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IntroductIon
Hyperbaric oxygen (HBO) improves outcome in experimen-
tal cerebral ischemia and is therefore emerging as a possible
co-treatment for acute ischemic stroke in addition of tissue
plasminogen activator (tPA), whose recombinant form is
considered the best approved treatment for acute brain
ischemia to date (Peplow, 2015). Thus, despite controversial
results that have shown that HBO enlarges ischemic brain
damage by blocking autophagy (Lu et al., 2014) and further
SHORT COMMUNICATION
produces vasoconstriction (Stirban et al., 2009), a condi-
tion thought to be deleterious in stroke disease, numerous
investigations have reported benecial effects of HBO on
infarct size and neurological decits (Veltkamp et al., 2000,
2005; Eschenfelder et al., 2008; Yang et al., 2010; Xu et al.,
2016). Although the mechanisms of action of HBO are not
well established and are still lively under discussion, HBO
has been shown to induce neurogenesis (Lee et al., 2013), to
improve the decrease in tissue oxygenation induced by isch-
Effects of normobaric versus hyperbaric oxygen on cell injury
induced by oxygen and glucose deprivation in acute brain slices
Laurent Chazalviel1, Jean-Eric Blatteau2, Nicolas Vallée3, Jean-Jacques Risso3, Stéphane Besnard4,
Jacques H. Abraini3, 5, 6, *
1 Normandie Université, UNICAEN, CNRS, UMR 6301 ISTCT, Equipe Cervoxy, Caen, France
2 Hôpital d’Instruction des Armées (HIA) Sainte-Anne, Service de Médecine Hyperbare et Expertise Plongée (SMHEP), Toulon, France
3 Institut de Recherche Biomédicale des Armées (IRBA), Equipe Résidente de Recherche Subaquatique Opérationnelle (ERRSO),
Toulon, France
4 Normandie Université, UNICAEN, INSERM, UMR 1075, Caen, France
5 Normandie Université, UNICAEN, Faculté de Médecine, France
6 Université Laval, Département d’Anesthésiologie, Québec, Canada
*Correspondence to: Jacques H. Abraini, jh.abraini@gmail.com.
orcid: 0000-0002-6435-9819
Normobaric oxygen (NBO) and hyperbaric oxygen (HBO) are emerging as a possible co-treatment of acute ischemic stroke. Both have
been shown to reduce infarct volume, to improve neurologic outcome, to promote endogenous tissue plasminogen activator-induced
thrombolysis and cerebral blood ow, and to improve tissue oxygenation through oxygen diffusion in the ischemic areas, thereby ques-
tioning the interest of HBO compared to NBO. In the present study, in order to investigate and compare the oxygen diffusion effects
of NBO and HBO on acute ischemic stroke independently of their effects at the vascular level, we used acute brain slices exposed to
oxygen and glucose deprivation, an ex vivo model of brain ischemia that allows investigating the acute effects of NBO (partial pressure
of oxygen (pO2) = 1 atmospheres absolute (ATA) = 0.1 MPa) and HBO (pO2 = 2.5 ATA = 0.25 MPa) through tissue oxygenation on
ischemia-induced cell injury as measured by the release of lactate dehydrogenase. We found that HBO, but not NBO, reduced oxygen
and glucose deprivation-induced cell injury, indicating that passive tissue oxygenation (i.e. without vascular support) of the brain
parenchyma requires oxygen partial pressure higher than 1 ATA.
Key words: hyperbaric oxygen; normobaric oxygen; oxygen diffusion; lactate dehydogenase; cell injury; brain slices; oxygen and
glucose deprivation; brain ischemia
doi: 10.4103/2045-9912.191364
How to cite this article: Chazalviel L, Blatteau JE, Vallée N, Risso JJ, Besnard S, Abraini JH
(2016) Effects of normobaric versus
hyperbaric oxygen on cell injury induced by oxygen and glucose deprivation in acute brain slices. Med Gas Res 6(3):169-173.
Abstract
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emia (Sun et al., 2008), to promote thrombolysis through
activation of endogenous tPA (Chazalviel et al., 2016b), and
to reduce the decrease in regional glucose metabolism (Lou
et al., 2007). Likewise, interestingly, normobaric oxygen
(NBO) has also been shown to reduce infarct size (Singhal
et al., 2002; Henninger et al., 2007; David et al., 2012), to
induce neurogenesis (Wagenfuhr et al., 2016), to promote
endogenous tPA-induced thrombolysis (David et al., 2012) ,
to increase cerebral blow ow and to improve the decrease
in tissue oxygenation induced by ischemia (Liu et al., 2004,
2006; Shin et al., 2007; Baskerville et al., 2011), thereby
questioning the interest of HBO compared to NBO in the
treatment of acute brain ischemia.
Therefore, in the present study, we investigated and
compared the effects of a post-insult treatment with NBO
(partial pressure of oxygen (pO2) = 1 atmospheres absolute
(ATA) = 0.1 MPa) or HBO (pO2 = 2.5 ATA = 0.25 MPa)
on the release of lactate dehydrogenase (LDH) – used as
a marker of cell injury – in acute brain slices exposed to
oxygen and glucose deprivation (OGD), an ex vivo model
of brain ischemia.
MaterIals and Methods
Materials
Brain slices were drawn from male adult Sprague-Dawley
rats (n = 15; Janvier, Le Genest Saint-Isle, France) weighing
250–280 g according to an animal use procedure approved
by the University of Caen ethics committee in accordance
with the Declaration of Helsinki and the framework of the
French legislation for the use of animals in biomedical
experimentation.
Rats were sacriced by decapitation under anesthesia,
and the brains were carefully removed and placed in ice-
cold freshly prepared articial cerebrospinal uid (aCSF)
containing 120 mM NaCl, 2 mM KCl, 2 mM CaCl2, 26
mM NaHCO3, 1.19 mM MgSO4, 1.18 mM KH2PO4, 11
mM D-glucose, and 30 mM HEPES (pH = 7.4). Coronal
brain slices of 400-μm thickness including the striatum
(anteriority: from −1.2 mm to +2 mm from bregma) were
cut using a tissue chopper (Mickie Laboratory Engineering
Co., Gomshall, Surrey, UK), and allowed to recover at room
temperature for 45 minutes.
Intervention and total LDH release analysis
After recovery at room temperature, brain slices were
incubated individually in a home made 16-vials versatile
normobaric-hyperbaric chamber (Blatteau et al., 2014)
that was placed in an oven at 36 ± 0.5°C. Temperature was
controlled using a temperature probe placed in an empty
vial. Each vial contained 1.3 mL of freshly prepared aCSF,
saturated, and continuously bubbled with 100% oxygen (25
mL/min per vial). After a 30-minute period of stabilization,
aCSF was renewed with oxygenated aCSF, and the slices
were then incubated for an additional 1-hour period to al-
low recording basal LDH levels. Whereas sham slices were
incubated for an additional 20-minute period in the same
conditions, those corresponding to the ischemic groups
were incubated in a glucose-free solution, saturated, and
continuously bubbled with 100% nitrogen (OGD slices).
After this 20-minute period of OGD, the medium was
replaced in all groups with freshly prepared aCSF, and the
slices were treated and continuously bubbled for a 3-hour
period with either normobaric medical air composed of
75% nitrogen and 25% oxygen (control slices) or with nor-
mobaric 100% oxygen (NBO-treated slices). HBO treated
slices were pressurized at a compression rate of 1 ATA/min
with 100% oxygen up to 2.5 ATA. After a 3-hour period at
2.5 ATA, during which increased oxygen level was provided
to the slices through oxygen diffusion and equilibrium be-
tween “air” and saline, decompression was performed at a
slow decompression rate of 0.1 ATA/min shown to induce
no cell injury (Baskerville et al., 2011; Blatteau et al., 2014).
To avoid multiple compression and decompression in the
HBO experiment, aCSF was not replaced and served as a
pool throughout the 3-hour period of treatment with medi-
cal air, NBO or HBO.
OGD-induced neuronal injury was quantied by the
amount of LDH released in the incubation solution samples.
LDH activity was measured using a spectrophotometer at
340 nm in 50 µL of incubation medium by following the
oxidation (decrease in absorbance) of 100 mL of β nico-
tinamide adenine dinucleotide (NADH) (3 mg in 10 mL
of PBS) in 20 µL of sodium pyruvate (6.25 mg in 10 mL
of PBS) using a microplate reader. OGD-induced LDH
efuxes were expressed as the amount of LDH measured
in the incubation solution and as a percentage of pre-OGD
control value. The number of animals and the number of
slices was respectively n = 4-6 and n = 24-32 per condition.
Statistical analysis
Data are expressed as the mean ± standard error of the mean,
and were analyzed using parametric statistics. Between-
group comparisons on total LDH release were performed
using parametric ANOVA. Following a significant F
value, post-hoc analysis was performed using the Tukey’s
honestly signicant difference method for samples of dif-
ferent size (online software: http://statistica.mooo.com/
OneWay_Anova_with_TukeyHSD). Level of signicance
was set up at P < 0.05.
results
Brain slices were exposed to experimental ischemia in the
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with the same device in our laboratory in in vitro models
of thrombolysis (Abraini, 2013; Chazalviel et al., 2016b).
In addition, from a clinical perspective, this point is not
of major critical importance since such a procedure with
10% oxygen is not current therapeutic practice. Finally, the
cerebral slices’ vital activity was not measured. However,
we have previously shown using pharmacological and
neurochemical approaches measuring carrier-mediated-
and KCl-evoked dopamine release that acute brain slices
exposed to similar control and OGD conditions that those
used in the present report remained functional (David et
al., 2008).
That said, both NBO and HBO have been shown to re-
duce infarct size (Veltkamp et al., 2000, 2005; Singhal et
al., 2002; Henninger et al., 2007; Eschenfelder et al., 2008;
Yang et al., 2010; David et al., 2012; Xu et al., 2016), to
promote endogenous tPA-induced thrombolysis (David et
al., 2012; Chazalviel et al., 2016b), to improve ischemia-
induced decrease in tissue oxygenation (Liu et al., 2004,
2006; Shin et al., 2007; Sun et al., 2008; Baskerville et
al., 2011), and to induce neurogenesis (Lee et al., 2013;
Wagenfuhr et al., 2016), thereby questioning the interest
of HBO compared to NBO in stroke. In the present study,
to investigate this question, we compare the oxygen diffu-
sion effects of NBO and HBO in acute brain slices exposed
to OGD, an ex vivo model of brain ischemia that allows
investigating the acute effects of NBO and HBO on tissue
(parenchyma) oxygenation independently of their facilitat-
ing action on cerebral blood ow and thrombolysis at the
vascular level and of their long term effects on neurogenesis.
We found that HBO, but not NBO, reduced OGD-induced
cell injury, thereby indicating that to be fully efcient
oxygen diffusion-induced tissue oxygenation of the brain
parenchyma requires oxygen partial pressure higher than 1
ATA. Consistent with our ndings of a lack of signicant
effect of NBO through passive-mediated oxygen transport is
the fact that both NBO and HBO, administered 1 hour before
thrombolysis, have been shown to reduce infarct size in rats
subjected to transient thromboembolic brain ischemia, but
that only HBO but not NBO has been further demonstrated
to decrease infarct volume in permanent thromboembolic
middle cerebral artery occlusion-induced ischemia (Sun et
al., 2010). The apparent discrepancy between our nding
of a lack of effect of NBO at reducing cell injury in brain
slices exposed to OGD and the benecial effect of NBO
at reducing infarct size in rats subjected to transient brain
ischemia (Sun et al., 2010) could be due to the fact that this
latter study was performed in vivo, conditions in which mi-
crovasculature could play a major role in oxygen transport
(Chazalviel et al., 2016a). Indeed, interestingly, as a possible
mechanism for the facilitating action of NBO on cerebral
form of OGD to determine the effect of NBO and HBO on
OGD-induced neuronal injury as assessed by the release of
LDH. Figure 1 illustrates the effects of a 3-hour treatment
with of NBO (pO2 = 1 ATA) or HBO (pO2 = 2.5 ATA) on
LDH release induced by OGD. Exposure to OGD led to an
increase in LDH release compared with sham slices (Tukey
HSD value = 0.0010053; P < 0.01). Post-insult treatment
with NBO showed no signicant effect on OGD-induced
LDH release compared to control slices treated with air
(Tukey HSD value = 0.8975409). In contrast, post-insult
treatment with HBO led to a signicant reduction in LDH
release compared to both control slices and NBO-treated
slices (Tukey HSD value = 0.0010053; P < 0.01).
dIscussIon
Before discussing our ndings, possible limitations in
study design should be examined. First, aCSF was used as
a pool for brain slices and was not replaced throughout the
experiment, conditions that could have lead to LDH decay
or accumulation. However, we used this protocol to avoid
multiple compression and decompression in the HBO ex-
periment, conditions that would have led to LDH release
induced by decompression stress (Blatteau et al., 2014,
2015) and therefore to experimental bias compared to the
control and NBO groups. Second, no hyperbaric experiment
was performed with 10% oxygen to investigate the possible
effect of pressure per se. However, support for an effect of
HBO rather than pressure per se is previous data performed
Figure 1: Exposure to oxygen and glucose deprivation (OGD) results in
an increase of lactate dehydrogenase (LDH) release compared to sham
(SHM) slices taken as a 100% value.
Note: Hyperbaric oxygen (HBO), but not normobaric oxygen (NBO), reduces
LDH release in brain slices exposed to OGD compared to control air-treated
slices (AIR). #P < 0.01, vs. sham slices; *P < 0.01, vs. control air-treated slices.
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highlights one of the mechanisms by which HBO, in ad-
dition of other multiple processes, seems to be efcient at
reducing brain damage in acute stroke models.
Author contributions
LC performed the experiments. JEB, NV, JJR, SB, and
JHA designed the experiments, analyzed data, and wrote
the manuscript.
Conflicts of interest
The authors declared no competing interest.
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increases brain damage (Chazalviel et al., 2016b). There-
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