280:R766-R770, 2001.Am J Physiol Regul Integr Comp PhysiolA. E. Badr, W. Yin, G. Mychaskiw and J. H. ZhangratsDual effect of HBO on cerebral infarction in MCAO

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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 ofMississippi Medical Center, Jackson, Mississippi 392164505Received 5 May 2000; accepted in final form 1 November 2000

Badr, A. E., W. Yin, G. Mychaskiw, and J. H. Zhang.Dual effect of HBO on cerebral infarction in MCAO rats. AmJ Physiol Regulatory Integrative Comp Physiol 280:R766R770, 2001. Various reports in the literature haveshown that hyperbaric oxygen (HBO) reduces cerebral infarc-tion both in animals and humans. After the initial ischemicinsult, however, initiating HBO treatment at different inter-vals has yielded conflicting results. The present study wasundertaken to determine the optimal therapeutic window inwhich to start HBO treatment for cerebral infarction aftertransient focal ischemia. In this study, the operator occludedthe middle cerebral artery (MCA) of anesthetized rats byintroducing a blunted nylon filament into the proximal MCAfrom the dissected external carotid artery. When the operatorremoved the filament after 2 h, focal ischemia and reperfu-sion occurred. The operator then placed the rat in the HBOchamber and administered 3 atm absolute HBO for 1 haccording to the protocol. The rat was killed 24 h afterreperfusion, and the percentage of infarction (infarct ratio)was calculated by dividing the infarction area by the totalarea of the ipsilateral hemisphere. The results showed thatthe percentage of infarcted area decreased significantly (P ,0.05) both in the 3- (7.59%) and 6-h (5.35%) HBO-treatmentgroups compared with the control (no treatment) group(11.34%). However, the percentage of infarcted area in-creased significantly (P , 0.01 and P , 0.05, respectively)both in the 12- (23%) and 23-h (20%) treatment groups. Theresults of this study suggest that applying HBO within 6 h ofischemia-reperfusion injury could benefit the patient butthat applying HBO 12 h or more after injury could harm thepatient.

cerebral ischemia; hyperbaric oxygen; infarct ratio

SINCE 1965, VARIOUS RESEARCHERS have investigated hy-perbaric oxygen (HBO) to attenuate cerebral ischemiain animal models and in humans. Takahashi et al. (18)found that HBO therapy [in a canine model of completeglobal cerebral ischemia; 15 min HBO treatment at 3atm absolute (ATA) for 1 h during the early postische-mic period and 3 h after ischemia] accelerated neuro-logic recovery and improved the survival rate of dogs.Shiokawa et al. (17) reported that HBO therapy admin-istered 3 h after inducing permanent incomplete brainischemia (by ligating the common carotid artery) sig-nificantly increased the survival time of spontaneouslyhypertensive rats compared with the survival time of

untreated ischemic animals. HBO (applied 2.5 and3.5 h after occlusion) reduced ischemic neuronal injury,brain edema, and infarct area in a rat middle cerebralartery occlusion (MCAO) model (4 h without reperfu-sion) (9). In contrast, Shiokawa et al. (17) reported thatHBO treatment did not show any therapeutic benefitwhen it was applied 1 h after cerebral ischemia in apermanent incomplete ischemia model in spontane-ously hypertensive rats. Roos et al. (16) claimed thatHBO therapy (2 ATA, 30 min) yielded no benefit in arat model of MCAO and reperfusion.

We undertook this study to determine 1) whetherHBO therapy yields a beneficial effect in an animalmodel of cerebral infarction induced through MCAOand reperfusion and 2) the optimal therapeutic windowfor starting HBO treatment for MCAO and reperfu-sion. The investigators in this study used a rat model ofMCAO and reperfusion and evaluated the data result-ing from HBO therapy (3 ATA HBO for 1 h) in theexperimentally infarcted cerebral area.

METHODS

The Animal and Ethics Review Committee at the Univer-sity of Mississippi Medical Center evaluated and approvedthe protocol used in this study.

Experimental groups. Forty-eight rats, each weighing 325375 g, were divided into six treatment groups each consistingof eight subjects. The operator in this study performed thefollowing procedures for each respective treatment group: 1)sham operation, exposure of the left common carotid arteryand left external carotid artery followed by neither MCAO,reperfusion, nor HBO treatment; 2) MCAO for 2 h followed byreperfusion for 24 h; 3) MCAO for 2 h followed by reperfusionfor 24 h and then HBO treatment applied at 3 h afterreperfusion; 4) MCAO for 2 h followed by reperfusion for 24 hand then HBO treatment applied at 6 h after reperfusion; 5)MCAO for 2 h followed by reperfusion for 24 h and then HBOtreatment applied at 12 h after reperfusion; 6) MCAO for 2 hfollowed by reperfusion for 24 h and then HBO treatmentapplied at 23 h after reperfusion.

MCAO model and HBO treatment. Forty-eight maleSprague-Dawley rats (assigned by study protocol to MCAO)underwent the procedure described by Longa et al. (10a).Accordingly, the operator anesthetized the rats with ke-tamine and xylazine and exposed the left common carotidartery. Then, the external carotid artery and its brancheswere 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 thepayment of page charges. The article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734solely to indicate this fact.

Am J Physiol Regulatory Integrative Comp Physiol280: R766R770, 2001.

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blunted tip was inserted into the internal carotid arterythrough the external carotid artery stump and advanced tothe anterior cerebral artery to occlude the middle cerebralartery (MCA). After occluding the MCA for 2 h, the operatorcarefully removed the suture to restore blood flow and thensutured the skin and allowed the rat to wake up. To completethe surgery, the operator applied 0.25% micaine locally to thewound and allowed the rat to recover.

After the treated rats were reperfused, they were placed inan HBO chamber (3 ATA for 1 h) at 3, 6, 12, and 23 haccording to the protocol schedule for their group. When theHBO chamber had attained the desired pressure, the flow ofoxygen was reduced to maintain constant pressure whileallowing air exchange in and out of the chamber. This con-stant exchange was aided by a tray of calcium carbonatecrystals placed inside the chamber to reduce CO2 accumula-tion in the chamber environment; thus the oxygen level wasmaintained at or .98%, and the CO2 level was maintained ator ,0.03%. After HBO therapy, the operator returned the ratto its cage until death. The operator used a rectal probe tomonitor the rats body temperature; during ischemia andpostoperative recovery, body temperature was maintained at37 6 0.5C. Death consisted of decapitation 24 h after theinitial induced ischemia. After the rats death, the operatorremoved its brain.

Observing and evaluating the treated rats for neurologicaldeficit. An experimenter, unaware of the treatments, testedthe animals for neurological deficits after 24 h of reperfusion.Menzies et al. (11) developed the method that tests bothmotor and behavioral deficits on a cumulative scale from 0 to4. This examination was used to evaluate ischemic injury: 0,no visible neurological deficits; 1, forelimb flexion; 2, con-tralateral forelimb grips weakly (the operator places theanimal on an absorbent pad and gently pulls the tail); 3,circling to the paretic side only when pulled by the tail (theanimal was allowed to move about freely on the absorbentpad); and 4, spontaneous circling.

Evaluation of infarcted area. After death had occurred, thecoronal sections of the brain (2 mm thick) were cut andimmersed in a 2% solution of 2,3,7-triphenyltetrazolium chlo-ride. The stained slices were then fixed by immersion inphosphate-buffered 4% paraformaldehyde. The infarctedarea and hemispheric area of each section were traced andmeasured using an image-analysis system (a Macintosh com-puter accessing the public domain National Institutes ofHealth Image program, written by Wayne Rasband andavailable from the internet). The percentage of infarction(infarct ratio) was calculated by dividing the infarcted areaby the total area of the ipsilateral hemisphere (19).

Statistical analysis. Data were represented as themeans 6 SD. Statistical differences between the control (noHBO treatment) and the other groups were compared byusing the one-way ANOVA and then Scheffes F test if asignificant difference was found; a P value ,0.05 was consid-ered statistically significant.

RESULTS

The study operator performed a pilot study to deter-mine the MCAO model used to conduct this study. Thesurgical method and the size of the suture and itsblunted tips were tested in different animals until aconsistent neurological deficit (evaluated 24 h afterreperfusion) was obtained. The rats used for this pilotstudy were not included among the 48 rats described

by the above protocol. No neurological deficit was ob-served in the sham-operated rats.

Figure 1 presents the typical results of the effect ofMCA occlusion on infarction size from each of thegroups: the sham-operated (no MCAO), MCAO-noHBO treatment, and HBO at 3, 6, 12, and 23 h afterreperfusion. The coronal sections were obtained bycutting the brain at a distance of 2, 4, 6, 8, and 10 mmfrom the rostral extremity of the frontal cortex. Thewhite-colored areas represent the infarction regions inthese sections.

Figure 2 shows the results of the neurological deficitscore in each group. Both the 3- and 6-h treatmentgroups exhibited a significantly improved neurologicalfunction (lower score) compared with the no-treatmentgroup. In contrast, the neurological deficit was in-creased after HBO treatment at 12 and 23 h afterreperfusion.

Figure 3 shows the percentage of infarction area inrats that underwent MCAO and reperfusion andMCAO/reperfusion 1 HBO therapy at 3, 6, 12, and23 h. No cerebral infarction was observed in the shamgroup. In the MCAO and reperfusion group (untreatedgroup), severe cerebral infarction was observed in allrats and the infarct ratio was 11.34%. The infarct ratiowas significantly decreased in rats treated with HBOat 3 (7.59%, P , 0.05 vs. untreated group) and 6 h(5.35%, P , 0.05 vs. untreated group) after reperfu-sion. However, the infarct ratio was significantly in-creased in rats treated with HBO at 12 (23%, P , 0.01vs. 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 ofHBO on the cerebral infarction is dual in an MCAOand reperfusion rat model. This finding suggests theexistence of an optimal therapeutic window in which toinitiate HBO therapy in this rat model of cerebralischemia: early therapeutic intervention using HBOwithin 6 h reduces infarction. Applying HBO therapylate (after 12 h, for example) aggravates cerebral in-farction; thus caution needs to be a consideration ofHBO therapy in such cases.

Because current stroke treatment is unsatisfactory,many physicians seek novel treatment modalities. Be-cause local anoxia and energy failures occur at thecellular level in ischemia, increasing the oxygen deliv-ery to the tissues might prolong functional activityduring severe ischemia (14). Animal studies and clini-cal experiences over the last two decades have pro-duced a set of applications for which HBO therapymight appear beneficial (1). However, most of thesestudies focused on forebrain ischemic or global ische-mic models that might have impeded the investigationof therapeutic HBO applications. In designing themodel for their study, these investigators chose toobserve and evaluate the parameters of survival timeand survival rate to determine the therapeutic effect ofHBO (10). Moreover, neuronal injury in the forebrain

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after brief global ischemia is a selective phenomenonthat sometimes fully demonstrates only after observa-tion for several days (19). By contrast, neuronal death,which follows an intense focal ischemic challenge in anarea at risk for infarction, is evident within 1224 h(19). The ischemic events characterizing neuronaldeath mimic more closely the clinical condition of is-chemic stroke (19). Considering these conditions, weused an experimental MCAO and reperfusion modelthat represents a likely clinical problem: incomplete,focal ischemia with the potential for reperfusion. Thismodel also mimics clinical disorders, such as large-vessel thrombosis, that lead to infarction, which issurrounded by ischemic penumbra. Theoretically, thismodel is an ideal candidate for therapeutic HBO (8).

Mainly, two patterns of cerebral damage character-ize focal ischemia: focal damage and penumbral dam-age. Complete flow cessation causes the greatest dam-age at the focus. The penumbral tissues surroundingan ischemic focus sustain less severe damage becausethe collateral vessels supplying the penumbral areayield a residual perfusion. Oxygenation is the most

critical function of blood flow; suddenly reduced oxy-genation is an inevitable consequence of severe ische-mia. If therapeutic intervention does not occur in atimely manner, penumbral zones could eventually losetheir ability to maintain ionic homeostasis, therebybecome subsumed into the focal area, and thus increas-ing the total ischemic brain damage. Through the ad-ministration of pharmacological agents, many investi-gators aim therapeutic stroke research at preventingthe penumbral recruitment into the ischemic focus (6).Pharmacological intervention might either improveblood flow (i.e., oxygen supply) or protect against neu-ronal death. HBO treatment is considered for cerebralischemia, because it might salvage the still viable,though nonfunctioning, tissues surrounding the in-farcted area (14). Mink and Dutka. (12) reported thatHBO can improve tissue oxygen delivery (especially toareas of diminished blood flow), can enhance neuronalviability, and can reduce brain edema. By raising thetissue PO2, HBO can trigger a mechanism controllingcellular and vascular repair. HBO therapy appliedafter radiation injury has demonstrated increased tis-

Fig. 1. Representative photographs of coronal sections of rat brains. From left to right are the sham-operated [nomiddle cerebral artery occlusion (MCAO)], MCAO-no hyperbaric oxygen (HBO) treatment, HBO at 3, 6, 12, and23 h after reperfusion. The coronal sections were obtained by cutting the brain at a distance of 2, 4, 6, 8, and 10mm from the top of frontal cortex (as shown from top to bottom). The white areas represent the infarct regions inthese sections.

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sue oxygen concentration, thereby stimulating angio-genesis and establishing a new capillary blood supply(5). HBO therapy salvages the still viable, though non-functioning, tissue surrounding the infarcted area pre-sumably by allowing time for collateral circulation todevelop. This collateralization forms the basis for theconclusion that HBO might benefit victims of cerebralischemia. Our results showed that HBO therapy, whenapplied at an earlier stage after reperfusion (at 3 andat 6 h after reperfusion), decreased the infarction areain the rat MCAO and reperfusion model. Our resultsagree with the report of Roos et al. (16) who state thatHBO therapy in the rat MCAO model without reper-

fusion is beneficial and agrees with the report of Kra-kovsky et al. (10) about other animal models of cerebralischemia.

Despite the beneficial effects resulting from HBOtherapy applied at an earlier stage (i.e., at 3 and 6 h),our results also show that HBO therapy applied at alater stage (i.e., 12 and 23 h) can yield less beneficialeffects in this rat MCAO and reperfusion model. Whenapplied at a later stage, such as 12 or 23 h afterreperfusion, HBO treatment increased the infarctedcerebral area. Although the exact mechanism remainsunclear, several possibilities account for the harmfuleffect of applying HBO therapy later. Deleteriousmechanisms involved in focal ischemic injury persistthroughout the postischemic period. An unresolvedcontroversy is whether these mechanisms are 1) trig-gered during ischemia and persist into the postische-mic period, 2) triggered during reflow (reperfusion in-jury), 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 bioen-ergetic state and mitochondrial function but that sec-ondary deterioration occurred after 4 h. Gido et al. (7)stated that delayed cell membrane dysfunction, as re-flected in a rise in K1, occurs ;6 h after reperfusion.Despite the suggestion that the generation of free rad-icals during reperfusion might cause secondary dam-age, it remains to be determined whether HBO appliedat an early stage might prevent the generation of freeradicals or the damage caused by free radicals andwhether HBO application at a later stage enhances theharmful effect of free radicals.

Our finding differs from the findings of other studiesthat demonstrate the failure of HBO to exert a benefi-cial effect. These differences might be related to theexperimental protocols of other investigations that pre-scribe prolonged HBO treatment. Long-term use ofHBO results in adverse effects due to the onset ofoxygen toxicity as manifested by induction of lipidperoxidation and seizures (14). Long-term HBO ther-apy might conflict with parameters such as the hemat-ocrit level that, in turn, might influence viscosity (14).A previous study showed that the exposure of rats to 4ATA of oxygen for 90 min was associated with anincreased level of lipid peroxidation product (malondi-aldehyde) and altered the enzymatic antioxidation(glutathione peroxidase) in the brain (15). Chavko etal. (4) stated that some studies used 100% O2 at 5 ATA,which induced seizures. The Committee of the Under-sea and Hyperbaric Medical Society recommends thata treatment pressure only from 2.4 to 3.0 ATA shouldbe used at the lowest effective pressure to avoid O2convulsions (3).

Perspectives

In conclusion, a dual effect of HBO on the cerebralinfarction in MCAO rats was observed in this study,indicating that the optimal therapeutic window forHBO treatment should be restricted to ,6 h afterreperfusion. Further study is needed to clarify whether

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

Fig. 2. Neurological evaluation was performed according to themethod of Menzies et al. (11). Animals were tested for neurologicaldeficits by a blinded observer after 24 h of reperfusion. Grades of 0-4were used. MCAO induced neurological deficits to an average level ofgrade 2.13 in rats without HBO treatment. HBO treatment for 1 h at3 and 6 h after reperfusion reduced markedly the neurological scores.HBO treatment for 1 h at 12 and 23 h after reperfusion increasedneurological scores. Eight rats were used in each group. *P , 0.05(compared with no-HBO group, ANOVA).

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HBO treatment provides long-term functional neuro-protection. Meanwhile, the mechanisms of HBO-in-duced neuroprotection remain unclear. In diseasesother than cerebral ischemia, molecular events such asgene expression change occur after HBO treatment.This new direction warrants further investigation, be-cause studies at the molecular level might not onlyassist in clarifying the mechanism of HBO, but alsolead to identifying genes that could be neuroprotective.In this regard, an understanding of how HBO reducesbrain damage after MCAO and reperfusion could be oftremendous value, because such understanding mightlead to a more selective and effective therapy.

This work was partially supported by a grant-in-aid from theAmerican Heart Association and by the Bugher Foundation Awardfor the investigation of stroke to J. H. Zhang.

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