Dual effect of HBO on cerebral infarction in MCAO

rats
A. E. Badr, W. Yin, G. Mychaskiw and J. H. Zhang
Am J Physiol Regul Integr Comp Physiol 280:R766-R770, 2001.
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Am J Physiol Regulatory Integrative Comp Physiol

280: R766R770, 2001.

Dual effect of HBO on cerebral infarction in MCAO rats

A. E. BADR,1 W. YIN,1 G. MYCHASKIW,2 AND J. H. ZHANG1
The Departments of 1Neurosurgery and 2Anesthesiology, the University of
Mississippi Medical Center, Jackson, Mississippi 392164505
Received 5 May 2000; accepted in final form 1 November 2000

untreated ischemic animals. HBO (applied 2.5 and

3.5 h after occlusion) reduced ischemic neuronal injury,
brain edema, and infarct area in a rat middle cerebral
artery occlusion (MCAO) model (4 h without reperfusion) (9). In contrast, Shiokawa et al. (17) reported that
HBO treatment did not show any therapeutic benefit
when it was applied 1 h after cerebral ischemia in a
permanent incomplete ischemia model in spontaneously hypertensive rats. Roos et al. (16) claimed that
HBO therapy (2 ATA, 30 min) yielded no benefit in a
rat model of MCAO and reperfusion.
We undertook this study to determine 1) whether
HBO therapy yields a beneficial effect in an animal
model of cerebral infarction induced through MCAO
and reperfusion and 2) the optimal therapeutic window
for starting HBO treatment for MCAO and reperfusion. The investigators in this study used a rat model of
MCAO and reperfusion and evaluated the data resulting from HBO therapy (3 ATA HBO for 1 h) in the
experimentally infarcted cerebral area.
METHODS

1965, VARIOUS RESEARCHERS have investigated hyperbaric oxygen (HBO) to attenuate cerebral ischemia
in animal models and in humans. Takahashi et al. (18)
found that HBO therapy [in a canine model of complete
global cerebral ischemia; 15 min HBO treatment at 3
atm absolute (ATA) for 1 h during the early postischemic period and 3 h after ischemia] accelerated neurologic recovery and improved the survival rate of dogs.
Shiokawa et al. (17) reported that HBO therapy administered 3 h after inducing permanent incomplete brain
ischemia (by ligating the common carotid artery) significantly increased the survival time of spontaneously
hypertensive rats compared with the survival time of

The Animal and Ethics Review Committee at the University of Mississippi Medical Center evaluated and approved
the protocol used in this study.
Experimental groups. Forty-eight rats, each weighing 325
375 g, were divided into six treatment groups each consisting
of eight subjects. The operator in this study performed the
following procedures for each respective treatment group: 1)
sham operation, exposure of the left common carotid artery
and left external carotid artery followed by neither MCAO,
reperfusion, nor HBO treatment; 2) MCAO for 2 h followed by
reperfusion for 24 h; 3) MCAO for 2 h followed by reperfusion
for 24 h and then HBO treatment applied at 3 h after
reperfusion; 4) MCAO for 2 h followed by reperfusion for 24 h
and then HBO treatment applied at 6 h after reperfusion; 5)
MCAO for 2 h followed by reperfusion for 24 h and then HBO
treatment applied at 12 h after reperfusion; 6) MCAO for 2 h
followed by reperfusion for 24 h and then HBO treatment
applied at 23 h after reperfusion.
MCAO model and HBO treatment. Forty-eight male
Sprague-Dawley rats (assigned by study protocol to MCAO)
underwent the procedure described by Longa et al. (10a).
Accordingly, the operator anesthetized the rats with ketamine and xylazine and exposed the left common carotid
artery. Then, the external carotid artery and its branches
were isolated and coagulated. A 30 nylon suture with a

Address for reprint requests and other correspondence: J. H.

Zhang, Dept. of Neurosurgery, Univ. of Mississippi Medical Center,
2500 North State St., Jackson, MS 392164505 (E-mail: jzhang
@neurosurgery.umsmed.edu).

The costs of publication of this article were defrayed in part by the

payment of page charges. The article must therefore be hereby
marked advertisement in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.

cerebral ischemia; hyperbaric oxygen; infarct ratio

SINCE

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0363-6119/01 $5.00 Copyright 2001 the American Physiological Society

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Badr, A. E., W. Yin, G. Mychaskiw, and J. H. Zhang.

Dual effect of HBO on cerebral infarction in MCAO rats. Am
J Physiol Regulatory Integrative Comp Physiol 280:
R766R770, 2001. Various reports in the literature have
shown that hyperbaric oxygen (HBO) reduces cerebral infarction both in animals and humans. After the initial ischemic
insult, however, initiating HBO treatment at different intervals has yielded conflicting results. The present study was
undertaken to determine the optimal therapeutic window in
which to start HBO treatment for cerebral infarction after
transient focal ischemia. In this study, the operator occluded
the middle cerebral artery (MCA) of anesthetized rats by
introducing a blunted nylon filament into the proximal MCA
from the dissected external carotid artery. When the operator
removed the filament after 2 h, focal ischemia and reperfusion occurred. The operator then placed the rat in the HBO
chamber and administered 3 atm absolute HBO for 1 h
according to the protocol. The rat was killed 24 h after
reperfusion, and the percentage of infarction (infarct ratio)
was calculated by dividing the infarction area by the total
area of the ipsilateral hemisphere. The results showed that
the percentage of infarcted area decreased significantly (P
0.05) both in the 3- (7.59%) and 6-h (5.35%) HBO-treatment
groups compared with the control (no treatment) group
(11.34%). However, the percentage of infarcted area increased significantly (P 0.01 and P 0.05, respectively)
both in the 12- (23%) and 23-h (20%) treatment groups. The
results of this study suggest that applying HBO within 6 h of
ischemia-reperfusion injury could benefit the patient but
that applying HBO 12 h or more after injury could harm the
patient.

THERAPEUTIC WINDOW OF HBO

RESULTS

The study operator performed a pilot study to determine the MCAO model used to conduct this study. The
surgical method and the size of the suture and its
blunted tips were tested in different animals until a
consistent neurological deficit (evaluated 24 h after
reperfusion) was obtained. The rats used for this pilot
study were not included among the 48 rats described

by the above protocol. No neurological deficit was observed in the sham-operated rats.
Figure 1 presents the typical results of the effect of
MCA occlusion on infarction size from each of the
groups: the sham-operated (no MCAO), MCAO-no
HBO treatment, and HBO at 3, 6, 12, and 23 h after
reperfusion. The coronal sections were obtained by
cutting the brain at a distance of 2, 4, 6, 8, and 10 mm
from the rostral extremity of the frontal cortex. The
white-colored areas represent the infarction regions in
these sections.
Figure 2 shows the results of the neurological deficit
score in each group. Both the 3- and 6-h treatment
groups exhibited a significantly improved neurological
function (lower score) compared with the no-treatment
group. In contrast, the neurological deficit was increased after HBO treatment at 12 and 23 h after
reperfusion.
Figure 3 shows the percentage of infarction area in
rats that underwent MCAO and reperfusion and
MCAO/reperfusion HBO therapy at 3, 6, 12, and
23 h. No cerebral infarction was observed in the sham
group. In the MCAO and reperfusion group (untreated
group), severe cerebral infarction was observed in all
rats and the infarct ratio was 11.34%. The infarct ratio
was significantly decreased in rats treated with HBO
at 3 (7.59%, P 0.05 vs. untreated group) and 6 h
(5.35%, P 0.05 vs. untreated group) after reperfusion. However, the infarct ratio was significantly increased in rats treated with HBO at 12 (23%, P 0.01
vs. untreated group) and 23 h after reperfusion (20%,
P 0.05 vs. untreated group).
DISCUSSION

The primary finding of this study is that the effect of

HBO on the cerebral infarction is dual in an MCAO
and reperfusion rat model. This finding suggests the
existence of an optimal therapeutic window in which to
initiate HBO therapy in this rat model of cerebral
ischemia: early therapeutic intervention using HBO
within 6 h reduces infarction. Applying HBO therapy
late (after 12 h, for example) aggravates cerebral infarction; thus caution needs to be a consideration of
HBO therapy in such cases.
Because current stroke treatment is unsatisfactory,
many physicians seek novel treatment modalities. Because local anoxia and energy failures occur at the
cellular level in ischemia, increasing the oxygen delivery to the tissues might prolong functional activity
during severe ischemia (14). Animal studies and clinical experiences over the last two decades have produced a set of applications for which HBO therapy
might appear beneficial (1). However, most of these
studies focused on forebrain ischemic or global ischemic models that might have impeded the investigation
of therapeutic HBO applications. In designing the
model for their study, these investigators chose to
observe and evaluate the parameters of survival time
and survival rate to determine the therapeutic effect of
HBO (10). Moreover, neuronal injury in the forebrain

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blunted tip was inserted into the internal carotid artery

through the external carotid artery stump and advanced to
the anterior cerebral artery to occlude the middle cerebral
artery (MCA). After occluding the MCA for 2 h, the operator
carefully removed the suture to restore blood flow and then
sutured the skin and allowed the rat to wake up. To complete
the surgery, the operator applied 0.25% micaine locally to the
wound and allowed the rat to recover.
After the treated rats were reperfused, they were placed in
an HBO chamber (3 ATA for 1 h) at 3, 6, 12, and 23 h
according to the protocol schedule for their group. When the
HBO chamber had attained the desired pressure, the flow of
oxygen was reduced to maintain constant pressure while
allowing air exchange in and out of the chamber. This constant exchange was aided by a tray of calcium carbonate
crystals placed inside the chamber to reduce CO2 accumulation in the chamber environment; thus the oxygen level was
maintained at or 98%, and the CO2 level was maintained at
or 0.03%. After HBO therapy, the operator returned the rat
to its cage until death. The operator used a rectal probe to
monitor the rats body temperature; during ischemia and
postoperative recovery, body temperature was maintained at
37 0.5C. Death consisted of decapitation 24 h after the
initial induced ischemia. After the rats death, the operator
removed its brain.
Observing and evaluating the treated rats for neurological
deficit. An experimenter, unaware of the treatments, tested
the animals for neurological deficits after 24 h of reperfusion.
Menzies et al. (11) developed the method that tests both
motor and behavioral deficits on a cumulative scale from 0 to
4. This examination was used to evaluate ischemic injury: 0,
no visible neurological deficits; 1, forelimb flexion; 2, contralateral forelimb grips weakly (the operator places the
animal on an absorbent pad and gently pulls the tail); 3,
circling to the paretic side only when pulled by the tail (the
animal was allowed to move about freely on the absorbent
pad); and 4, spontaneous circling.
Evaluation of infarcted area. After death had occurred, the
coronal sections of the brain (2 mm thick) were cut and
immersed in a 2% solution of 2,3,7-triphenyltetrazolium chloride. The stained slices were then fixed by immersion in
phosphate-buffered 4% paraformaldehyde. The infarcted
area and hemispheric area of each section were traced and
measured using an image-analysis system (a Macintosh computer accessing the public domain National Institutes of
Health Image program, written by Wayne Rasband and
available from the internet). The percentage of infarction
(infarct ratio) was calculated by dividing the infarcted area
by the total area of the ipsilateral hemisphere (19).
Statistical analysis. Data were represented as the
means SD. Statistical differences between the control (no
HBO treatment) and the other groups were compared by
using the one-way ANOVA and then Scheffes F test if a
significant difference was found; a P value 0.05 was considered statistically significant.

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THERAPEUTIC WINDOW OF HBO

after brief global ischemia is a selective phenomenon

that sometimes fully demonstrates only after observation for several days (19). By contrast, neuronal death,
which follows an intense focal ischemic challenge in an
area at risk for infarction, is evident within 1224 h
(19). The ischemic events characterizing neuronal
death mimic more closely the clinical condition of ischemic stroke (19). Considering these conditions, we
used an experimental MCAO and reperfusion model
that represents a likely clinical problem: incomplete,
focal ischemia with the potential for reperfusion. This
model also mimics clinical disorders, such as largevessel thrombosis, that lead to infarction, which is
surrounded by ischemic penumbra. Theoretically, this
model is an ideal candidate for therapeutic HBO (8).
Mainly, two patterns of cerebral damage characterize focal ischemia: focal damage and penumbral damage. Complete flow cessation causes the greatest damage at the focus. The penumbral tissues surrounding
an ischemic focus sustain less severe damage because
the collateral vessels supplying the penumbral area
yield a residual perfusion. Oxygenation is the most

critical function of blood flow; suddenly reduced oxygenation is an inevitable consequence of severe ischemia. If therapeutic intervention does not occur in a
timely manner, penumbral zones could eventually lose
their ability to maintain ionic homeostasis, thereby
become subsumed into the focal area, and thus increasing the total ischemic brain damage. Through the administration of pharmacological agents, many investigators aim therapeutic stroke research at preventing
the penumbral recruitment into the ischemic focus (6).
Pharmacological intervention might either improve
blood flow (i.e., oxygen supply) or protect against neuronal death. HBO treatment is considered for cerebral
ischemia, because it might salvage the still viable,
though nonfunctioning, tissues surrounding the infarcted area (14). Mink and Dutka. (12) reported that
HBO can improve tissue oxygen delivery (especially to
areas of diminished blood flow), can enhance neuronal
viability, and can reduce brain edema. By raising the
tissue PO2, HBO can trigger a mechanism controlling
cellular and vascular repair. HBO therapy applied
after radiation injury has demonstrated increased tis-

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Fig. 1. Representative photographs of coronal sections of rat brains. From left to right are the sham-operated [no
middle cerebral artery occlusion (MCAO)], MCAO-no hyperbaric oxygen (HBO) treatment, HBO at 3, 6, 12, and
23 h after reperfusion. The coronal sections were obtained by cutting the brain at a distance of 2, 4, 6, 8, and 10
mm from the top of frontal cortex (as shown from top to bottom). The white areas represent the infarct regions in
these sections.

THERAPEUTIC WINDOW OF HBO

sue oxygen concentration, thereby stimulating angiogenesis and establishing a new capillary blood supply
(5). HBO therapy salvages the still viable, though nonfunctioning, tissue surrounding the infarcted area presumably by allowing time for collateral circulation to
develop. This collateralization forms the basis for the
conclusion that HBO might benefit victims of cerebral
ischemia. Our results showed that HBO therapy, when
applied at an earlier stage after reperfusion (at 3 and
at 6 h after reperfusion), decreased the infarction area
in the rat MCAO and reperfusion model. Our results
agree with the report of Roos et al. (16) who state that
HBO therapy in the rat MCAO model without reper-

fusion is beneficial and agrees with the report of Krakovsky et al. (10) about other animal models of cerebral
ischemia.
Despite the beneficial effects resulting from HBO
therapy applied at an earlier stage (i.e., at 3 and 6 h),
our results also show that HBO therapy applied at a
later stage (i.e., 12 and 23 h) can yield less beneficial
effects in this rat MCAO and reperfusion model. When
applied at a later stage, such as 12 or 23 h after
reperfusion, HBO treatment increased the infarcted
cerebral area. Although the exact mechanism remains
unclear, several possibilities account for the harmful
effect of applying HBO therapy later. Deleterious
mechanisms involved in focal ischemic injury persist
throughout the postischemic period. An unresolved
controversy is whether these mechanisms are 1) triggered during ischemia and persist into the postischemic period, 2) triggered during reflow (reperfusion injury), or 3) both 1 and 2 foregoing. Canevari et al. (2)
reported that in a rat MCAO model (2 h occlusion),
recirculation for 12 h temporarily restored the bioenergetic state and mitochondrial function but that secondary deterioration occurred after 4 h. Gido et al. (7)
stated that delayed cell membrane dysfunction, as reflected in a rise in K, occurs 6 h after reperfusion.
Despite the suggestion that the generation of free radicals during reperfusion might cause secondary damage, it remains to be determined whether HBO applied
at an early stage might prevent the generation of free
radicals or the damage caused by free radicals and
whether HBO application at a later stage enhances the
harmful effect of free radicals.
Our finding differs from the findings of other studies
that demonstrate the failure of HBO to exert a beneficial effect. These differences might be related to the
experimental protocols of other investigations that prescribe prolonged HBO treatment. Long-term use of
HBO results in adverse effects due to the onset of
oxygen toxicity as manifested by induction of lipid
peroxidation and seizures (14). Long-term HBO therapy might conflict with parameters such as the hematocrit level that, in turn, might influence viscosity (14).
A previous study showed that the exposure of rats to 4
ATA of oxygen for 90 min was associated with an
increased level of lipid peroxidation product (malondialdehyde) and altered the enzymatic antioxidation
(glutathione peroxidase) in the brain (15). Chavko et
al. (4) stated that some studies used 100% O2 at 5 ATA,
which induced seizures. The Committee of the Undersea and Hyperbaric Medical Society recommends that
a treatment pressure only from 2.4 to 3.0 ATA should
be used at the lowest effective pressure to avoid O2
convulsions (3).
Perspectives

Fig. 3. The infarct ratio was calculated as the %infarcted tissue per
ispilateral hemisphere. In the no HBO-treated group, the infarct
ratio is 11.34% of the ispilateral hemisphere. HBO treatment at 3
and 6 h reduced markedly the infarct ratio. However, HBO treatment at 12 and 23 h enhanced infarct ratio. Eight rats were used in
each group. * and **, P 0.05 and 0.01, respectively (compared with
no-HBO group, ANOVA).

In conclusion, a dual effect of HBO on the cerebral

infarction in MCAO rats was observed in this study,
indicating that the optimal therapeutic window for
HBO treatment should be restricted to 6 h after
reperfusion. Further study is needed to clarify whether

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Fig. 2. Neurological evaluation was performed according to the

method of Menzies et al. (11). Animals were tested for neurological
deficits by a blinded observer after 24 h of reperfusion. Grades of 0-4
were used. MCAO induced neurological deficits to an average level of
grade 2.13 in rats without HBO treatment. HBO treatment for 1 h at
3 and 6 h after reperfusion reduced markedly the neurological scores.
HBO treatment for 1 h at 12 and 23 h after reperfusion increased
neurological scores. Eight rats were used in each group. *P 0.05
(compared with no-HBO group, ANOVA).

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THERAPEUTIC WINDOW OF HBO

HBO treatment provides long-term functional neuroprotection. Meanwhile, the mechanisms of HBO-induced neuroprotection remain unclear. In diseases
other than cerebral ischemia, molecular events such as
gene expression change occur after HBO treatment.
This new direction warrants further investigation, because studies at the molecular level might not only
assist in clarifying the mechanism of HBO, but also
lead to identifying genes that could be neuroprotective.
In this regard, an understanding of how HBO reduces
brain damage after MCAO and reperfusion could be of
tremendous value, because such understanding might
lead to a more selective and effective therapy.
This work was partially supported by a grant-in-aid from the
American Heart Association and by the Bugher Foundation Award
for the investigation of stroke to J. H. Zhang.
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