Review Mechanisms of hyperbaric oxygen and...

Pathophysiology 12 (2005) 65–80

Review

Mechanisms of hyperbaric oxygen and neuroprotection in stroke

John H. Zhanga,b,∗, Takkin Loc, George Mychaskiwd, Austin Colohana

a Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USAb Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA

c Department of Internal Medicine, Loma Linda University, Loma Linda, CA, USAd Department of Anesthesiology, University of Mississippi Medical Center, Jackson, MS, USA

Received 7 December 2004; accepted 18 January 2005

Abstract

Cerebral vascular diseases, such as neonatal encephalopathy and focal or global cerebral ischemia, all result in reduction of blood flow to theaffected regions, and cause hypoxia–ischemia, disorder of energy metabolism, activation of pathogenic cascades, and eventual cell death. Dueto a narrow therapeutic window for neuroprotection, few effective therapies are available, and prognosis for patients with these neurologicalinjuries remains poor. Hyperbaric oxygen (HBO) has been used as a primary or adjunctive therapy over the last 50 years with controversialr pplicationso al tissueso rvations ofH©

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esults, both in experimental and clinical studies. In addition, the mechanisms of HBO on neuroprotection remain elusive. Early af HBO within a therapeutic window of 3–6 h or delayed but repeated administration of HBO can either salvage injured neuronr promote neurobehavioral functional recovery. This review explores the discrepancies between experimental and clinical obseBO, focusing on its therapeutic window in brain injuries, and discusses the potential mechanisms of HBO neuroprotection.2005 Elsevier Ireland Ltd. All rights reserved.

eywords:Hyperbaric oxygen; Cerebral ischemia; Neurological injury; Mechanisms

ontents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2. Effect of HBO in stroke models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1. Neonatal hypoxia–ischemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.1. Overview of neonatal hypoxia–ischemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.2. Effect of HBO in neonates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.1.3. Side effect of HBO in neonates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.2. Focal cerebral ischemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.2.1. Overview of local cerebral ischemia and HBO. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.2.2. Therapeutic window for HBO therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.2.3. Single versus multiple treatments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.2.4. Side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.3. Global cerebral ischemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.3.1. Overview of global cerebral ischemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.3.2. Effect of HBO on global ischemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. Mechanisms of HBO in stroke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.1. Oxygen supply. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.2. Cerebral metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Present address: Department of Neurosurgery, Loma Linda University, 11234 Anderson Street, Room 2562B, Loma LA 92354, USA. Tel.: +1 909 558 4723; fax: +1 909 558 0119.E-mail address:[email protected] (J.H. Zhang).

928-4680/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.pathophys.2005.01.003

66 J.H. Zhang et al. / Pathophysiology 12 (2005) 65–80

3.3. Inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743.4. Apoptosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753.5. Plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753.6. Ischemic tolerance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

4. Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

1. Introduction

Hyperbaric oxygen (HBO) has been used in multipleneurological diseases, including cerebral air embolism[1],carbon monoxide poisoning[2], vegetative state[3], globalcerebral ischemia caused by cardiac arrest[4], focal cerebralischemia[5–7], acute spinal cord injury[8–10], chronic braininjury [11,12], and cerebral vasospasm after subarachnoidhemorrhage[13]. The safety of HBO has been tested inall age and gender groups, including neonates[14–16] andpregnant patients[17,18]. The mechanisms of HBO onneuroprotection include improvement of brain metabolism[12,19], reduction of blood–brain barrier permeability andbrain edema[20], decreasing intracranial pressure[21],attenuation of inflammatory response[22], and preventionof apoptotic cell death[23,24]. In addition, HBO producesischemic tolerance or preconditioning neuroprotection[25].

In this review, we will focus on the application of HBOin neonatal hypoxia–ischemia, focal cerebral ischemia, andglobal cerebral ischemia. Additionally, we will discuss ex-perimental data on the mechanisms of HBO neuroprotectionand the side effects of HBO as a result of high barometricpressures and long duration.

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impairment in blood supply of brain tissue caused either bylocal or general circulatory failure. With ischemia occurringalongside hypoxia (termed hypoxia–ischemia), the severityof the outcome of the hypoxic event increases and the chanceof survival of the affected neurons decreases[28].

One of the primary setbacks to the brain after ahypoxia–ischemia insult is the reduction of oxygen deliv-ery to the tissue. Administration of 100% oxygen under in-creased ambient pressure is a potent means of increasing theamount of oxygen dissolved in blood plasma, thereby po-tentially increasing oxygen delivery to the brain[29]. Stud-ies have shown that HBO treatment in adults has improvedSPECT imaging, increased cerebral oxygenation, improvedpatient condition[12,30], and prevented recurrent cerebralstroke in patients[31].

2.1.2. Effect of HBO in neonatesDespite the critical, clinical, and socio-economic conse-

quences of perinatal brain damage, no effective clinicallytherapeutic strategy has been developed. With better under-standing of the mechanisms that underlie neuronal cell death,several diverse possibilities have presented themselves forpharmacological intervention[32]. Previous studies have fo-cused on the administration of oxygen free radical scavengers[33], nitric oxide inhibitors[34], glutamate antagonists[35],cg a[ n tob in thec

owt gicali im-i ideso BOi xam-p iitiso iv-i ied[h BOt n oftW ningd reg-i

. Effect of HBO in stroke models

.1. Neonatal hypoxia–ischemia

.1.1. Overview of neonatal hypoxia–ischemiaHypoxia–ischemia is a common cause of brain injur

he perinatal period. It is thought to be the single mostificant contributor to static encephalopathies in childrenulting in mental impairment, seizures, and permanent meficits, such as cerebral palsy[26]. Statistics show that 2ut of every 1000 full-term infants experience systemichyxia, and 20–50% of asphyxiated neonates who experhypoxia–ischemia insult expire during the newborn pef those who survived, 25% exhibit some level of permaeuropsychological handicap[27].

Hypoxia is one of the major pathological factors thatuce neuronal cell injury, neurodegeneration, and cell dnbalanced intracellular Ca2+ homeostasis, followed byascade of potentially hazardous cellular challenges suxcitatory amino acid toxicity, glycopenia, and acidosis[28].t often acts in combination with ischemia due to a ser

alcium antagonists[36], potassium channel agonists[37],rowth factors[38], anti-cytokines[39], and hypothermi

40]. Although many of these studies have been showe effective in the laboratory, none have been approvedlinical arena as effective treatments.

Early application of HBO in neonates within a narrherapeutic window might prevent or attenuate neurolonjury and offer a reasonable and viable alternative. Lted literature available in perinatal or neonatal care provnly for a slim view of the effectiveness and safety of H

n diseases other than neonatal hypoxia–ischemia. For ele, HBO was used in the treatment of necrotizing fascf the abdominal wall in four newborns with two surv

ng, whereas the other three infants without HBO all d41]. Another study reported 63 newborns (4± 1 days) withypoconjugation neonatal jaundice. Within 5 days of H

herapy, bilirubin decreased by 40%, enzymatic functiohe liver normalized, and mixed acidosis was arrested[42].

hen HBO was used in acute carbon monoxide poisouring pregnancy at 2.5 atm and 100% oxygen for 90 min

men, all the babies were delivered at term[43]. In addition,

J.H. Zhang et al. / Pathophysiology 12 (2005) 65–80 67

HBO has been a successful treatment of radiation inducedbone and soft tissue complications, cyanotic congenital heartdisease, as well as in newborns and children with acute COpoisoning[44,45]. We have recently reported the first con-trolled experimental study using HBO in a neonatal rat modelof cerebral hypoxia–ischemia[46].

We used an established 7-day postnatal rat model becauseof the histologic similarity between the development of therat’s brain and that of a 32–34-week gestation human fetus ornewborn infant[47]. This model has proven to be useful inmany studies and is used in the United States and abroad[48].Briefly, the carotid artery of a rat pup is exposed and ligated.The animal is then subjected to a period of hypoxia at normalatmospheric pressure (8% O2 for 2 h). This model yields areproducible pattern of isolated ipsilateral hemispheric injuryjust distal to the ligated carotid artery. Furthermore, it allowsfor assessment of mechanisms of brain injury and testingof neuroprotective agents and strategies[49]. Animals thatexperienced hypoxia–ischemia showed retardation in braingrowth, especially in the hemisphere ipsilateral to the ligatedartery. Similar to other studies[40], we have shown that se-vere tissue loss and atrophy accompanied hypoxia–ischemiaand led to reduction in brain development using this model[46,50]. However, animals treated with HBO at 3 atm abso-lute (ATA) pressure for 1 h experienced less brain damage, asrepresented by improved brain morphology (Fig. 1) and brainw h to

6 weeks after hypoxia insult. The size of the brain doubledover 6 weeks in normal pups, while only half of the ipsilat-eral hemisphere remained at 6 weeks in hypoxia–ischemia in-sult pups. HBO treatment largely prevented the brain atrophyin hypoxia–ischemia pups. Light and electron microscopydemonstrated neurons as being spared following treatmentwith HBO [46]. Morphology of the brain slides confirmedthe results from the photographs that more brain tissues arepreserved after HBO treatment (Fig. 2).

When functional status was clinically assessed, it wasfound that animals that had experienced hypoxia–ischemiascored worse in the postural reflex test than the controlanimals[46], as previously reported[51]. In contrast, an-imals that were treated with HBO had similar scores tonormal control animals. The finding that in most cases,HBO is able to prevent the sensorimotor deficits caused byhypoxia–ischemia in neonates is in agreement with a pre-vious study that used adult rats[52], suggesting that HBOmay provide similar neuroprotection in reducing brain in-jury and improving neurological outcome. Our observationin neonates is consistent with most other reports that utilizedadult animals[53–55] that point to HBO’s ability to reducebehavioral deficits, infarction volumes, and edema, which allultimately lead to an improved outcome.

In summary, the results of these earlier studies suggest thatHBO is able to attenuate the effects of hypoxia–ischemiao neu-

FHh

eight.Fig. 1demonstrated photos of brains taken at 24

ig. 1. Brain atrophy and effect of HBO. Photos of normal rat pup’s brainypoxia–ischemia (HI) injures ipsilateral hemisphere, initially shown as braineads). HBO (HI + HBO) at 3 ATA for 1 h reduced brain edema and prevente

n the neonatal brain by reducing the progression of

are shown on the top line. The size of the brain doubled over 6-week time.edema at 48–72 h (arrows), followed by brain atrophy from 1 to 6 weeks(arrow

d brain atrophy.


Fig. 2. Brain morphology. Brain slides at hippocampal level show normal brain growth in control animals. Severe brain injury and atrophy occurred at 2and 6weeks after hypoxia–ischemia insult (HI) (arrow heads). HBO treatment (HI + HBO) largely prevented brain atrophy (arrows).

ronal injury and increasing sensorimotor function. SinceHBO has been used to treat humans in the past with acertain degree of success, and since it is currently beingused as an effective treatment in infants with various dis-orders, it may provide an effective strategy for the preven-tion of numerous neurological handicaps that plague manychildren.

2.1.3. Side effect of HBO in neonatesConcerns regarding the toxicity of oxygen that can occur

while HBO is administered at high pressures or over longduration will be discussed in the section of focal cerebralischemia, since relatively low level of HBO pressures areintended in the treatment of newborns. However, a uniquephenomenon regarding HBO in neonates that needs to beaddressed is that of retinopathy of prematurity.

2.1.3.1. Retinopathy of prematurity.The emergence ofretinopathy of prematurity as a leading cause of blindnessin infants has occurred over the past 60 years, seeminglyas a result of the advances in neonatal intensive carepractices that allowed for the survival of premature infantshaving significant immature retinal vasculature[56,57].The incidence for threshold of retinopathy of prematurity(disease progression to the point of necessitating peripheralretinal ablation therapy) for premature infants weighing< esei ti nsivec urityh t

elevated levels of oxygen causes retinopathy of prematurityis the main reason why physicians are hesitant about treatinghypoxic or premature infants with normobaric or hyperbaricoxygen. This stigma regarding supplemental oxygen hasbeen around since the early 1950s[60,61] when, for lackof a better explanation, it was thought that the oxygenused to treat the infants was causing the blindness, eventhough retinopathy of prematurity also occur in term andpreterm infants not exposed to elevated levels of oxygen[62].

Oxidant stress appears to play a role in the retinal vaso-obliteration associated with retinopathy of prematurity[63].Exposure to hyperoxia affects developing retinas by leadingto microvascular degeneration which produces inner retinalhypoxia, which in turn leads to structural and functionalchanges. These changes can lead to abnormal vascular-ization resulting in the development of vision-threateningretinopathy [63]. If supplemental oxygen therapy (pres-surized or not) is to be used in the treatment of prematureor hypoxic infants, questions concerning the safety ofhyperoxia, especially in regards to the retina, need to beaddressed.

2.1.3.2. Transient HBO does not cause retinopathy.Wetested the hypothesis that a single exposure to 100% oxy-gen for 1 h at various pressures (1, 1.5, and 3.0 ATA) wouldn Ourr odeld 1.0A r ah this

1.25 kg is roughly 5%, with about 20–30% of thnfants becoming blind despite treatment[58]. Despite vasmprovements that have been made in neonatal inteare practices, the incidence of retinopathy of prematas been steady over the last two decades[59]. The idea tha

ot produce retinopathy of prematurity in newborn rats.esults using the same neonatal hypoxia–ischemia rat memonstrated that hyperoxia at pressures ranging fromTA to 3 ATA is neuroprotective when administered afteypoxic–ischemic insult and that hyperoxia, as used in


Fig. 3. Retina and HBO. Slides of retina from normal pups are shown on the right side at different magnifications. The top picture shows distribution of arterials(A), venous (V), and capillaries (C). Higher magnifications in the middle pictures show the density of capillaries. The bottom picture shows the morphologyof retina with different anatomical layers of cells. Two weeks after treatment with HBO, the density of vasculatures and layer of cells remain the sameas incontrol animals.

study, does not cause the structural changes or abnormal vas-cularization in the retina that are associated with retinopathyof prematurity[64]. Fig. 3showed morphological studies ofthe retina from normal control and from HBO-treated pupsat 2 weeks after HBO. No major differences were observedbetween the two groups upon the density of arterioles, veins,and capillaries.

One of the most sensitive markers for morphologicalchanges in retinopathy is the thickness of the outer plexiformlayers (OPL). The OPL is the retinal layer where synaptic

contacts between the photoreceptors and second order neu-rons occur and its formation in rats begins aroundunclear(P5and commences on P12)[65]. Exposure to hyperoxia duringthe first 14 days of postnatal life in rat pups can prevent thenormal development of the OPL and result in long-term ef-fects that can eventually impair vision[65,66]. Dembinskaet al.[66] have shown that a progressive increase in the du-ration of hyperoxia causes a gradual thinning of the OPL.In our study, a single exposure to hyperoxia at normobaricand hyperbaric pressures did not result in the thinning of the


OPL, suggesting that this short exposure does not producethe structural anomalies in the retina that are associated withprolonged hyperoxia exposure[64]. Our results, however, donot rule out the possibility of retinal changes induced by highpressure during prolonged duration of treatment. Torbati etal. [67] have shown that retinopathy of prematurity can de-velop in newborn rats exposed to 100% oxygen at 5 ATAfor 5 h, echoed by our observation[64]. Increased ambientpressure can constrict the choriocapillaries and reduce theamount of oxygen transported from the choroid to the innerretina during the period of hyperoxia. The vasoconstrictiveresponse will vary with the degree of hyperbarism, so thatat high pressures, constriction may cause a severe and pro-longed reduction in choroidal and retinal blood flow. Uponreturning to room air from exposure to low levels of hyper-barism, the oxygen levels will be reduced and the stimulusfor vasoproliferation will be decreased[68]. In contrast, uponreturning to room air from exposure to higher levels of hy-perbarism, oxidative damage created by hypoxia–ischemiacan lead to the induction of retinal vasoproliferation[67].These results suggest that it is the duration of the expo-sure that is important when hyperoxia is given at normo-baric pressure, that the pressure is important when hyperoxiais given at hyperbaric pressures, and finally, that hyperoxicexposures can be safely administered at the appropriate pres-sure and duration. Thus, a single 1 h application of oxygen,e treat-m nsult[ pent ento gen[ ee ver,a spi-r bralc leart ts int barico

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accumulation, collapse of cytoskeletal elements, and apop-tosis [71]. If oxygen supply to the ischemic penumbra canbe restored, the cascade of ischemic neuronal damage mightbe interrupted[72]. However, there are no effective therapiesto restore blood supply and oxygen to the ischemic areas af-ter a focal cerebral ischemia. Although thrombolytic therapyhas been reported to be effective in a select subset of strokepatients, the limited therapeutic window allowed for only asmall percentage of patients to be treated, since there is a riskof possible transformation to a harmful hemorrhage[73]. Inthis regard, HBO may serve as an important adjunct or al-ternative means to increase the amount of oxygen physicallydissolved in the blood plasma, thereby increasing oxygen de-livery to the brain[74].

HBO has been used in the treatment of cerebral ischemiain animal models and in human subjects since 1963, when asmall pioneer study performed by Jacobson found no benefitof HBO at 2.0 ATA after permanent occlusion of the middlecerebral artery (MCA) in dogs[75]. While the effect of HBOin permanent ischemia is debatable, more controversial dataare reported regarding the effectiveness of HBO in cerebralischemia with reperfusion[29]. Some laboratory studies re-ported improved outcome[53–55,76–84]while others failedto show any benefit[87,88]. A detailed review of these exper-imental studies suggests that methodological shortcomings,conceptual problems, and differences in experimental designm

2ess

o fort oket ndeda l vi-a et bes of3 ved.

cali sionr al-l BOa fterr erfu-s eree nfarctv 9%)a witht farctv 3%)a s thatH oc-c dowf of as centr

ither normobaric or hyperbaric, appears to be a safeent protocol for neonates after a hypoxia–ischemia i

64]. The results obtained in this study may help to ohe door for the use of hyperoxia therapy for the treatmf hypoxic newborn infants since both normobaric oxy

69,70] and hyperbaric oxygen[46] have been shown to bffective in neonate and adult models of stroke. Howeproblem with hyperbaric oxygenation is increased re

ation and arterial hypocapnia, both will affect the cereirculation and perhaps arterial blood pressure. It is chat we do not know what happens to neonatal rodenerms of arterial gases and blood pressure with hyperxygenation.

.2. Focal cerebral ischemia

.2.1. Overview of local cerebral ischemia and HBOAn investigation from the American Heart Association

icates that more than 700,000 cases of stroke occur eacn the United States. Among them, 80% have focal cereschemia, either due to thromboses or embolism, as af interruption of blood flow to brain tissues. During fo

schemia, the ischemic core is thought to be surrounden area that is viable yet non-functioning, a so-calledhemic penumbra”, from which neuronal cells might beaged with adequate therapy[71]. In this area, one of thrimary factors causing neuronal damage is energy fattributable to hypoxia, which causes unregulated cal

nflux and subsequently activates enzymes such as phosase, protease, and endonuclease, leading to arachidon

r

d

ight account for these discrepancies[53].

.2.2. Therapeutic window for HBO therapyThe most important factor determining the effectiven

f HBO in ischemic stroke is the therapeutic windowreatment. The primary supposition of HBO therapy in strreatment is not to treat the ischemic core but the surroureas that are viable yet non-functioning, where residuable neuronal cells might be salvaged[71]. Therefore, th

herapeutic window for intervention with HBO shouldimilar to that for thrombolytic therapy, with a window–6 h when the ischemic neuronal tissues can still be sa

We have studied the therapeutic window of HBO in foschemic stroke in an established MCA occlusion/reperfuat model[52]. After 2 h of occlusion, reperfusion wasowed, and the rats were placed in the HBO chamber. Ht 3 ATA for 1 h was administered at 3, 6,12, and 23 h aeperfusion. The rats were sacrificed at 24 h after repion and the infarct volume and neurological function wvaluated. The results showed that the percentage of iolume was significantly decreased in both the 3 h (7.nd 6 h (5.35%) HBO treatment groups when compared

he control group (11.15%). However, the percentage inolume was significantly increased in both the 12 h (2nd 23 h (17.3%) treatment groups. This study suggestBO has a dual effect on the cerebral infarction in MCAlusion/reperfusion in rats and that the therapeutic winor treatment should be confined to 6 h after the onsettroke[52]. This observation was also reconfirmed by a reeport[5].


Fig. 4. TTC staining and HBO. TTC staining shows negative in normal rats (control). Positive staining (white color) was observed in rats undergone middlecerebral artery occlusion and reperfusion (MCAO/R) at 1 and 4 weeks. HBO treatment initiated at 6 h (6-h HBO) after MCAO reduced markedly infarct areas(TTC positive staining). HBO initiated at 24 h (24-h HBO) after MCAO reduced infarct even though not effective as 6 h group.

2.2.3. Single versus multiple treatmentsAnother important factor to consider when HBO is

used as a stroke treatment is the issue of multiple treat-ments. In most clinical studies, the application of HBOwas delayed up to 24 h but multiple applications wereused [86,88]. On the other hand, most animal studiesutilized one treatment within 3 h of ischemia/reperfusion[7,20,53–55,69,70,76–79,81,82,84,85,89–91]. Very fewstudies reported on the multiple HBO treatments in animals[54,81,82]. Thus, when comparing the differences betweenthe clinical approach and the experimental protocol, itwould seem that multiple treatments may be beneficialeven if it is used after a prolonged time following ischemicstroke.

As mentioned above, the known therapeutic windowof HBO application was set within 6 h after ischemia/reperfusion[52]. This narrow therapeutic window limits thepotential use of HBO in clinical practice for two major rea-sons. First of all, many patients arrived at the hospital muchlater than the therapeutic window. In addition, even if thesepatients are admitted into the hospital within the 3–6 h afterthe onset of stroke, most of them will be initiated thrombolytictherapy[73], thus eliminating them from being potential can-didates for HBO trials. To target a patient population that isnot suitable for thrombolytic treatment due to delayed hospi-tal admittance, we re-examined delayed HBO applications at6 and 24 h after reperfusion in the same rat MCA occlusionand reperfusion model[52] but using multiple treatments.This treatment protocol was designed according to severalprevious reports that an adaptive response of the plasma oc-curs as a result of repeated exposure to HBO[54,92,93]and

that repeated applications of HBO may actually prevent dele-terious side effects[93,94].

We found that delayed, but repeated HBO treatments (withan average of total of seven treatments) have long-term pro-tective effects against ischemic brain damage in rats withregards to neurological outcome and histopathological ob-servations[145]. Delayed HBO treatment, especially at 6 h,significantly decreased cerebral infarct size and improved be-havioral outcome in MCA occlusion/reperfusion rats. De-layed, multiple treatments at 24 h had a significant effect oncerebral infarct and neurological functional improvement 4weeks after ischemia/reperfusion.Fig. 4 demonstrated TTCstaining of brain slides, showing evidence of infarction (whitecolor) after MCA occlusion/reperfusion at 1 and 4 weeks.Multiple HBO treatments initiated either at 6 or 24 h re-duced infarction at 1 and 4 weeks. This study indicatedthat the delayed use of multiple HBO treatments, even 24 hafter ischemia/reperfusion, improved clinical outcome by re-ducing the extent of cerebral infarction. Therefore, HBOcould be an alternative therapy in the clinical managementof acute stroke, particularly in a patient population that isnot suitable for thrombolytic treatment due to late hospitaladmittance.

From these results, it is possible that, with multiple re-peated HBO treatments, one might be able to expand the ther-apeutic window from 6 to 24 h after ischemia/reperfusion,s fteri l im-p sp layedm am-

ince delayed, but multiple applications of HBO 24 h aschemia/reperfusion accelerated neurological functionarovement when tested at 4 weeks[145]. Furthermore, thireliminary observation seems to demonstrate that deultiple HBO treatments at 24 h did not aggravate brain d


age. Therefore, even though a single, delayed treatment withHBO may enhanced cerebral infarction[52], multiple treat-ments improve neurological function at long-term evaluation.It appeared that the initial harmful effect of delayed appli-cation within 24 h was corrected and abolished due to theadaptive effect generated by the multiple HBO applications[93,94].

2.2.4. Side effectsThe side effects of pressured oxygen therapy have been

noted, especially for high pressure (>3 ATA) and long dura-tion. It has been shown that HBO (4.96 ATA for 1 h) adminis-tered to rats can cause CNS toxicity[95]. A previous study hasshown that exposing rats to 4 ATA at 100% oxygen for 90 minwas associated with an increased level of lipid peroxidationproduct, and altered enzymatic anti-oxidation (glutathioneperoxidase) in the brain[96]. High levels of HBO reducedcerebral blood flow, possibly by reducing nitric oxide syn-thase[97]. Chavko et al.[98] stated that 100% O2 at 5 ATAinduced seizures. Long duration of HBO at high pressurelevels results in adverse effects due to the onset of oxygentoxicity as manifested by the induction of lipid peroxidationand seizures[29].

At lower pressures, Mink and Dutka[91] found that HBO(2.8 ATA for 75 min) was not associated with an increase oflipid peroxidation or with a reduction of neurophysiologicalr icalsi emicr im-m motee tud-i eu-rS lu-s f is-c Oi act-i emict wasa athert oxy-g lipidp byHp t-t com-m ATAs id Oc

urag-i thec flowb tion[ s hy-pT uce

a free radical load in the ischemic penumbra in theory, eventhough it was not the case in a recent study using a focalcerebral ischemic rat model[99]. Nevertheless, the combina-tion of HBO and free radical scavengers in acute stroke mayhave the potential of enhancing the beneficial effects of HBOwithout suffering its consequential harmful effects.

2.3. Global cerebral ischemia

2.3.1. Overview of global cerebral ischemiaGlobal ischemia after cardiac arrest, anesthesia accident

during surgery, obstruction of airway, drug intoxication orhemorrhagic shock are some of the major causes of braininjury resulting in severe neurological and neurobehavioraldeficit [104–107]. Aggressive and selective treatment strate-gies for global ischemia have been developed over the pastyears such as the anti-excitotoxicity, free radical scavengers,prevention of neuroinflammation, and inhibition of apopto-sis These strategies have all achieved limited success, how-ever, primarily because of an incomplete understanding of themechanisms of neuronal death after global ischemia[106].Hypothermia, which targets multiple molecular pathways, of-fers significant brain protection in animal models and in pa-tients after cardiac arrest[108,109]. HBO, another pan-brainprotective therapy, increases oxygen delivery to the ischemicbrain, rescues neuronal tissues, preserves the functional ac-t ury”i li

2ia is

t ptoticd hav-i tec-t fort d byc ning,e , orh

vivalt days[ 5%r enc BO,e en-ts ineg teg f thea rvivalr ofHi rresta andi t

ecovery, despite increased amounts of oxygen free radn the brain, as demonstrated in a global cerebral ischabbit model. The authors suggested that HBO appliedediately after global cerebral ischemia does not proarly brain injury. This report is supported by other s

es using similar animal models, in that HBO provided noprotection without enhancing lipid peroxidation[76,99].unami et al.[76] used a model of permanent MCA occion and exposed the rats (within 10 min of the onset ohemia) to HBO (3 ATA, 100% oxygen) for 120 min. Pa2

ncreased 10-fold from 18.53 to 209.41 kPa without impng or reducing cerebral blood flow at the edge of the ischerritory. This large increase in arterial oxygen contentchieved by increasing the plasma’s dissolved oxygen r

han hemoglobin-bound oxygen. Despite the increase inen tension, there was no increase in the products oferoxidation[76]. Thus, lipid peroxidation is producedBO at pressures higher than 4 ATA[100,101]but not byressure less than 3 ATA[91,102]. Therefore, the Commi

ee of the Undersea and Hyperbaric Medical Society reends that a treatment pressure only from 2.4 to 3.0

hould be used at the lowest effective pressure to avo2onvulsions.

Even though the above-mentioned results are encong, HBO may still produce certain adverse effects onentral nervous system. HBO reduces cerebral bloody 20–30% in the normal brain via cerebral vasoconstric

74,20], which might be the consequence of spontaneouerventilation attributable to regional cerebral acidosis[103].he combination of reperfusion and HBO might then ind

ivity of the brain, and attenuates the “secondary brain injn animals[12,19,46,53,54,110,111], including in the globaschemia animal models[4,20,79,82,112,113].

.3.2. Effect of HBO on global ischemiaThe most vulnerable brain region after global ischem

he hippocampus where neuronal death, especially apoeath, leads to impairment of neurological and neurobe

oral function. Due to the shortage of effective neuroproive therapies, HBO is an extremely attractive alternativehe treatment of global ischemia, especially when causeardiac arrest, anesthesia accident during surgery, drowlectric shock, obstruction of airway, drug intoxicationemorrhagic shock.

In an established four-vessel rat occlusion model, surime and rate after global ischemia were recorded for 1479]. All animals died in the no treatment group, while 4ats survived after treatment with HBO (3 ATA, 1 h). Whompared to control animals that did not receive any Hven the HBO-treated animals that did not survive theire 14-day period still notably lived longer (59.8± 9.1 h ver-us 17.9± 2.7 h). Similar observation was made in a canlobal ischemic model[82]. Fifteen minutes of complelobal cerebral ischemia was achieved by occlusion oscending aorta and the caval veins. HBO increased suate and improved neurological function. A combinationBO with nicardipine achieved similar results[81]. Post-

schemic HBO was tested after experimental cardiac and resuscitation and found to inhibit neuronal death

mprove neurological outcome[4]. In a global ischemic ra


Fig. 5. Global ischemia and HBO. At 96 h after global ischemia and hypotension, marked neuron loss is detected by Nissl staining especially at CA1 ofhippocampus. Higher magnification (middle) clearly shows cell loss as indicated by an arrow in CA1. Cell shape changes are shown in the cortex (right) withcondensed nuclei. HBO at 2.5 ATA for 2 h preserved neuronal loss in hippocampus and cell shape changes in the cortex.

model with hypotension (by way of exsanguination), HBOreduced cell death in the hippocampal regions[113]. Fig. 5demonstrated Nissl staining of hippocampus and cortex inrats at 96 h after global ischemia–hypotension. Most neu-rons in CA1 region died as shown by lacking of Nissl stain-ing. Many neurons showed sign of damages in the cortexwith condensed nuclei. HBO (3 ATA, 2 h) applied at 1 h afterglobal ischemia–hypotension prevented a significant numberof neuronal cell death in the CA1 and the cortex.

The treatment protocols for global ischemia, to include thetherapeutic window, multiple applications, and low pressureof HBO within 3 atm, are all similar to those of focal cerebralischemia.

3. Mechanisms of HBO in stroke

The mechanism of HBO-induced neuroprotection in-cludes enhancing of neuronal viability via an increase oftissue oxygen delivery to the area of diminished flow, reduc-ing brain edema, and improving post-ischemia metabolism[29]. The major factor precluding neurological recovery af-ter ischemia is reperfusion failure. The dissolved oxygen pro-vided by HBO could “reperfuse” the ischemic area due to thegreater pressure gradient, even in the presence of reducedcerebral blood flow. In the interim, HBO decreases the de-f nt elptt ayc l in-j BOn

3.1. Oxygen supply

One of the major beneficial effects of HBO in ischemiccerebral ischemia is in its ability to improve tissue oxygendelivery [76]. HBO enhances neuronal viability by increas-ing the amount of dissolved oxygen in the blood withoutsignificantly changing blood viscosity. High plasma oxygenconcentration in an ischemic episode is important becausecapillary blood flow during ischemia consist mainly ofplasma blood flow[117]. Enhanced oxygen delivery mightlead to the improvement of penumbral energy metabolismand, as a result, decrease susceptibility to additionalmetabolic challenges, such as peri-infarct depolarization[71,72]. In addition, HBO reduces brain edema, reducesbrain vascular permeability, and enhances blood–brainbarrier integrity[20]. HBO also restores ion pump function,improves post-ischemic cerebral metabolism, and allowstime for collateral circulation to develop[4,30]. Furthermore,by raising the tissue PO2, HBO might initiate a cellular andvascular repair mechanism. When used after radiation injury,HBO has been shown to increase tissue oxygen concentra-tion, thereby stimulating angiogenesis and establishing a newcapillary blood supply[118]. In contrary, a recent study in-dicated that HBO improved cerebral oxygen extraction ratiobut failed to enhance oxygen delivery and metabolic rate foroxygen[4].

3

icalm siblei tra-c igh

ormability of the red blood cells[114,115]. A decrease ihe deformability of the impaired red blood cells may ho prevent irreversible neurological injury[115,116]. Addi-ionally, there are other effects of HBO therapy that montribute to the prevention of permanent neurologicaury. Fig. 6 summarizes the general mechanisms of Heuroprotection.

.2. Cerebral metabolism

It has been previously demonstrated that biochemechanisms are involved in the development of irrever

schemic brain injury. Excessive lactic acidosis, high inellular calcium levels, formation of free radicals, and h


Fig. 6. Mechanisms of HBO neuroprotection. Cerebral hypoxia–ischemia disables energy metabolism, reduces ATP production, releases glutamate, andcauses calcium overload and depolarization. Mitochondrial damage follows, with oxygen radical generation and inflammatory reactions. All these patho-logical events not only lead to apoptotic neuron death, but also result in brain infarction, brain edema and the dysfunction of blood–brain barrier. The finaloutcome is the death or disability of patients. HBO either improves oxygen delivery or oxygen extraction to enhance neuronal viability. HBO protectstheblood–brain barrier and reduces cerebral edema. Cerebral metabolism is improved by HBO and levels of glutamate, glucose, and pyruvate are stabilized.The inhibitory effect of HBO on inflammatory agents and on apoptosis may be mediated by the re-regulation of superoxide dismutase and by enhanc-ing the expression of pro-survival Bcl-2 genes. Finally, HBO decreases the deformability of the red blood cells to improve microcirculation and reducehypoxia–ischemia.

concentrations of excitatory amino acids are associated withischemic neuronal damage[71].

Fluctuations in the extracellular fluid levels of energy-related substances such as glucose, lactate, pyruvate, andexcitatory amino acids (i.e., glutamate) reflect intracellularmetabolic disturbances produced by ischemia[71]. HBOmight increase oxygen concentration, enhance neuronal vi-ability, and initiate cellular and vascular repair[20,76,118].These factors could partially restore the neurochemical up-take mechanism and increase their storage in astrocytes. Forexample, HBO decreased glucose, pyruvate, and glutamatelevel from ischemic penumbra almost to the control level(pre-occlusion level)[19]. This study suggests that regula-tion of these striatal metabolites by HBO may partially reducecerebral infarction. In addition, HBO enhances hippocampalsuperoxide dismutase and preserves Na+, K+-ATPase activi-ties[112]. The mechanism of HBO-induced neuroprotectionin focal cerebral ischemia was suggested, at least in part, tobe a result of a reduced level of extracellular dopamine[119].The effect of HBO on improvement of brain metabolism hasalso been observed in these patients[12,120].

3.3. Inflammation

Several studies suggest that HBO may protect the brainf ro-c oft the

progression of cerebral ischemic damage[124]. In periph-eral organs, such as in a rat’s intestinal ischemia–reperfusionmodel, HBO reduced leuko-sequestration and neutrophil pre-activation. The percentage of NBT-positive cells increasedin all of the animals after reperfusion, but the increase wassignificantly reduced by HBO treatment[123]. Weisz et al.reported that HBO treatment in Crohn’s disease (a perianalinflammatory bowel disease) decreased TNF-�, IL-1, andIL-6 secretion by circulating monocytes[122]. Exposureto HBO (3 ATA, 45 min) inhibited the carbon monoxide-mediated adherence of leukocytes in brain microvessels dueto B2 integrins [121]. Another inflammatory factor whichis normally expressed in neurons of the brain in adult an-imals is the cyclo-oxygenase-2 (COX-2). Up-regulation ofCOX-2 expression occurs after inflammatory stimuli, includ-ing in cerebral ischemia and hypoxia[125,126]. HBO re-duced COX-2 mRNA and protein expression in ischemichemispheres after MCA occlusion/reperfusion in rats[22].In addition, a recent study indicates that cellular protec-tion of HBO is associated with diminished infiltration ofpolymorphonuclear neutrophils into the injured brain[127].HBO reduces the ischemia-induced down-regulation of theneurotrophin-3 mRNA level at 4 h post-ischemia, and signif-icantly increases cell survival 7 days after reperfusion, sug-gesting that HBO can maintain the neurotrophin-3 mRNAlevel in the hippocampus, and thus, be beneficial to the is-c ame[

rom ischemic damage by inhibiting the inflammatory pess[121–123]. After cerebral ischemia, an infiltrationhe affected brain by inflammatory cells contributes to

hemic brain when administered within a certain time fr128].


3.4. Apoptosis

Cell death, either by necrosis or apoptosis, occurs inthe brain tissues during the first few days after cerebralischemia [129]. Necrotic cell death is characterized bycellular swelling, nuclear pyknosis with karyorrhexis,and cytoplasmic eosinophilia. Apoptosis is characterizedby morphological and biochemical features, including cellshrinkage, formation of apoptotic bodies, and extensive inter-nucleosomal fragmentation. Cerebral hypoxia–ischemiaproduces a cascade of interconnected pathological pro-cesses, including changes in intracellular calcium, excitatoryamino acid, oxidative stress, and inflammatory response,leading to apoptosis in the ischemic penumbra[71]. Pre-vention of apoptosis becomes a therapeutic strategy topreserve brain tissues and promote functional recovery[130].

One of the most important mechanisms of HBO neuro-protection is the inhibition of apoptosis in injured brain tis-sues. HBO reduces brain injury in neonatal hypoxia–ischemiaby inhibition of apoptosis[23], in focal cerebral ischemia[24], and in global cerebral ischemia[113]. Multiple analyticmethods were used and consistent results demonstrated thatHBO decreased the activity and expression of caspase-3, re-duced PARP cleavage, and abolished DNA fragmentation. Itis likely that inhibition of apoptosis by HBO translates intoreduction of cerebral infarction and brain tissue preservation[23,24].

The mechanism responsible for HBO-induced anti-apoptotic effect is not clear, although several plausibleexplanations have been proposed. The first likely mechanismmay be that, by increasing oxygen delivery to an area withdiminished blood flow, HBO counteracts hypoxia and re-duces brain injury. Secondly, by reducing hypoxia–ischemia,HBO reduces all the pathological events as a consequenceof hypoxia, including brain edema, increased blood–brainbarrier permeability, post-ischemia derangement of brainmetabolism [19], and inflammation [22,131]. Thirdly,HBO may directly affect gene expression in those that aresensitive to oxygen or hypoxia. Our recent observation hasshown that HBO decreases hypoxia-inducible factor-l�(HIF-l�) and multiple other genes related to apoptosis[146]. Fig. 7 showed a schematic cascade of apoptotic celldeath after hypoxia–ischemia. Deprivation of oxygen duringhypoxia–ischemia triggers the accumulation of HIF-l�,which in turn activates its target genes including the genesfor angiogenesis (VEGF), erythropoiesis (erythropoietin),and glycolysis (glycolytic enzymes and glucose transporters)(not shown inFig. 7). In addition, HIF-l� activates tumorsuppressor gene p53, Nip3 from the pro-apoptotic BC1-2family, and caspase-9, all of which have strong association toapoptosis. Activation of p53 leads to release of cytochromeC and the activation of caspase-9 and caspase-3, resultingin cell death, especially by apoptosis. Several studies alsoreported that HIF-la is involved in neuronal death after braininjury.

Fig. 7. Apoptosis and HBO. Oxygen depletion leads to the stabilizationof hypoxia-inducible factor-l� (HIF-1�) in cells. HIF-l� binds with tumorsuppressor p53 or other apoptotic genes. Released cytochromec activatescaspase-9 and caspase-3 leads to cell death. HBO restores oxygenation,improves energy levels, and interrupts this cell death pathway.

3.5. Plasticity

Following the initial cerebral ischemia, post-acute brainplasticity is an important mechanism for determinationof functional brain improvement[132,133]. The absenceof neuroanatomical plasticity following brain trauma orhypoxia–ischemia is attributable to several factors, includ-ing glial scars, lack of neurotrophins, and growth inhibitorymolecules [134]. Nogo-A is one of the most powerfulgrowth inhibitors among these myelin-associated inhibitors[135,136]. Nogo-A binds to the Nogo receptor (Ng-R) and ac-tivates intracellular Rho GTPase signal pathways[137]. Anenhanced activity of the Nogo-A pathways might interferewith CNS plasticity and hamper the neurological functionalimprovement. IN-1 (a Nogo-A antibody) and NEP1-40 (anantagonist of Ng-R) treatments attenuated spinal cord lesions[136] and improved stroke outcome[132,134].

We have studied the effect of HBO on the expression ofNogo-A, Ng-R, and RhoA in the ischemic brain cortex fol-lowing global ischemia. Transient global ischemia (10 min)produced remarkable brain cell loss at 96 h and 7 days.Accompanying the morphological injuries is an immediateelevation in the expression of Nogo-A, Ng-R, and theirdownstream effector RhoA, present in the ischemic cerebralcortex HBO has been found to reduce their expressions[113]. An interesting observation is that all factors in theN ithin6 Thiso f the

ogo-A pathways responded immediately, increased wh, and peaked around 48 h after global ischemia.bservation is surprising, considering that the function o


Nogo-A system during the post-acute regeneration phase isthat of growth inhibition. Therefore, it would appear that themechanism for neuronal plasticity begins during the acutestage after global ischemia. Indeed, Nogo-A plays an impor-tant role in preventing regeneration immediately after injury,and before glial scar formation[132]. Early applicationof a Nogo-A antibody within 24 h improved behavior andneuroanatomical plasticity after experimental stroke[132].These results indicate that suppression of Nogo-A pathwaysby HBO might partially contribute to the improvement ofthe neurological function observed previously in globalischemic animal models[4,20,79,82,112].

3.6. Ischemic tolerance

An extremely promising area of HBO application is is-chemic tolerance or ischemic preconditioning. Non-lethalstimulations, including HBO, induce ischemic tolerancewhich may decrease brain injury caused by lethal stimula-tions. Even though the role of ischemic tolerance in acutestroke is debatable, HBO has been tested to produce is-chemic tolerance in stroke models. In a rat MCA occlu-sion/reperfusion model, animals received 1 h HBO at 2.5 atmabsolute in 100% oxygen every day for 3–5 days before con-ducting ischemic surgery. Preconditioned rats had a muchbetter neurological outcome, with decreased infarct volume[ ce,wt el ofs

ed tot utasea

pto-s d tot sc mict dt raint kp

4

BOi ialsa sun-d cala re,c f itsf fromb n bec HBOt ures( ally

not used in routine treatment protocols. The possibility ofretinopathy of prematurity, as shown in this paper, is limitedif low pressure and short duration of HBO is applied. Infuture clinical trials, several important factors need to beconsidered: therapeutic window, optimal pressure, and du-ration of HBO treatment. In addition, one needs to be awarethat lower pressure[144], and at times, even normobaricpressure[69,70]can be neuroprotective, at least in animals.

Acknowledgements

This work was partially supported by a grant from theAmerican Heart Association Bugher Foundation Award forStroke Research, an award from United Cerebral PalsyFoundation, and grants from NIH NS45694, HD43120, andNS43338 to J.H.Z.

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