’s disease-MPTP Hsu et al., 2022 7 sessions at 2.5 ATA, 7 days/ Neuroprotection and improved motor
mouse week, 60 min/day function and increased mitochon-
dria biogenesis signaling
Motor neuron disease-Wobbler Dave et al., 2003 30 days at 2 ATA, 60 min/day Delaying onset via decrease in mito-
mouse chondrial dysfunction

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activation of NF-κB[45] and enhancing of superoxide both paw condition and walking; from 36 ± 4.3 days
dismutase, an antioxidative enzyme, in rat hippocam- to 59 ± 8.2 days (walking) and from 40 ± 5.7 days to
pal tissue [47]. Pre-treatment of HBOT has also been 63 ± 7.6 days (paw condition) [53].
shown to lower the rate of hippocampal p38 mito-
gen-activated protein kinase phosphorylation with Mechanisms of HBOT
a reduction of hippocampal damage [48]. In a Par-
kinson’s disease rodent model (6-hydroxydopamine HBOT affects diverse cellular and molecular path-
model), the combinatory effect of HBOT and Mado- ways that are important for cellular and neuronal
par (levodopa-used for management of Parkinson’s recovery such as oxidative stress, mitochondrial
disease) therapy was evaluated. Both HBOT and the functions, inflammation, apoptosis, microcircula-
combination therapy reduced apomorphine-induced tion, and epigenetics via interconnected pathway [30,
turning in PD rats and offered neuroprotective effect 31] (Table 3). As aforementioned, these processes
on substantia nigra’s dopaminergic neurons [49]. In and pathways are fundamental and common in most
another model of PD, the 1-methyl-4-phenyl-1,2,3,6- NDDs.
tetrahydropyridine (MPTP) mice, protective mecha-
nisms of HBOT on neurons and motor function were Effect of HBOT on inflammation, oxidative stress,
evaluated. The locomotor activity and grip strength and mitochondrial functions
of the mice were increased alongside increased mito-
chondria biogenesis signaling (SIRT-1, PGC-1α, and HBOT reduces neuroinflammation in severe brain
TFAM) [50]. Furthermore, mild hyperbaric oxygen dysfunctions. HBOT has the capacity to down-
inhibited the decrease of dopaminergic neurons in regulate proinflammatory cytokines (IL-1β, IL-12,
the substantia nigra [51]. The improvement of motor TNFα, and IFNγ) and upregulate an anti-inflamma-
deficits in Parkinson’s disease has also partly been tory cytokine (IL-10) as shown in an atherosclerosis
attributed to the increase in norepinephrine after rodent model [6]. More so, it is reported to inacti-
HBOT exposure [52]. HBOT has also been shown to vate cyclooxygenase, the same target enzyme for
improve function in a model of human motor neuron non-steroidal anti-inflammatory disease [54]. Evi-
disease (Wobbler mouse). HBOT was administered at dence suggests that even though HBOT increases
2 ATA for 1 h daily for 30 days. The treatment signifi- the level of lipid peroxidation and/or protein oxi-
cantly delayed the onset of the disease as measured by dation in blood and tissues of HBOT-exposed

Table 3  Summary of
the mechanisms of action Neuroinflammation Down-regulates pro-inflammatory cytokines (IL-1β,
of hyperbaric oxygen IL-12, TNFα, and IFNγ)
treatment Upregulate an anti-inflammatory cytokine (IL-10, IL-4)
Reduction in astrogliosis and microgliosis
Inactivate cyclooxygenase
Oxidative stress Increase glutathione, superoxide dismutase and catalase
Increase in Nrf2, Heme oxygenase (HO-1)
Reduce cytochrome c release
Neuroprotection and apoptosis Increase mitochondrial transfer from astrocytes to neurons
Increase humanin expression
Increased ATP production and brain metabolism
Increased neurotrophins (BDNF)
Reduction in caspase9/3 mediated apoptotic pathway
Increase in Bcl-2 and decrease in Bax
Microcirculation and neurogenesis Improving of blood–brain barrier permeability
Promotes angiogenesis via VEGF/ERK signaling
Epigenetics Lengthening of telomeres and reduction in cellular senes-
cence
Downregulation of DNA methyltransferase 3a (DNMT3a)
mRNA and protein expression

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organisms under certain conditions [12, 14], how- a result of the transfer of mitochondria from astro-
ever, HBOT has also been associated with a sig- cytes to neurons [64].
nificant elevation in antioxidants defenses such as
superoxide dismutase, catalase, and glutathione Effect of HBOT on apoptosis and neuroprotection
peroxidase [17]. What is even more fascinating is
that some researchers argue that ROS generated by HBOT has been found to reduce hippocampal p38
HBOT mediates and signals some of the beneficial mitogen-activated protein kinase (MAPK) phospho-
effects of HBOT [14, 17, 55]. Thus, aside from the rylation which led to improvement in cognition and
pressure-dependent effervescence-reducing action reduction in hippocampal damage [48]. Individu-
and the hyperoxygenation saturation of tissues, ally and in combination with Gingko Biloba extract,
the beneficial effect of HBOT has been argued to HBOT reduced Bax expression and the activity of
be in part, dependent on the physiological roles caspase-9/3 leading to a reduction in apoptotic rate in
of the reactive oxygen species generated [56, 57]. Aβ25-35-induced toxicity in rats [46]. In another study,
Superoxide radicals along with hydrogen peroxide HBOT pre-conditioning induced tolerance to cerebral
are known to be the major fraction of ROS pro- ischemia mediated via an increase in SIRT1 with
duced via HBOT [58]. Through a series of steps, an associated increase in B-cell lymphoma 2 Bcl-2)
they activate transcription factors, nuclear factor expression and reduction in cleaved caspase 3 [65].
erythroid 2-related factor 2 (Nrf2), and hypoxia- These corroborate the neuroprotection and anti-apop-
inducible factor-1 alpha (HIF-1α) along with their totic effects of HBOT.
main target protein, heme oxygenase-1 (HO-1), also
called heat shock protein (HSP)32, which provides Effect of HBOT on microcirculation and
robustness to the organism against oxidative dam- neurogenesis
age and plays a vital role in the regulation of cell
proliferation, differentiation, oxidant/antioxidant HBOT exposure has been observed to have a plethora
systems, and apoptosis [59]. HIF-1α is induced in of effects on the cerebrovasculature of the brain [30],
response to hypoxia. Ironically, in HBOT where including improvement of blood–brain barrier perme-
hyperoxia instead of hypoxia is produced, HIF-1α ability [66], angiogenesis [31], and edema reduction
is also induced because of the rapid fall of tissue [30]. HBOT, in addition to providing increased access
oxygen levels after the hyperoxic state, i.e., mimick- of oxygen to tissues, enhances the formation of blood
ing hypoxia. While chronic hypoxia stimulates only vessels via activation of transcription factors such as
HIF-1α, intermittent hypoxia induces both HIF-1α vascular endothelial growth factor as well as neuronal
and Nrf2 [60]. HIF-1α normally downregulates stem cell proliferation [67].
HO-1 induction, but in Nrf2 over-expression, the
inhibitory effect of HIF-1α is reversed, contribut- Effect of HBOT on epigenetics
ing to [the HO-1-mediated action [61]. In accord-
ance, the cycling of hyperoxia-normoxia-hyperoxia It has been found that, after exposure of human
between HBOT sessions can be placed in the con- microvascular endothelial cells (HMEC-1) to HBOT
text of normoxia-hypoxia-normoxia loops, therefore or 24 h later, 8101 genes are significantly regulated
simulating intermittent hypoxia. As a result, HBOT [68]. This includes both up- and downregulation of
stimulates both HIF-1α and Nrf2 [17]. This explains gene expression with increased expression observed
in part the convergence of intermittent hypoxia and in antioxidant response pathways. Hachmo et al. also
HBOT. Mitochondria act as an oxygen sensor by reported that exposure to HBOT led to a lengthening
generating ROS signals through the electron trans- of telomeres and a reduction in cellular senescence
port chain in hypoxic conditions [62]. Following [69]. Shortening of telomeres and increased cellular
HBOT treatment, humanin expression (a neuropro- senescence are two major hallmarks of the aging pro-
tective mitochondrion-derived peptide in humans) cess at the cellular level [69]. What these data suggest
was increased in vascular dementia patients is the capacity of HBOT to exert some influence at
[63]. Recent studies have also suggested that the the genetic level, probably through epigenetic modi-
increased resiliency of neurons exposed to HBOT is fications. Recent evidence suggests dysregulation of

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epigenetic mechanisms such as DNA methylation, major role. Simply said, more work on the potential
and histone post-translational modifications are impli- of HBOT as a therapy for NDDs needs to be funded
cated in NDDs [70]. Rats exposed to long-term-inter- and completed.
mittent hypoxia exhibited increased DNA methyla-
tion and suppression of several antioxidant enzymes Funding BvB Foundation Dallas; Lowdon Family Founda-
tion; Office of Vice President for Research and Innovation, the
[71]. Also, histone demethylases (chromatin regula- Institute for Healthy Aging, and National Institutes of Health/
tors), such as KDM6A and KDM5A, are oxygen sen- National Institute on Aging (T32 AG020494); GSBS seed
sors that are inactivated by chronic hypoxia [72, 73]. grant; Grant in Aid of Research from the National Academy of
Based on these studies and the fact that the removal Sciences, administered by Sigma Xi, The Scientific Research
Society.
of methyl from lysine and DNA requires oxygen,
we anticipate that one of the major roles of HBOT Declarations
will be through epigenetic modification. In fact, the
pain-relieving effect of HBOT in neuropathic pain is Conflict of interest The authors declare no competing inter-
ests.
believed to be mediated in part through down-regula-
tion of DNA methyltransferase 3a (DNMT3a) mRNA
and protein expression which is an enzyme that plays
a significant role in epigenetic modification [74]. This References
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