Epilepsy Research (2012) 100, 37—41

journal homepage: www.elsevier.com/locate/epilepsyres

Do hyperbaric oxygen-induced seizures cause brain

damage?
Liran Domachevsky a,∗, Chaim G. Pick b, Yehuda Arieli a, Nitzan Krinsky a,
Amir Abramovich a, Mirit Eynan a

a
Israel Naval Medical Institute, IDF Medical Corps, Haifa, Israel
b
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Received 6 June 2011; received in revised form 4 January 2012; accepted 7 January 2012
Available online 30 January 2012

KEYWORDS Summary It is commonly accepted that hyperbaric oxygen-induced seizures, the most severe
Oxygen; manifestation of central nervous system oxygen toxicity, are harmless. However, this hypothesis
High pressure; has not been investigated in depth. We used apoptotic markers to determine whether cells in
Central nervous the cortex and hippocampus were damaged by hyperbaric oxygen-induced seizures in mice.
system; Experimental animals were exposed to a pressure of 6 atmospheres absolute breathing oxygen,
Toxicity; and were randomly assigned to two groups sacrificed 1 h after the appearance of seizures or
Convulsions; 7 days later. Control groups were not exposed to hyperbaric oxygen. Caspase 9, caspase 3,
Apoptosis and cytochrome c were used as apoptotic markers. These were measured in the cortex and
the hippocampus, and compared between the groups. Levels of caspase 3, cytochrome c, and
caspase 9 in the hippocampus were significantly higher in the hyperbaric oxygenexposed groups
compared with the control groups 1 week after seizures (p < 0.01).
The levels of two fragments of caspase 9 in the cortex were higher in the control group
compared with the hyperbaric oxygen-exposed group 1 h after seizures (p < 0.01). Hyperbaric
oxygen-induced seizures activate apoptosis in the mouse hippocampus. The reason for the
changes in the cortex is not understood. Further investigation is necessary to elucidate the
mechanism underlying these findings and their significance.
© 2012 Elsevier B.V. All rights reserved.

Introduction

The central nervous system (CNS) is a major site of oxygen

∗ Corresponding author at: Israel Naval Medical Institute, P.O. Box
8040, 31080, Haifa, Israel. Tel.: +972 4 8693040;
fax: +972 4 8693240.
E-mail address: liranura@gmail.com (L. Domachevsky).
toxicity when breathing oxygen at high pressure. Prolonged
exposure to 100% oxygen at a pressure of more than 3 atmo-
spheres absolute (ATA) will result in CNS oxygen toxicity
(Lambertsen, 1965). Also referred to as hyperbaric oxy-
gen (HBO)-induced seizures, these are the most disturbing
sign of CNS oxygen toxicity, although they are reversible,

0920-1211/$ — see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.eplepsyres.2012.01.004
38
disappearing on reduction of the partial pressure of the
inspired oxygen. They are believed to cause no residual neu-
rologic damage (Lambertsen, 1965), a belief that has led
most researchers to focus on the mechanisms of CNS oxygen
toxicity and to abandon the question of its long-term effect
on the brain.
One way of evaluating whether an insult such as HBO-
induced seizures can cause neurologic damage may be to
determine whether apoptosis has occurred. Apoptosis is
recognized as a mode of ‘‘programmed cell death’’. The pro-
cess is energy dependent, and has unique biochemical and
morphologic features such as plasma and nuclear membrane
blebbing, cell shrinkage, and the activation of proteases and
endonucleases (Kerr et al., 1972; Häcker, 2000). In princi-
ple, there are two well established apoptotic pathways, the
extrinsic and the intrinsic.
The extrinsic pathway is initiated by binding of a lig-
and with a transmembrane death receptor (Ashkenazi and
Dixit, 1998). Upon ligand binding, cytoplasmic adaptor pro-
teins are recruited along with procaspase 8 and form a
death-inducing signaling complex. This complex activates
procaspase 8, which propagates into the executive pathway
(Kischkel et al., 1995).
The intrinsic pathway is mediated by intracellular signals
that lead to increased permeability of the outer mitochon-
drial membrane, resulting in the massive release of proteins
into the cytosol from the mitochondrial intermembrane
space (Saelens et al., 2004). Cytochrome c, which is one
of the proteins released, binds with and activates Apaf-
1. These recruit procaspase 9 to form an ‘‘apoptosome’’
(Chinnaiyan, 1999). The apoptosome is responsible for the
activation of procaspase 9, which propagates into the exec-
utive pathway.
When the intrinsic and extrinsic pathways converge at
the executive pathway, caspase 3, caspase 6, and caspase 7
function as effector or ‘‘executioner’’ caspases, resulting in
the activation of endonucleases and proteases (Slee et al.,
2001). This results in cleavage of nuclear and cytoplasmic
substrates, some of which control DNA repair and nuclear
integrity (Datta et al., 1997; Enari et al., 1998; Sakahira
et al., 1998). The final step of apoptosis is phagocytosis of
the apoptotic cells.
In the present study, we examined whether HBO-induced
seizures initiate the process of apoptosis in an animal model
at two time intervals: immediately after seizures and one
week later. Apoptosis was evaluated by measuring levels
of caspase 3, caspase 9, and cytochrome c in the cortex
and the hippocampus. This model, in which the outcome is
generalized convulsions, might perhaps serve to investigate
epilepsy, which manifests as repeated generalized seizures.
Materials and methods
Animals
The experimental protocol was approved by the ethics committee of
the Sackler School of Medicine, in compliance with the guidelines for
animal experimentation of the National Institutes of Health (DHEW
publication 85-23, revised 1995). The minimum possible number of
animals was used, and every effort was made to minimize their
suffering. Male ICR mice weighing 25—30 g were kept five per cage
L. Domachevsky et al.
in a constant 12-h light/dark cycle at room temperature (23 ◦ C).
Food (Purina rodent chow) and water were available ad libitum.
Study groups
Sixteen mice were used in the study. Eight experimental mice were
exposed to a pressure of 6ATA breathing oxygen to induce seizures.
They were randomly assigned to two groups sacrificed 1 h after the
appearance of HBO-induced seizures (compressed: immediate), or 7
days later (compressed: 1-week), four animals in each. The remain-
ing eight mice, which were not exposed to HBO, served as control
groups (control: immediate and control: 1-week).
After the animals were sacrificed, the entire brain was quickly
removed and the hippocampus was separated from the cortex. Both
were kept at a temperature of −80 ◦ C for later biochemical analysis.
Hyperbaric exposure
Mice were placed in a double-walled metal exposure cage measuring
13 cm × 25 cm × 25 cm. One side of the cage is made of Perspex,
enabling continuous observation of the animal. The mouse was able
to move about freely inside the cage. The exposure cage was closed
and placed inside a 150-l hyperbaric chamber (Roberto Galeazzi, La
Spezia, Italy), which was then sealed. At this stage, the pressure was
raised to 6 ATA at a rate of 1 ATA per minute with oxygen flowing
through the experimental cage.
The mouse has no problem with pressure equalization of the
middle ear, and any changes in its behavior can be seen through
the Perspex wall. During the exposure to high pressure oxygen,
the mouse was observed until the appearance of the first clinical
seizures. The exposure was terminated immediately on appearance
of the first convulsions, as determined by the observer. The pressure
was reduced at 180 kPa/min, and the mouse was removed from the
chamber and sacrificed. The hippocampus and cortex were removed
on ice as soon as possible after sacrifice (2 ± 1 min), washed in 10 mM
phosphate buffer saline (PBS, pH 7.4), placed in liquid nitrogen, and
stored at −80 ◦ C for biochemical analysis.
Biochemical assays: Western blot analysis of cytochrome
c, caspase 3, and caspase 9
The hippocampus and the cortex from the four animals in each group
were thawed and homogenized with SDS buffer (20% glycerol and
6% SDS in 0.12 M Tris buffer, pH 6.8), centrifuged at 13,000 × g for
20 min at 4 ◦ C, and boiled for 10 min. The protein concentration of
the brain specimens was quantified by the Bradford method (Bio-
Rad Laboratories, Richmond, CA, U.S.A.). Fifty micrograms total
proteins were loaded in each gel well. After blotting, the mem-
branes were incubated for 1 h in blocking solution containing 5%
skimmed milk in tris-buffered saline Tween-20 (TBST). The mem-
branes were then washed briefly in TBST and incubated overnight
at 4 ◦ C with the polyclonal cytochrome c, caspase 3, and caspase
9 antibody diluted 1:1000 (Cell Signaling Technology, Beverly, MA,
U.S.A.). Caspase 9 antibody detects levels of full length mouse cas-
pase 9 (49 kDa) and two fragments of mouse caspase 9 (37 kDa and
39 kDa). After 3 repeated washings in TBST, the membranes were
incubated at room temperature for 1 h with a secondary antibody
(horseradish peroxidaseconjugated goat anti-rabbit IgG) in a 1:2000
dilution (Cell Signaling Technology, Beverly, MA, U.S.A.). After three
repeated washings in TBST, the membranes were then developed
to enhance detection by chemiluminescence (Pierce Biotechnol-
ogy, Inc., Rockford, IL, U.S.A.) and exposed to X-ray film. Levels of
cytochrome c, caspase 3, and caspase 9 were measured by scanning
the films, and were evaluated with densitometry using Tina 2.0 soft-
ware (Raytest, Straubenhardt, Germany). The value of each band
was normalized to the level of the positive control for cytochrome
Do hyperbaric oxygen-induced seizures cause brain damage? 39

Table 1 Caspase 9 levels in the cortex in the immediate

groups (sacrificed 1 h after the appearance of HBO-induced
seizures).

Caspase 9 fragment Mean ± SD p value

37 kDa
Compressed (n = 4) 0.38 ± 0.16
Control (n = 4) 2.26 ± 0.31 <0.01
39 kDa
Compressed (n = 4) 0.48 ± 0.23
Control (n = 4) 1.41 ± 0.15 <0.01

c, caspase 3, and caspase 9 loaded in each gel well (15 ␮g). Each
Figure 1 Levels of caspase 3 in the hippocampus in the con-
band density was measured five separate times and averaged.
trol group (n = 4) and compressed group (n = 4) 1 week after
Statistical analysis seizures. Results are presented as mean ± SD. *p < 0.01. P.C.,
positive control.
Statistical significance was evaluated by the Student t test. All data
are expressed as mean ± SD. The level of significance was p < 0.01.

Results

Caspase 3, caspase 9, and cytochrome c

immunoblotting

Cortex—–immediate evaluation
There were no significant differences in the levels of caspase
3 and cytochrome c between the compressed and control
groups. However, caspase 9 levels were higher in the control
group compared with the compressed group in the 37 kDa
and 39 kDa fragments (p < 0.01; Table 1), but not in the full
length 49 kDa segment.

Cortex—–evaluation after 1 week

No significant differences were found between the com- Figure 2 Levels of caspase 9 (39 kDa) in the hippocampus in
pressed and control groups. the control group (n = 4) and compressed group (n = 4) 1 week
after seizures. Results are presented as mean ± SD. *p < 0.01.
Hippocampus—–immediate evaluation P.C., positive control.
No significant differences were found between the com-
pressed and control groups.

Hippocampus—–evaluation after 1 week

Levels of caspase 3, cytochrome c, and caspase 9 (the
39 kDa fragment) in the compressed groups were signifi-
cantly higher compared with the control groups (p < 0.01;
Figs. 1—3).

Discussion

CNS oxygen toxicity was first described by Paul Bert in 1878

(Bert, 1978), since when it has been extensively investi-
gated. Lambertsen et al. (1987) established a dose-response
curve that relates the appearance of CNS oxygen toxicity
to the partial pressure of the inspired oxygen. Prolonged
exposure to 100% oxygen at a pressure of more than 3
ATA will result in CNS oxygen toxicity (Lambertsen, 1965). Figure 3 Levels of cytochrome c in the hippocampus in the
The greater the partial pressure of the inspired oxygen, control group (n = 4) and compressed group (n = 4) 1 week after
the earlier the symptoms and signs will appear. The man- seizures. Results are presented as mean ± SD. *p < 0.01. P.C.,
ifestations of CNS oxygen toxicity include a variety of positive control.
40
symptoms and signs (Butler and Thalmann, 1986; Donald,
1992). Non-specific symptoms include nausea, dizziness,
abnormal sensations, headache, disorientation, lighthead-
edness, and a feeling of apprehension. Specific symptoms
include blurred vision, tunnel vision, and tinnitus. Signs of
CNS oxygen toxicity include respiratory disturbances, eye
twitching, twitching of the lips, mouth and forehead, and
seizures. There is no consistency in the order of appear-
ance of symptoms and signs prior to the development of
seizures. The two main populations that may be affected by
this kind of seizure are professional divers, who use dive pro-
files in which an elevated partial pressure of oxygen exposes
them to the risk of HBO-induced seizures, or patients being
treated in the hyperbaric chamber for diseases that require
the delivery of high pressure oxygen to tissues. In both cases
oxygen is the trigger for seizures, and the supply of pure or
elevated oxygen is interrupted immediately seizures appear.
Seizures are the most disturbing sign of CNS oxygen toxicity,
although they are reversible, disappearing on reduction of
the oxygen partial pressure. The mechanism of CNS oxygen
toxicity is yet to be fully understood. However, the increased
production of reactive oxygen and nitrogen species seems to
play a pivotal role by oxidizing lipids and proteins (Fridovich,
1998).
The hippocampus is influenced by CNS oxygen toxicity,
and may be responsible for the initiation of seizures. Chavko
and Harabin (1996) have shown that lipid and protein perox-
idation occurs in the hippocampus of rats exposed to oxygen
at 5 ATA.
A study conducted by Gutsaeva et al. (2006) revealed
mitochondrial DNA damage in the hippocampus of rats
exposed to the same pressure. In another study (Wang
et al., 1998), hyperbaric oxygen exposure in rats led to the
accumulation of intrasynaptosomal free calcium in the hip-
pocampus. Increased calcium levels stimulate the synthesis
of nitric oxide, which is also involved in the pathogenesis of
HBO-induced seizures.
The question of whether epileptic seizures cause perma-
nent brain damage is one that has been investigated over
the years. The leading theory in the past was that only
status epilepticus or prolonged seizures result in damage
to the brain. This was supported by a number of studies
which demonstrated neuronal death both in the hippocam-
pus itself and in extra-hippocampal regions. Tissue damage
was caused via apoptotic or necrotic pathways, depending
mainly on the time course of injury and the specific cell
population (Kubová et al., 2002; Chen et al., 2010).
However, over the last three decades there has been
a growing body of evidence suggesting that even brief
seizures may damage the brain. Cavazos and Sutula (1990)
demonstrated that brief sporadic seizures caused by kindling
stimulation of limbic structures can induce neuronal loss in
the hippocampal formation. Zhang et al. (1998) reported
that even a single seizure evoked by kindling induced neu-
ronal apoptosis in the hippocampus. A study conducted by
Kotloski et al. (2002) showed that repeated brief seizures
in rats induced subfield specific hippocampal neuronal loss,
resulting in characteristic deficits in spatial memory func-
tion. The pattern of neuronal loss resembled that seen in
hippocampal sclerosis in cases of temporal lobe epilepsy, in
which CA3c, CA1a, CA1c, and the hilus of the dentate gyrus
are involved. It therefore seems clear that even a single
L. Domachevsky et al.
seizure may cause some damage to brain tissue, mainly in
the hippocampus which is the most vulnerable region.
In the present study, we wished to elucidate whether
HBO-induced seizures behave in a similar fashion, and
whether breathing increased partial pressures of oxygen
may thus cause neurologic damage.
The commonly held belief that one or more brief seizures
have no adverse effect on the brain has for many years been
used to support the contention that HBO-induced seizures
cause no harm. Indeed, in spite of its toxic effect at higher
pressures, oxygen was considered to play a protective role
in seizure outcome.
Of the small number of studies that have discussed
this question, one made the observation that schizophrenic
patients treated with hyperbaric oxygen as a mode of ther-
apy did not exhibit any clinical deterioration (Lambertsen,
1965). Another study conducted by Donald (1947) stated
that no changes in neurologic integrity, intellectual abil-
ity or personality were noted in a three-year follow-up of
experimental divers. However, there was no description of
the methods used to evaluate patients. We used an animal
model to examine whether HBO-induced seizures result in
damage to brain tissue. Our criterion was apoptosis, which
can appear after stressful events and represents active, pro-
grammed cascades by which irreversibly damaged cells are
destroyed and removed.
The time interval for the appearance of apoptotic mark-
ers is variable, and is influenced by a large number of
factors (DiPietrantonio et al., 1999; Carambula et al., 2002).
We therefore measured the levels of apoptotic markers at
two points in time to increase the probability of detec-
tion. We examined the hippocampus, because it is known
to be involved in both conventional seizures and CNS oxy-
gen toxicity. We also evaluated the cortex to see whether
an extra-hippocampal region may be affected. Our results
have shown that all three caspase levels were increased in
the hippocampus 1 week after seizures, implying that apo-
ptosis occurred in the hippocampus. The elevated levels
of caspase 9 and cytochrome c indicate the role of mito-
chondria in that process. It must be emphasized that the
absence of markers at two separate points in time does not
rule out apoptosis. The kinetics of apoptosis in the cortex
might be quite different from that in the hippocampus, and
only strict follow-up can determine whether apoptosis has
occurred or not. The finding of decreased apoptotic markers
in the cortex immediately after convulsions warrants further
investigation, with a repeat examination as the first step.
The mechanism by which HBO-induced seizures cause
apoptosis remains to be determined. One possibility is via
reactive oxygen species, which are known to induce apo-
ptosis (Simon et al., 2000) and are elevated in HBO-induced
seizures (Jamieson, 1989). Of the two components of HBO,
high atmospheric pressure and oxygen breathing, either or
both might be responsible for the initiation of apoptosis,
although it may also be attributable to the same factors
involved in other types of seizure. It was not the purpose of
the present study to determine which of the aforementioned
parameters plays a more important role in seizure pathogen-
esis, but rather to determine whether HBO-induced seizures
as such cause postictal CNS changes.
In conclusion, HBO-induced seizures activate apoptosis in
the mouse hippocampus. Further investigation is necessary
Do hyperbaric oxygen-induced seizures cause brain damage?
to elucidate the mechanism underlying this finding and its
significance. The findings of the present study must also be
interpreted very carefully due to a number of unresolved
issues. We do not know exactly which cells are affected,
glial or neuronal. We do not know whether the damage
is reversible, or whether it is accompanied by structural
change or neurologic impairment. Further investigation will
be required to correlate our findings with structural changes
in the brain, and with comprehensive neurologic and cogni-
tive assessment.
Acknowledgements
This study was supported by research grant no. 4440162662
from the Israel Defense Forces Medical Corps. The opin-
ions and assertions contained herein are the private ones
of the authors, and are not to be construed as official or as
reflecting the views of the Israel Naval Medical Institute.
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