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JOURNAL OF NEUROTRAUMAVolume 22, Number 1, 2005© Mary Ann Liebert, Inc.Pp. 42–75

Invited Review

Lateral Fluid Percussion Brain Injury: A 15-Year Review and Evaluation

HILAIRE J. THOMPSON,*,1,5 JONATHAN LIFSHITZ,*,1,6 NIKLAS MARKLUND,1,2,7

M. SEAN GRADY,1 DAVID I. GRAHAM,3 DAVID A. HOVDA,4 and TRACY K. MCINTOSH1,2

You can’t always get what you wantBut if you try sometimes,

You just might findYou get what you need!

—Mick Jagger and Keith Richards The Rolling Stones

ABSTRACT

This article comprehensively reviews the lateral fluid percussion (LFP) model of traumatic brain in-jury (TBI) in small animal species with particular emphasis on its validity, clinical relevance and reli-ability. The LFP model, initially described in 1989, has become the most extensively utilized animalmodel of TBI (to date, 232 PubMed citations), producing both focal and diffuse (mixed) brain injury.Despite subtle variations in injury parameters between laboratories, universal findings are evident acrossstudies, including histological, physiological, metabolic, and behavioral changes that serve to increasethe reliability of the model. Moreover, demonstrable histological damage and severity-dependent be-havioral deficits, which partially recover over time, validate LFP as a clinically-relevant model of hu-man TBI. The LFP model, also has been used extensively to evaluate potential therapeutic interven-tions, including resuscitation, pharmacologic therapies, transplantation, and other neuroprotective andneuroregenerative strategies. Although a number of positive studies have identified promising thera-pies for moderate TBI, the predictive validity of the model may be compromised when findings are

1Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania.2The Veterans Administration Medical Center, Philadelphia, Pennsylvania.3Academic Unit of Neuropathology, University of Glasgow, Scotland, United Kingdom.4Division of Neurosurgery, Departments of Surgery and of Molecular and Medical Pharmacology, UCLA Brain Injury

Research Center, University of California, Los Angeles, California.5Current address: Biobehavioral Nursing and Health Systems, University of Washington, Seattle, Washington.6Current address: Department of Anatomy & Neurobiology, Medical College of Virginia Campus of Virginia Commonwealth

University, Richmond, VA.7Current address: Department of Neurosurgery, University Hospital, Uppsala, Sweden*These authors contributed equally to the work.

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INTRODUCTION

INITIALLY DEVELOPED FOR USE in cat and rabbit (Hayeset al., 1987; Stalhammar et al., 1987), the midline fluid

percussion model of brain injury was adapted to the rat(Dixon et al., 1987; McIntosh et al., 1987) and then mod-ified to produce the injury over a single hemisphere in therodent (McIntosh et al., 1989a). The lateral fluid percus-sion (LFP) model has since become the most extensivelyused and well characterized model of experimental TBI(Laurer et al., 2002). After exposure of the skull and trephi-nation, injury is produced by the rapid impact of a fluidbolus against the intact dural surface (Fig. 1). Reproduciblelevels of injury severity can be achieved by adjusting thependulum height, which defines the force of the fluid pres-sure pulse transmitted through the saline reservoir. Varia-tions on the injury device have included physical changes,such as the substitution of a high pressure pump for thependulum and saline reservoir (Toulmond et al., 1993a).

Although the initial aim for developing the LFP model wasto generate coup-contrecoup injury in a small animalmodel (T.K. McIntosh, personal notes), the resultingpathology has been identified, rather, as a mixed model ofTBI, with both focal and diffuse injury characteristics (sub-dural hematoma, subarachnoid hemorrhage, white mattertears) (Cortez et al., 1989; Hicks et al., 1996; Bramlett etal., 1997b; Graham et al., 2000b). Over the years, LFP hasbeen used primarily to identify TBI-induced cellular andmolecular changes and evaluate potential therapies whichhave established it as a valid and reliable model to studythe pathophysiology of human TBI.

Intra- and Inter-Laboratory Reliability of the LFP Model of TBI

The LFP brain injury model has been widely adaptedas a standard experimental model of TBI. The reliabilityof this model within each laboratory can be maintainedthrough periodic examination of cognitive, neuromotor,

translated to severely injured patients. Recently, the clinical relevance of LFP has been enhanced bycombining the injury with secondary insults, as well as broadening studies to incorporate issues of gen-der and age to better approximate the range of human TBI within study design. We conclude that theLFP brain injury model is an appropriate tool to study the cellular and mechanistic aspects of humanTBI that cannot be addressed in the clinical setting, as well as for the development and characteriza-tion of novel therapeutic interventions. Continued translation of pre-clinical findings to human TBI willenhance the predictive validity of the LFP model, and allow novel neuroprotective and neuroregener-ative treatment strategies developed in the laboratory to reach the appropriate TBI patients.

Key words: animal models; head injury; therapeutic interventions; reliability; validity

FIG. 1. Representative placement and site of originally described lateral (parasaggital) fluid percussion brain injury (inset) andschematic of a fluid percussion brain injury device. A pendulum from a known height impacts the piston of a saline-filled reser-voir, forcing a brief fluid bolus into the sealed cranial cavity.

and histological injury-induced alterations and compari-son to historical data; however systematic evaluation ofmodel reliability across institutions remains difficult toachieve. Since publication of the original model paper,investigators purposefully or inadvertently have variedthe craniectomy location (Yoshino et al., 1991; Dietrichet al., 1994b), the choice of anesthesia (Toulmond et al.,1993b; Dietrich et al., 1994b; Saatman et al., 1997;Hamm, 2001; Marklund et al., 2002), the size of craniec-tomy (Sato et al., 2001; D’Ambrosio et al., 2004), andthe attachment method of the animal to the injury devicevia the implantation of a plastic cap (Toulmond et al.,1993b; Sato et al., 2001). Variations in attachment meth-ods include the use of caps of different internal diame-ters, the placement of caps on top of versus inside thecraniectomy, and the use of straight, 90° angle or longextension tubes, all which markedly change the resistancedelivered by the fluid pulse and alter the forces deliveredto the brain. In addition to the above factors, the actualconfiguration of the fluid percussion device varies be-tween laboratories, confounding the interpretation of in-jury severity. Although common presentation of atmo-spheric pressure as a measure of injury severity indicatesthe pressure produced by the apparatus (not what the an-imal received), the return of reflexes or mortality maybetter serve as biological indicators of injury severity.Movement of the craniectomy location or incident angleof injury can change dramatically the cellular character-istics of the injury [for reviews see (Povlishock et al.,1994; Laurer et al., 2002)].

As originally described for the rat, LFP involves a 4.8-mm craniectomy centered over the left parietal bone, 4.0mm lateral to the sagittal suture (McIntosh et al., 1989a).The neuropathological sequelae evolves as a cortical con-tusion lateral to the actual impact site and cell death inthe hippocampus, thalamus, and cortex, with limited in-volvement of the brainstem and contralateral hemisphere(Hicks et al., 1996; Smith et al., 1997a). Dietrich et al.(1994) modified the model to include a craniectomy cen-tered over the right parietal bone, 2.0 mm more medialand 0.2 mm more rostral than originally described, re-sulting in ipsilateral neuronal cell loss in the hippocam-pus, thalamus, and cortex. However, neuronal loss in theCA2/CA3 region of the ipsilateral hippocampus was notreported in a subsequent study using this model (Bram-lett et al., 1997a).

To accommodate transgenic technology and the asso-ciated molecular and genetic tools, Carbonell et al. (1998)adapted LFP to the mouse. As expected, the incident im-pact angle, craniotomy size, craniotomy location andanesthesia were varied to accommodate smaller bodyweight, skull size, and skull thickness. Despite the sub-tle variations in the injury induction, similar patterns of

pathobiology (neuronal and glial) and behavioral deficitsto the rat were observed (Carbonell et. al., 1998, 1999).Additionally, LFP in the mouse results in uniform, non-progressive neuronal loss from all hippocampal subre-gions ipsilateral, but not contralateral, to the injury (Wit-gen et al., 2003; Tran et al., 2004), where an initialimpairment of anterograde hippocampal-dependent cog-nitive function recovers by one month post-injury (Lif-shitz et al., 2004).

Two more recent studies (Vink et al., 2001; Floyd etal., 2002) have emphasized the influence of craniectomyposition in LFP injury. At craniectomy positions less than3.5mm away from the sagittal suture, both ipsilateral andcontralateral cortical damage could be identified usingmagnetic resonance imaging (MRI) and conventional his-tological analysis, where the increased size of ipsilaterallesions were associated with greater motor deficits (Vinket al., 2001). When craniectomy positions were movedto a location greater than 3.5 mm from the sagittal su-ture, no contralateral cortical lesion developed (Vink etal., 2001). In contrast, the extent of hippocampal damagedid not appear to correlate with craniotomy location.Larger rostral, caudal, medial and lateral shifts in craniec-tomy location within the boundaries of lambda, bregma,the sagittal suture and the temporal ridge also affectedcognitive and histological outcome (Floyd et al., 2002).The extreme medial and rostral shifts in craniectomy lo-cation blunted the injury-induced cognitive deficit, androstral shifts lessened the injury-induced hippocampalpathology. Thus, careful attention to craniectomy posi-tion on the part of the surgeon can enhance repro-ducibility and reliability of the model.

The use of different anesthesia paradigms may alterthe extent of injury via neuroprotective or vascular ef-fects (Salzman et al., 1993; Warner et al., 1996; Statleret al., 2000), thereby complicating the interpretation ofdata across laboratories. However, therapeutic evaluationof anesthesias alone has yet to be evaluated after LFP.Despite these variations in the mechanics of producingLFP brain injury, numerous reports across several dif-ferent groups present a close association between injuryseverity and extent of injury (Perri et al., 1997; Saatmanet al., 1998; Dhillon et al., 1999; Sanders et al., 1999;Vink et al., 2001), defining the reproducibility of themodel across laboratories.

Histology/Pathophysiology

Time course and regional degeneration. It is generallyaccepted that LFP reproduces the histopathology associ-ated with multiple types of human traumatic brain injury.Depending on the severity of injury, the predominanthistopathological feature of LFP is a focal contusion in

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the cortex with accompanying petechial or intra-parenchymal hemorrhage (Cortez et al., 1989; McIntoshet al., 1989a; Bramlett et al., 1997b), similar to that ob-served after human closed head injury (Graham et al.,2002). Histological markers of degeneration used to doc-ument the regional and temporal pattern of cell death anddysfunction following LFP include: loss of Nissl sub-stance, degeneration as seen in silver stained preparationand by acid fucsin, gene activation, and immunohisto-chemical detection of kinases, phosphatases, and struc-tural proteins. Acutely after injury, contused tissue is ev-ident in the cortex beneath the injury site, which enlargesover weeks to become a cavity lined with glia (glia lim-itans) that progressively expands due to ongoing celldeath up to one year post-injury (Smith et al., 1997a;Pierce et al., 1998; Bramlett et al., 2002). Over days tomonths, progressive degenerative cascades persist in ad-ditional, selectively vulnerable brain regions, includingthe hippocampus (Cortez et al., 1989; Smith et al., 1991;Lowenstein et al., 1992; Hicks et al., 1993, 1996; Contiet al., 1998; Carbonell et al., 1999; Dhillon et al., 1999),thalamus (Hicks et al., 1996; Conti et al., 1998; Pierce etal., 1998; Saatman et al., 1998; Carbonell et al., 1998;Sato et al., 2001; Raghupathi et al., 2003), medial sep-tum (Sinson et al., 1997; Smith et al., 1997a), striatum(Hicks et al., 1996; Pierce et al., 1996; Hallam et al.,2004), and amygdala (Hallam et al., 2004). Due to thelateralization of the injury, however, few reports havedemonstrated pathology extending into the brainstem orcontralateral hemisphere (Lowenstein et al., 1992; Pierceet al., 1998; Grady et al., 2003), where hippocampal at-rophy and hilar neuronal loss have been demonstrated.Yet, the lateralization of the pathology may allow forqualitative comparisons between the directly injuredhemisphere and the contralateral hemisphere, which mayor may not exhibit damage depending on the outcomemeasure and specific configuration of the injury. The timecourse and extent of degeneration demonstrate that LFPis a mixed model of brain injury (both focal and diffuse),which progresses through time and across brain regions.Although variations in the model can affect the extentand progression of degeneration observed after LFP, cor-tical damage without brainstem compression is a charac-teristic feature of LFP.

In the human condition, moderate to severe TBI is of-ten associated with skull fracture and surface contusionsacross multiple gyri (Graham et al., 2005). Despite theseclinical features that cannot be modeled by LFP, in-tracranial hemorrhage, brain swelling and progressivegray matter damage are hallmarks of the pathophysiol-ogy of both TBI and LFP (Graham et al., 2000a). Although the primary mechanical injuries differ, thecraniectomy after severe human TBI allows the ensuing

secondary damage to occur under similar conditions inboth animal and man. Subdural and intraparenchymalhematomas increase intracranial pressure and brainswelling, which may result in the progressive distortionand herniation of brain tissue.

Secondary cellular damage and loss. Within differentbrain regions, all cell types are susceptible to the me-chanical forces of TBI. The primary injury consists ofrapid deformation of the brain, leading to rupture of cellmembranes, escape of intracellular contents, and disrup-tion of blood flow (McIntosh, 1994), resulting in pri-marily necrotic cell death (Dietrich et al., 1994b; Rink etal., 1995). The delayed or secondary injury, however, isa complex series of biochemical, structural and molecu-lar changes that, in combination, can lead to cellular dam-age and loss resembling both apoptosis and necrosis(Rink et al., 1995; Conti et al., 1998; Raghupathi et al.,2002). Pathologic release of excitatory amino acid (EAA)neurotransmitters (glutamate, aspartate) and subsequentactivation of glutamate receptors, results in the influx ofNa�, efflux of K�, and subsequent Ca2� influx into thecell (Faden et al., 1989; Katayama et al., 1990), causingcellular swelling (cytotoxic edema) and the excitotoxicdestruction of cells through direct or indirect pathways.Although, the initial rise in extracellular potassium, cel-lular depolarization and uncontrolled release of excita-tory neurotransmitters define the excitotoxic insult, sec-ondary progression of the injury after LFP can affectselectively specific cell types, as demonstrated by neu-ronal damage across brain regions, including the cortex,hippocampus, thalamus and striatum using FluroJade(Sato et al., 2001; Hallam et al., 2004). Acute damageprogresses to apoptotic and necrotic neuronal death afterLFP in rodents and remains detectable for months (Diet-rich et al., 1994b; Rink et al., 1995; Hicks et al., 1996;Yakovlev et al., 1997; Bramlett et al., 1997b; Conti etal., 1998; Keane et al., 2001; Bramlett et al., 2002;Raghupathi et al., 2002; Knoblach et al., 2002b). More-over, glial susceptibility to the pathology associated withLFP has been demonstrated at both acute and chronictime points throughout the brain (Cortez et al., 1989; Hillet al., 1996; Conti et al., 1998; Carbonell et al., 1999;D’Ambrosio et al., 1999; Hill-Felberg et al., 1999; Zhaoet al., 2003; Grady et al., 2003). Regional degenerationcan be identified by astrocyte, macrophage and microgliaactivation (Lowenstein et al., 1992; Soares et al., 1995a;Okimura et al., 1996; Bramlett et al., 1997a; Hill-Felberget al., 1999; Zhao et al., 2003; Grady et al., 2003). Theinitial increase in neutrophils lining the vasculaturespreads into surrounding contused tissue (Soares et al.,1995a), while damage and loss of endothelial cellsdemonstrate significant alterations to the microvascula-

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ture (Balabanov et al., 2001; Lin et al., 2001). Hence, theongoing pathology of LFP establishes an inhospitable en-vironment that perpetuates the sequelae of brain injury.In severe human TBI, microdialysis measurements haveconfirmed similar ionic and excitatory amino acid dis-ruptions in the acute post-injury period (Altura et al.,1995; McCracken et al., 1999; Polderman et al., 2000;Hlatky et al., 2002), affording the LFP model further con-struct validity in terms of the secondary pathophysiology.

Subcellular and molecular response. The focal and dif-fuse nature of LFP affects most, if not all, componentsof the CNS. Reports have documented pathology associ-ated with subcellular organelles (Vink et al., 1990a;Hovda et al., 1991; Lifshitz et al., 2003a), gene tran-scription (O’Dell et al., 2000c; Natale et al., 2003), pro-tein translation and folding (Tanno et al., 1993; Lowen-stein et al., 1994; Raghupathi et al., 1995b; Fan et al.,1999), cytoskeletal components (Saatman et al., 1998),and synapses (Emery et al., 2000). In injured tissue, meta-bolic function is impaired, which may reflect damage directly to mitochondria or trafficking of metabolic sub-strates. Not only cell death genes, but an array of house-keeping, neurotrophic, cytokine, cell adhesion and im-mediate early genes are known to change their expressionpatterns significantly after LFP brain injury (Hayes et al.,1995; Raghupathi et al., 1995a, 1996; Hicks et al., 1997b;McIntosh et al., 1998; Truettner et al., 1999; Giza et al.,2002; Natale et al., 2003). Moreover, the integrity ofDNA lies susceptible to injury-induced cascades (Contiet al., 1998; Zhang et al., 1999; LaPlaca et al., 1999). Ad-ditionally, the levels and distribution of proteins involvedin cell death, cell signaling, inflammation, cytoskeleton,and synaptic transmission also are altered by this modelof TBI (Yakovlev et al., 1997; Knoblach et al., 1999; Di-etrich et al., 1999; O’Dell et al., 2000c; Lotocki et al.,2003). Stretching and shearing of axons, both in the di-rect vicinity of the injury and in areas remote to the im-pact, contribute to the cytoskeletal damage that disruptsthe cytoarchitecture related to network function and cel-lular transport (Hicks et al., 1997a; Bramlett et al., 1997b;Saatman et al., 1998; Carbonell et al., 1998). Total cel-lular disruption, from transcription to function, has beenexplained by increases in the intracellular calcium con-centration from plasma membrane disruption and the ac-tivation of calcium-permeable ion channels (Fineman etal., 1993; McIntosh, 1994; Osteen et al., 2001). Subse-quent kinase activation initiates transcription factors, heatshock proteins and signaling cascades that effect the de-layed sequelae of brain injury. These intracellular sig-naling cascades occur concurrently with cytokine-medi-ated inflammation (Fan et al., 1995; Toulmond et al.,1995; Raghupathi et al., 1995a; Fan et al., 1996). In con-

trast to tissue pathology, the injury-induced activation ofsignaling pathways extends into the contralateral hemi-sphere (Raghupathi et al., 1995a; Raghupathi et al., 1996;Fan et al., 1996). Whether the cellular and molecular re-sponses to LFP result from the initial injury, secondarypathology or reflect a recovery process remain to be de-termined.

Physiology

Vital signs and arterial blood gases. Cerebral au-toregulation is impaired to some degree in severely brain-injured patients (Overgaard et al., 1974; Bouma et al.,1990; Golding et al., 1999), with increased likelihood for exacerbation of secondary injury by hypotension(Struchen et al., 2001). In LFP brain injury, severity-de-pendent increases in mean arterial blood pressure (MAP)immediately after injury became depressed in severely-injured animals (McIntosh et al., 1989a). In more mod-erate injury severities, MAP returned to baseline and re-mained stable by five minutes post-injury (McIntosh etal., 1989a). Subsequently, the severity-dependent patternof hypertension has become a physiological hallmark ofLFP (Dietrich et al., 1994b; Prins et al., 1996; Fukuda etal., 1996; Marklund et al., 2001a). Interestingly, adult ratssubjected to LFP brain injury lose vascular tone after in-duction of secondary hemorrhagic shock (Law et al.,1996).

Episodes of hypoxemia, defined as apnea/cyanosis oran PaO2 arterial blood gas less than 60 mm Hg in theacute phase of severe brain injury increases morbidityand mortality (Brain Trauma Foundation, 2000b). Simi-larly, periods of apnea and unconsciousness (McIntoshet al., 1989a; Smith et al., 1991; Dietrich et al., 1994b;Prins et al., 1996; Fukuda et al., 1996), as well as PaO2

decreases and PaCO2 increases, are evident in severeLFP-injured, spontaneously breathing rats (McIntosh etal., 1989a).

Intracranial pressure, cerebral blood flow, and metab-olism. Intracranial pressure (ICP) increases over the initialminutes across a wide range of ages following LFP braininjury (Prins et al., 1996; Armstead, 1999b). The magni-tude of the ICP increase depends on injury severity and isaccompanied by an initial increase in mean arterial bloodpressure (MAP; Cushing’s response). However, the Cush-ing’s response is attenuated markedly in developing ani-mals (post-natal day 17) (Prins et al., 1996).

Although injury-induced increases in ICP have beenthought to contribute to secondary reductions in localcerebral blood flow (lCBF) after LFP, this concept issomewhat simplistic. In fact, a transient hyper-acute in-crease in lCBF (Muir et al., 1992) is followed by a pro-

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longed decrease starting within 15–30 min after injury(Yamakami et al., 1989; Ozawa et al., 1991; Muir et al.,1992; Ginsberg et al., 1997), and lasting up to 4 h (Ya-makami et al., 1989; Muir et al., 1992). Similar dynamicresponses in ICP and lCBF have been documented afterhuman TBI (Kelly et al., 1996; Kelly et al., 1997; Mar-tin et al., 1997). Underlying mechanisms responsible forchanges in lCBF following brain injury may include aloss of vasoreactive signaling, spasm and chronic con-striction due to ionic disturbance. Although CBF is re-duced after LFP, it rarely approaches a CBF range tradi-tionally considered to be below the ischemic threshold,unless the injuries are severe (Yamakami et al., 1989;Graham et al., 2002). However, the contribution of cere-bral ischemia after TBI may be related more to the meta-bolic demands of the tissue, rather than the actual rate offlow.

The metabolic demands of LFP-injured brain, as it re-lates to glucose utilization, has been explored using 14C-2-deoxy-D-glucose autoradiography (Sunami et al.,1989a,b; Yoshino et al., 1991; Kawamata et al., 1992;Hovda et al., 1992). During the acute phase after LFP,both the developing and adult brain exhibit a marked increase (up to 150%) in the utilization of glucose, pri-marily within the cerebral cortex and dorsal hippocam-pus ipsilateral to the injury, and evident in the contralat-eral hemisphere also (Thomas et al., 2000). Glucosemetabolism increases due to the increase in extracellularpotassium (Katayama et al., 1990) and concomitant acti-vation of glutamate receptors (Yoshino et al., 1991;Kawamata et al., 1992). The short-lived increase in glu-cose utilization after LFP can last for over an hour, de-pending on the severity of injury, after which the sameregions enter a state of glucose metabolic depression thatcan last for up to 2 weeks. More importantly, during thedays after LFP, the delivery of glucose may be compro-mised, given a reported loss of coupling between localcerebral glucose metabolism and cerebral blood flow, acondition consistently seen in human TBI (Jaggi et al.,1990; Bergsneider et al., 1997), particularly in areas pre-viously associated with neuronal necrosis (Kawamata etal., 1992; Ginsberg et al., 1997).

Over the last 10 years, similar dynamic changes incerebral glucose metabolism have been reported in pa-tients following severe TBI using 18F-deoxy-D-glucoseincorporating positron emission tomography (Hovda etal., 1995; Bergsneider et al., 1997; Bergsneider et al.,2000, 2001; Wu et al., 2004), further validating the clin-ical relevance of the LFP brain injury model. The changesin glucose metabolism are more prolonged in patientsthan those after LFP, lasting for as long as 2 weeks bothregionally and globally. In contrast, the subsequent glu-cose metabolic depression in brain-injured patients is ev-

ident for over a year. Interestingly, the degree of increaseor subsequent decrease in glucose metabolism after hu-man TBI is not related to the severity of injury, in agree-ment with the LFP model. In fact, the severity of injurymay be defined by the length of time animals or patientsexhibit the ensuing metabolic disturbances.

In addition to glucose utilization, oxidative capacityafter LFP exhibits prolonged reductions in the cerebralcortex and underlying hippocampus as assessed using cy-tochrome oxidase histochemistry (Hovda et al., 1991).Deficits in oxidative capacity may stem from mitochon-drial dysfunction imposed by increases in intracellularcalcium after LFP (Lifshitz et al., 2003a). In human TBI,monitoring oxidative metabolism remains a hallmark ofneuro-intensive care management. As the LFP modeldemonstrates, patients exhibit a pronounced decrease inoxidative metabolism for days to weeks after injury(Obrist et al., 1984, 1987; Glenn et al., 2003). Similarly,the mechanisms behind oxidative metabolic reductions inhuman patients appear to be similar to those reported forLFP brain injury (Verweij et al., 2000).

Dynamic changes in metabolic demand, dysfunctionalmitochondria, and the loss of coupling between cerebralblood flow and metabolism demonstrate that the injuredbrain may be in a state of energy crisis. The energy cri-sis may explain how secondary activation of the injuredbrain could overwhelm the energy demands of the tissueand result in secondary cell death (Ip et al., 2003). Thus,the reductions in ATP after LFP are associated with en-ergy crisis, rather than ischemic levels of cerebral bloodflow (Lee et al., 1999; Lifshitz et al., 2003a).

Electrophysiology

The examination of ensuing electrophysiological al-terations began with the initial description of the LFPmodel. At the higher levels of injury, disturbances inbrainstem auditory-evoked potentials were observed,suggestive of disruptions in auditory neuronal processing(McIntosh et al., 1989a). The initial response to injuryincludes an indiscriminant recurrent release of excitatoryneurotransmitters, leading to widespread depolarization(Faden et al., 1989; Katayama et al., 1990; Hayes et al.,1992). Only recently have electrophysiological distur-bances in cortical neuronal activity been examined in theacute post-injury period. The number of cortical spread-ing depression cycles increases as injury severity in-creases, with almost constant activity at more severe in-jury levels (Rogatsky et al., 2003). And spontaneousseizures recorded by electrocorticography up to 2 monthspost-injury demonstrate post-traumatic epileptic episodesassociated with hyperexcitability of the neocortex(Kharatishvili et al., 2003; D’Ambrosio et al., 2004).

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In the hippocampus, however, significant injury-in-duced electrophysiological changes repeatedly have beenconfirmed, and are almost entirely confined to the hemi-sphere ipsilateral to the injury. Pathological alterations inGABA-mediated inhibition are implicated in LFP hip-pocampal dysfunction (Reeves et al., 1997; Toth et al.,1997; Santhakumar et al., 2001). At seven days post-in-jury, the disruption of dentate gyrus excitability mani-fests as an injury severity-dependent lowering of seizurethreshold (Lowenstein et al., 1992). The greater disinhi-bition in the dentate gyrus lowered thresholds for devel-oping self-sustained seizure activity 1–12 weeks post-in-jury compared to sham (Coulter et al., 1996; Santhakumaret al., 2001). A proposal for the reduction in inhibitionincludes the selective loss of inhibitory interneurons,since the frequency of miniature inhibitory synaptic cur-rents decreases (Coulter et al., 1996; Toth et al., 1997;Santhakumar et al., 2000), which reverses months afterinjury potentially due to enhanced excitatory input ontopreserved inhibitory interneurons (Santhakumar et al.,2001). Seemingly contradictory results that demonstrateopposite shifts in excitability have been attributed to prox-imity of the recordings to the injured cortex and the re-maining anatomical connections in the slice preparation(Reeves et al., 1997; Muraoka, 2002). Similarly, LFP dis-rupts neuronal activity, primarily inhibition, in area CA1of the hippocampus (Reeves et al., 1997; D’Ambrosio etal., 1998; Akasu et al., 2002), establishing regional shiftsin excitability within the injured hippocampus. Globalfunctional disruption is paralleled by the inability to in-duce or express long-term potentiation up to 8 weeks post-injury (Miyazaki et al., 1992; Sick et al., 1998; D’Am-brosio et al., 1998; Sanders et al., 2000). The regional shiftsin excitability and impairments in long-term potentiationmay contribute to injury-related learning and memorydeficits (Smith et al., 1991; Floyd et al., 2002).

Behavioral Outcomes

Significant neuromotor, sensory and cognitive dys-function are frequent sequelae of human TBI (Caprusoet al., 1992; Sullivan et al., 1994; Levin, 1995; Koelfenet al., 1997; NIH Consensus Conference, 1999). Thus,behavioral analyses have been adapted or developed foruse with LFP brain injury in an attempt to replicate eventsassociated with human TBI. To date, behavioral evalua-tions after LFP brain injury have been limited to the ratand mouse models. Behavioral assessments can be usedto determine the severity of the LFP injury (McIntosh etal., 1989a) and functionally evaluate treatments with var-ious therapeutic interventions. The use of specific be-havioral outcome measures after experimental brain in-jury has been reviewed recently (Fujimoto et al., 2004).

With behavioral testing after LFP, the choice of testsshould address appropriately the recovery process ortreatment paradigm to maintain clinical and experimen-tal relevance throughout the investigation (Hamm, 2001).Most importantly, behavioral evaluation should consistof several tests at numerous post-injury time points todocument various sequelae and recovery occurring afterLFP brain injury. As the aim of experimental brain in-jury research is to allow brain-injured patients to live longand relatively normal lives, long-term behavioral testingneeds to be incorporated into the study design, particu-larly in interventional studies.

Return of reflexes. After LFP, the corneal, pinnal, pawflexion, and righting reflexes are transiently lost andrapidly return (Floyd et al., 2002; Hallam et al., 2004;Lee et al., 2005). Individual reflexes substitute reason-ably well for motor components of the Glasgow ComaScale (GCS) (Teasdale et al., 1974; Dixon et al., 1987),and reflect the loss of reflexes often seen in the acutephase of human head injury, providing the model addi-tional validity. As such, the return of the righting reflex,and other reflexes, has served routinely as an indicatorof severity of LFP injury (Morehead et al., 1994; Schmidtet al., 1995; Carbonell et al., 1998; Hallam et al., 2004;Lee et al., 2005), which appears to correlate with neuro-motor deficits.

Neuromotor outcome. After TBI in humans, manylong-term neuromotor deficits including difficulties withcoordination, posture and steadiness of movement havebeen shown years after injury (Schalen et al., 1994). Thedegree of neurological motor impairment depends uponthe severity of injury, allowing the testing of motor func-tion to further characterize the magnitude of injury, toevaluate the progression of motor impairment, and toevaluate the efficacy of pharmacological treatments tar-geting the mechanisms responsible for motor dysfunc-tion. After LFP, a composite neuromotor score (com-posite neuroscore or neurologic sum score) has been usedroutinely assess neurological motor function and corre-sponds to motor components of the GCS in the clinicalsetting (Hamm, 2001). Components of the compositescore vary by laboratory, but generally include evalua-tions of gross limb strength and reflex function, whichmay include a measure of activity level (Faden et al.,1989; McIntosh et al., 1989a; Sun et al., 1995a; Knoblachet al., 1998). The composite score of neuromotor func-tion remains a reliable test to assess the level of neuro-logical motor impairment from 48 hours to one year af-ter LFP injury (Sun et al., 1995a; Saatman et al., 1997;Pierce et al., 1998; Knoblach et al., 2002a; Furukawa etal., 2003).

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In addition to reflexive motor tests, vestibulomotortests determine the degree of fine motor coordination af-ter injury (Table 1). Through tests such as the rotatingpole (Mattiasson et al., 2000; Piot-Grosjean et al., 2001),beam balance (Hamm, 2001; Floyd et al., 2002; Alessan-dri et al., 2002), beam walk (Saatman et al., 1996; Lyethet al., 2001; Piot-Grosjean et al., 2001; Floyd et al., 2002;Alessandri et al., 2002), rotarod (Hamm, 2001), and ropegrip (Long et al., 1996), vestibulomotor deficits havebeen shown days to weeks after LFP.

Sensorimotor outcome. Recently, sensorimotor func-tion has been tested after LFP brain injury. The stickypaper test (adhesive paper test) has been adapted for usein LFP from other rodent models of neurologic injury(Schallert et al., 1982; Hernandez et al., 1988), and issensitive to detect sensorimotor deficits and treatment ef-ficacy (Schallert et al., 1982; Riess et al., 2001). Also,

limb placement (whisker test) has been adapted for usein LFP from ischemia models (De Ryck et al., 1989;Schallert et al., 2000), and measures injury-induced def-icits in somatosensory and motor integration (O’Dell etal., 2000b). The progression of these sensorimotor im-pairments (and recovery) over time provides insight tosensory information processing in the injured brain.

Cognitive outcome. Cognitive tests in a clinical settinginclude both verbal and visual recognition tests, whereaslaboratory tests typically rely on performance in a vari-ety of hippocampal-dependent spatial mazes. After LFP,both anterograde and retrograde cognitive function is im-paired, as tested in several cognitive tasks. Designed toassess the cognitive processes of learning and workingmemory (Morris et al., 1982; D’Hooge et al., 2001), theMorris water maze (MWM) was the first cognitive testused with the LFP model (Smith et al., 1991) and remains

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TABLE 1. OUTCOME MEASURES USED TO DETECT NEUROLOGICAL IMPAIRMENT AFTER FLUID PERCUSSION BRAIN INJURY

Neurologic outcome measure Selected test Selected “key” references

Reflex supression Righting Reflex Hamm, J. Neurotrauma, 2001Hallam et al., J. Neurotrauma, 2004Schmidt and Grady, J. Neurosurg., 1995

Neuromotor impairment Composite Neuroscore McIntosh et al., Neuroscience, 1989Saatman et al., Proc. Natl. Acad. Sci. U. S. A, 1996Furukawa et al., J. Neurotrauma, 2003Stutzmann et al., CNS. Drug Rev., 2002Faden et al., Exp. Neurol., 2001

Beam Balance Hamm, J. Neurotrauma, 2001Lyeth et al., J. Neurotrauma, 1993

Beam Walk Lyeth et al., Exp. Neurol., 2001Piot-Grosjean et al., Neurobiol. Dis., 2001Hamm et al., J. Neurotrauma, 1996

Rotarod Hamm et al., J. Neurotrauma, 1994Hamm, J. Neurotrauma, 2001

Rotating Pole Mattiasson et al., J. Neurosci. Methods, 2000Piot-Grosjean et al., Neurobiol. Dis., 2001Hoover et al., J. Neurotrauma, 2004

Rope Hang/Grip Test Long et al., J. Neurotrauma, 1996Tapered Beam Klint et al., J. Neurotrauma, 2003

Sensory impairment Sticky Paper Riess et al., Restor. Neurol. Neurosci., 2001Limb Placement O’Dell et al., Restor. Neurol. Neurosci., 2000

Cognitive deficits Morris Water Maze (Memory) Hicks et al., J. Neurotrauma, 1993Smith et al., J. Neurotrauma, 1991Lyeth et al., Exp. Neurol., 2001Sanders et al., J. Neurotrauma, 1999

Morris Water Maze (Learning) Hoover et al., J. Neurotrauma, 2004Griesbach et al., Neuroscience, 2004Sanderson et al., J. Cereb. Blood Flow Metab, 1999Pierce et al., Neuroscience, 1998

Lashley Maze Piot-Grosjean et al., Neurobiol. Dis., 2001Radial Arm Maze Lyeth et al., Exp. Neurol., 2001

the most frequently used test of cognitive function afterLFP brain injury. Cognitive deficits in memory are ob-served 48 h to 2 weeks after injury LFP (Smith et al.,1991; Sinson et al., 1997; Pierce et al., 1998; Bramlett etal., 1999a; Leoni et al., 2000), while learning deficits aredetectable up to 1 year depending on injury severity(Pierce et al., 1998; Sanderson et al., 1999; Schmidt etal., 1999; Sanders et al., 1999; Lyeth et al., 2001). TheLashley maze and the 8-arm radial maze, which evalu-ate working memory, have demonstrated injury-inducedcognitive deficits after LFP (Lyeth et al., 2001; Piot-Grosjean et al., 2001). Furthermore, cognitive functionrelated to classical conditioning and associative memoryhas been tested using conditioned fear and shows hip-pocampal-dependent cognitive deficits after LFP (Hogget al., 1998a,c). Similarly, severe human TBI leads to en-during memory and learning dysfunction (Barth et al.,1983; Bennett-Levy, 1984; Leplow et al., 1997).

VALIDITY OF THE FLUID PERCUSSIONMODEL OF TBI

Face Validity

When evaluating the validity of LFP to model clinicalTBI, one must address what is known about human TBI,to date. In human closed head injury, biomechanical, phys-iological, neurological, and morphological alterations re-sult from the primary injury. Although other experimentalTBI models may appear to better replicate the mechanismsinvolving the primary impact, the pathophysiological se-quelae and functional deficits after LFP represent an in-jury to the brain that closely reproduces those seen fol-lowing clinical TBI. The LFP model reproduces severalaspects of human TBI, including focal contusion, petechialintraparenchymal and subarachnoid hemorrhages, tissuetears and traumatic axonal injury (McIntosh et al., 1989a;Graham et al., 2000b). Other sequelae of human head in-jury include blood–brain barrier (BBB) disruption, axonalinjury, neuronal loss, changes in glucose metabolism, al-terations in cerebral blood flow, seizure activity, excita-tory amino acid release, and altered levels of conscious-ness (vide supra, and see Narayan et al., 1996). After LFP,the sequelae include BBB disruption (Cortez et al., 1989;Tanno et al., 1992; Soares et al., 1992), white matter dam-age (Hicks et al., 1997a; Graham et al., 2000b), neuronalloss (Cortez et al., 1989; Toulmond et al., 1993a; Hicks etal., 1996; Smith et al., 1997a; Saatman et al., 1998; Sulli-van et al., 2000; Sato et al., 2001), altered cerebral me-tabolism (Hovda et al., 1990; Yoshino et al., 1991), alteredcerebral blood flow (Yuan et al., 1988; Yamakami et al.,1989; Kelly et al., 2000), altered brain electrical activity

(Miller et al., 1990; Lowenstein et al., 1992), and bothacute and chronic behavioral abnormalities (McIntosh etal., 1989a; Pierce et al., 1998; Sanders et al., 1999; Fadenet al., 2001; Lyeth et al., 2001; Hamm, 2001). AlthoughLFP injury, like most experimental models, cannot fullyreproduce the entire heterogeneous and multifaceted spec-trum of clinical TBI, the distinct correlations between clin-ical and preclinical pathophysiological sequelae affordLFP face validity in modeling human TBI.

Predictive Validity: Evaluation of PotentialTherapeutic Strategies Using LFP

Stabilization therapies. Brain-injury patient manage-ment focuses on post-injury stabilization, and the Guide-lines for the Management of Severe Traumatic Brain Injury (Brain Trauma Foundation, 2000a) offers options,not recommendations, for treatment. Despite the tremen-dous need for the evaluation of interventions in the initialmanagement phase, experimental evidence is sparse. Withthe energy demands and metabolic uncoupling followingboth experimental and human TBI, the infusion of certainfluids can influence the duration and extent of acute meta-bolic/cerebrovascular alterations and ensuing neuropathol-ogy. Intravenous infusion of lactate after LFP increasedbrain lactate levels in brain-injured animals when com-pared to a saline infusion, and recovery of dialysate glu-cose occurred more rapidly (Chen et al., 2000), suggest-ing that lactate infusion reduced the characteristic fall inbrain glucose observed after LFP (Kawamata et al., 1995;Chen et al., 2000; Bentzer et al., 2000). Brain-injured an-imals treated with lactate have also been shown to havesignificantly shorter learning latencies in the MWM at 2weeks post-injury than saline-treated animals (Rice et al.,2002), indicating that lactate may serve as a potential clin-ical therapy for moderately brain-injured patients (Bon-doli et al., 1978). In addition, intravenous infusion of high-dose and high-concentration human serum albuminreduced contusion volume and improved ipsilateral CA3neuronal survival after LFP (Belayev et al., 1999). Albu-min treatment reduced local cerebral metabolic rate of glu-cose compared to both vehicle-treated injured animals andsham-injured animals, indicating that albumin fluid re-suscitation may be a potential acute management strategyfor the TBI patient (Ginsberg et al., 2001). However, amulti-center, randomized, double-blind trial comparingthe effects of albumin and saline fluid resuscitation de-tected increased mortality at 28 days in a sub-group ofbrain-injured ICU patients treated with albumin (SAFEStudy Investigators, 2004). But the low patient numbersand acute 28-day time point leave ambiguity as to albu-min treatment. Since the initial physiologic responses af-

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ter LFP (e.g., changes in BP, O2, CO2) closely parallelthose observed in human TBI, a tremendous opportunityexists to explore stabilization therapies using the LFPmodel. To date, however, studies concentrating on factorsin the initial management of TBI have been limited andare worthy of further investigation.

Pharmacology. The disturbance of cognition and neu-rological function, the development of cerebral edemaand the progressive tissue loss in selectively vulnerablebrain regions ipsilateral to injury have been used as out-

come measures in the preclinical assessment of the ther-apeutic efficacy of various pharmacological compoundsafter LFP (McIntosh et al., 1998; Laurer et al., 2000;Royo et al., 2003) and see Tables 2–4. Due to the clini-cally relevant features of the LFP brain injury model, highexpectations have emerged for the development of newpharmacological treatments. Owing to the complexity ofthe secondary post-injury cascade, no single target treat-ment is likely to attenuate all post-injury behavioral andhistological alterations. Although a detailed overview ofthe pharmacology of TBI is beyond the scope of this re-

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TABLE 2. PHARMACOLOGICAL MODULATION OF EXCITOTOXICITY AFTER LATERAL FLUID PERCUSSION BRAIN INJURY

Drug and Time and routereference of administrationa Outcome

Glutamate release inhibitorsBW1003C871 Iv, 15 min Edema ↓Riluzole2–5 2–5Iv, 15 min 2–4LV ↓, 2,5NS ↑, 3Edema ↓,

4CA3 →, 5memory ↓, 5LV →619C896 Iv, pre NS ↑, CA3 ↓Lubeluzole7 Iv, 15 min CA3 →, NS →, limb placement →, MWM →

Competitive and non-competitive NMDA receptor antagonistsMK-8018–10 8–10Iv, 8pre, 8–95 min, 106h 8pre: NS ↑, 8post: NS →,

9Edema ↓, 10LV →Dextrorphan11–12 11Iv, 30 min, 12Iv, 30 min 11–12NS ↑CPP11 Icv, pre NS ↑Remacemide13 Iv, 15 min LV ↓, MWM →NPS 150614 Iv, 10 min CA3 ↓, MWM ↑, LV →Ketamine15 Iv, 15 min MWM ↑CP-101,60616 Ip, 15 min Edema →, MWM ↑CP-98,11316–17 16–17Ip, 15 min 16–17Edema ↑, 16–17MWM ↑, 17NS ↑

NMDA (polyamine site) receptor antagonistsCP-101,58116 Ip, 15 min Edema →, MWM ↑Eliprodil10,18 10Ip, 15 min - 18h 10LV ↓, 18freezing deficit ↓

18Iv, 15 min - 12hAMPA/KA receptor antagonists

Talampanel19 Iv, 30 min or 3h CA1 ↓, LV ↓YM87220–21 Iv, 15 min Edema ↓, IgG ↓,

31LV ↓, 31NS ↓RPR11782422 Iv, 15 min LV ↓

NMDA (glycine and Mg2� sites) receptor antagonistsI2CA23 Iv, 15 min Edema ↓, MWM ↑, NS ↑KYNA23–24 Iv, 15 min 23Edema ↓, 23memory ↑, 23NS ↑, 24CA3 ↓Mg1,15,25–31 1,15,29Iv, 15 min, 25Iv, pre, 15MWM ↑, 1,28Edema ↓, 25–26,28–29NS ↑,

26Iv, 30 min, 27Iv, 60 min, 26open field ↑, 27CA3 →, 27,30LV ↓,28Iv, 20 min, 3010 min, 31Icv 28LV →, 29MWM →, 29CA3 ↓, 31apoptosis ↓

Zinc chelation (CaEDTA)32 Icv, pre Tunel � cells ↓Inhibitors of NMDA subunits

Antisense oligos33 Icv, pre Mortality ↓, NS ↑, CA3 →Metabotropic receptor (group II–III) agonists

DCG-IV and (R,S)-PPG34 Intracerebr., �5 min CA3 →, DCG-IV: CA3 ↓LY35474035 Iv, 30 min NS ↑

(continued)

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TABLE 2. PHARMACOLOGICAL MODULATION OF EXCITOTOXICITY AFTER LATERAL FLUID PERCUSSION BRAIN INJURY (CONT’D)

Drug and Time and routereference of administrationa Outcome

Metabotropic receptor (group 1) antagonistsMCPG36–38 36–38Icv pre, 37Iv 15 min 36LV ↓, 36NS →, 36MWM → 36Mort ↓,

37icv: NS ↑, 37CA3 ↓, 37Iv: NS ↑, 38MWM ↑, 38BW ↑AIDA36,39 36Icv, pre, 39Intracerebr., 5 min 36MWM →, 36NS ↑, 36LV ↓, 39MWM ↑,

39CA3 ↓, 39BW ↓MPEP40 Icv, pre LV ↓, NS ↑, MWM ↑

NMDA receptor agonistCycloserine41 Ip, 24h MWM ↑

Abbreviations used in Tables 2–4: aAll time points are given as minutes or hours post-injury, except for pre, which means ad-ministration prior to LFP brain injury. Icv, intracerebroventricularly; Intracerebr, intracerebral and/or intraparenchymatous; Po, peroral; Sc, subcutaneous; Iv, intravenous; IA, intraarterial; →, no effect; ↑, increased; ↓, decreased; mort, mortality; LV, lesion vol-ume; MWM, Morris water maze (learning and memory); NS, composite neuroscore; CA3, CA3 cell death; CA1, CA1 Cell death;TUNEL�, TdT-mediated dUTP nick end labeling; IgG, blood-brain barrier disturbance; BW, beam walk; BB, beam balance test;RP, rotating pole test; ctx, cortex; SP; Sticky paper.

Abbreviations for compounds in Table 2: BW1003C87, [5-(2,3,5-trichlorophenyl) pyrimidine 2.4-diamine ethane sulphonate];Riluzole, 2-amino-6-trifluro methoxy benzthiazole; 619C89, [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlrophenyl)pyrimi-dine mesylate monohydrate]; Lubeluzole, [(2)-4-(2-benzothiazolylmethyl-amino)-�-[(3,4 diflurophenoxy)methyl]-1-piperdi-neethanol]; MK-801, Dizocilpine maleate; CPP, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; Ramacemide, 2-amino-N-(1-methyl-1.2-diphyenylethyl) acetamide hydrochloride; NPS 1506, 3,3-Bis-(m-fluorophenyl)-N-methylpropylamine hydrochloride;CP-101,606, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; Talampanel, (R-7-acetyl-5-(4-amino-phenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5-h)(2,3) benzodiazepine); YM872, [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]-acetic acid monohydrate;RPR117824, 9-carboxymethyl-imidazo-[1-2�]indenol[12e]); I2CA,Indole-2-carboxylic acid; KYNA, kynurenate; Mg, Magnesium; CaEDTA, calcium disodium ethylenediaminetetraacetate; Oligos,oligonucleotides; DCG-IV, 2,(2�,3�)-dicarboxycyclopropylglycin; (R,S)-PPG, (R,S)-4-phosphonophenylglycline; LY354740,(1S,2S,5R,6S)-(�)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid);MCPG, (S)-�-4-caboxyphenylglycine; AIDA, (RS)-1-aminoindan-1,5-dicarboxylic acid; MPEP, 2-methyl-6-(phenylethynyl)-pyridine; Cycloserine, R(�)-4-Amino-3-isoxazolidinone.

References to Table 2: 1Okiyama et al., J. Neurochem., 1995. 2Wahl et al., Brain Res., 1997. 3Bareyre et al., J. Neurotrauma,1997. 4Zhang et al., J. Neurosci. Res., 1998. 5McIntosh et al., J. Neurotrauma, 1996. 6Sun and Faden, Brain Res., 1995. 7O’Dell etal., Restor. Neurol. Neurosci., 2000. 8McIntosh et al., J. Neurotrauma, 1989. 9McIntosh et al., J. Neurochem., 1990. 10Toulmond etal., Brain Res., 1993. 11Faden et al., Science, 1989. 12Faden, J. Neurotrauma, 1993. 13Smith et al., Neurosci. Lett., 1997. 14Leoni etal., Exp. Neurol., 2000. 15Smith et al., Neurosci. Lett., 1993. 16Okiyama et al., J. Neurotrauma, 1997. 17Okiyama et al., Brain Res.,1998. 18Hogg et al., J. Neurotrauma, 1998. 19Belayev et al., J. Neurotrauma, 2001. 20Atsumi et al., Acta Neurochir. Suppl, 2003.21Furukawa et al., J. Neurotrauma, 2003. 22Mignani et al., Bioorg. Med. Chem., 2002. 23Smith et al., J. Neurosci., 1993. 24Hicks etal., Brain Res., 1994. 25McIntosh et al., J. Neurotrauma, 1988. 26McIntosh et al., Brain Res., 1989. 27Bareyre et al., J. Neurotrauma,2000. 28Guluma et al., J. Neurotrauma, 1999. 29Bareyre et al., J. Neurochem., 1999. 30Saatman et al., J. Neuropathol. Exp. Neurol.,2001. 31Lee et al., J. Neurotrauma, 2004. 32Hellmich et al., Neurosci. Lett., 2004. 33Sun and Faden, Brain Res., 1995. 34Zwienenberget al., Neurosurgery, 2001. 35Allen et al., J. Pharmacol. Exp. Ther., 1999. 36Faden et al., Exp. Neurol., 2001. 37Mukhin et al., J.Neurosci., 1996. 38Gong et al., Brain Res., 1995. 39Lyeth et al., Exp. Neurol., 2001. 40Movsesyan et al., J. Pharmacol. Exp. Ther.,2001. 41Temple and Hamm, Brain Res., 1996.

view (McIntosh et al., 1998; Royo et al., 2003; Marklundet al., 2004b), several classes of targeted pharmacologictherapies, tested in the LFP model, are reviewed below.

ATTENUATION OF EXCITOTOXICITY. After LFP, an early,marked increased in extracellular glutamate (Faden et al.,1989; Katayama et al., 1990; Panter et al., 1992) estab-lishes excitotoxicity as a component of post-injurypathology, although normal physiological glutamate con-centrations may be toxic in injured brain (Di et al., 1999).

Glutamate receptors are classified as the N-methyl-D-as-partate (NMDA; the subunits NR1, NR2A, NR2B, NR2Cand NR2D), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate (GluR5-9, KA1 andKA2), and the Group I (mGluR1and mGluR5), Group II(mGluR2 and mGluR3) and Group III (mGluR4,mGluR6, mGluR7 and mGluR8) metabotropic receptors.Administration of glutamate release inhibitors (Riluzoleand 619C89) reduces the indiscriminate rise in extracel-lular glutamate to minimize the excitotoxic influence on

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TABLE 3. CLASSES OF COMPOUNDS EVALUATED AFTER LATERAL FLUID PERCUSSION BRAIN INJURY

Drug and Time and routereference of administrationa Outcome

Anti-inflammatory drugsAnti-ICAM-142 Iv, 30 min NS ↑IL1ra43–45 43Icv, 15 min, 44Sc, 15 min, 43LV ↓, 44NS ↓, 44CA3 ↑

45Icv, 15 min 44ctx ↑, 44MWM ↑, 45NS →sIL-1R45 Icv, 15 min NS →IL-1046 Iv, pre; Sc, 10 min; Icv, 25 min Sc, Iv:NS ↑, Icv:NS →TNF/IL-6 MAB47 Icv, 1h NS →, Edema →, MWM →,

BB →, RP →sTNFR:Fc48 Icv/Iv, 15 min Icv: NS ↑, Iv: NS →P-selectine PB1.349 Iv, � 5 min MWM ↑, cholinergic cell death ↓Prostacycline50–51 50–51Iv, 5 min 50Edema ↑, 51LV ↓, 51CA3→, 51NS →Cyclosporin52–53 52Iv, pre (high/low dose), 52BW ↑(high) ↓(low), 52BB →,

53Ip, 15 min 52MWM ↑, 53MWM →, 53SP ↑, 53NS ↑VCP54 Intracerebr., 15 min LV →, MWM ↑

Free radical scavengers and NOS inhibitorsTirilazad mesylate55–57 55–56Iv, 15 min, 55–56Edema ↓, 55–56mortality ↓, 57Edema →,

57Iv, 3 min 57Rotarod →, 57NS ↑PEG-SOD58 Iv, 30 min NS →, MWM ↑MDL 74,18059 Iv, � 5 min Edema ↓PBN, SPBN60 Iv, 30 min LV ↓, NS ↑, MWM ↑ (SPBN only)STAZN61 Ip, 5 min LV ↓, NS ↑LY34112262 Po, pre; Iv, 5–30 min LV ↓, ctx ↓7-NI63–64 63–64Iv, pre, 64� 5 min 63Sensorimotor deficits ↓,

64pre: LV ↓, post: LV →L-arginine64 Iv, � 5 min LV ↓SIN-164 IA, � 5 min LV →L-NAME63–64 63–64Iv, pre, 64� 5 min 63Sensorimotor deficits →, 64LV →AG65–67 65–67Ip, 64pre, 675 min or 65–6630 min 65–66TUNEL�↓, 65Rotarod ↓, 65Locomotor

activity ↓, 66LV ↓, 67LV →, 67neuronal cell loss↓Neurotrophic factors

IGF-168 Sc, 15 min NS ↑, MWM ↑NGF69–70 Intracerebr., 24h 69MWM ↑, 69–70NS →, 69CA3 →, 70TUNEL�↓,

70cholinergic cell loss ↓, 70MWM →BDNF71 Intracerebr., 4h CA3 →, hilus →, NS →, MWM →, LV →BFGF28,72–73 28Iv, 20 min; 72Intracereb., 24h; 28NS ↑, 28,72LV →, 72CA3 →

73Iv, 30 min 72Memory ↑, 73NS →, 73LV ↓, 73Cell loss ↓Inhibitors of apoptosis and endocrinological approaches

z-DEVD-fmk--a74 Icv, pre NS ↑1-ARA-35b75–76 Iv, 30 min 75–76NS ↑, 75MWM ↑, 75LV ↓, 75TUNEL�↓57a76 Iv, 30 min NS ↑YM-1467312, 77 12Ip, 30 min, 77Iv, 30 min NS ↑4(5)-NO2 TRH78 Iv, 30 min NS ↑2,4 diiodo TRH78 Iv, 30 min NS ↑2-ARA-53a76,79 Iv, 30 min NS ↑D-phe CRH80 Icv, 15 min LV ↓Estrogen81 Ip, pre NS ↑

(continued)

cellular pathology. The improved outcomes reported withthe glutamate release inhibitor Riluzole using the LFPmodel (McIntosh et al., 1996; Bareyre et al., 1997; Wahlet al., 1997; Zhang et al., 1998) (Table 2) have prompted

the current clinical trial with this drug that is ongoing inEuropean centers.

NMDA receptor activation and calcium influx are con-tingent on the binding of glutamate and the release of the

voltage-sensitive magnesium block (Nowak et al., 1984).The post-LFP loss of intracellular magnesium may pro-mote NMDA-receptor activation (Vink et al., 1990b;Golding et al., 1994; Vink et al., 1996). The competitiveNMDA NR2B antagonist CP101,606 has shown efficacyin the LFP model (Okiyama et al., 1997) (Table 2) and iscurrently being evaluated in a multi-center clinical trial inTBI patients in the United States. Limiting NMDA-re-ceptor activation by the blockade of co-agonist glycine,polyamine and zinc sites (Fields et al., 1991) also haveproven differentially successful in LFP brain injury (Table2) (Lea et al., 2003; Marklund et al., 2004b). NMDA chan-nel blockers including, but not limited to dextromethor-

phan, dextrorphan, ketamine, MK-801, NPS1506 andremacemide hydrochloride, decrease neuronal death,edema and/or neurological dysfunction after LFP brain in-jury (Table 2). Inhibiting NMDA-receptor activation (Mk-801 and PCP) after LFP may disrupt LTP and cognitiveprocesses necessary for post-injury recovery (Davis et al.,1992; Hamm et al., 1994a). However, these compoundsoften show strong psychomimetic side-effects, may beneurotoxic, and have not fared well in clinical trials (Bul-lock et al., 1999; Maas et al., 1999). Synthetic competi-tive polyamine site blockers (eliprodil) and AMPA-receptor antagonists (e.g., RPR117824, YM872 and Talampanel) can reduce cortical lesion volume and im-

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TABLE 3. CLASSES OF COMPOUNDS EVALUATED AFTER LATERAL FLUID PERCUSSION BRAIN INJURY (CONT’D)

Drug and Time and routereference of administrationa Outcome

Cation channel blockers and calpain inhibitorsS-emopamil82 Ip, 15 min Memory ↑, NS ↑, Edema ↓LOE90883 Iv, 15 min LV →, MWM →, NS ↑BMS-20435284 Iv, 10 min Edema ↓, NS ↑, MWM →, LV →AK29585–86 IA, 15 min 85MWM ↑, 85NS ↓, 85LV →,

86TUNEL� ctx/CA3 →

Abbreviations for compounds in Table 3: NOS, Nitric oxide synthase;ICAM, Intercellular adhesion molecule;IL1ra,Interleukin-1 receptor antagonist;sILra, soluble IL1ra;IL-10, interleukin-10;TNF, tumor necrosis factor;IL-6, interleukin-6;sTNFR:Fc, soluble TNF alpha receptor fusion protein;VCP, vaccinia virus complement control protein;PEG-SOD, polyethyleneglycol-conjugated superoxide dismutase;MDL 74,180, 2,3-dihydro-2,2,4,6,7-pentamethyl-3-(4-methylpiperazino)-methyl-1-ben-zofuran-5-ol dihydrochloride;PBN, �-phenyl-N-tert butyl-nitrone;S-PBN, 2-sulfophenyl-N-tert-butyl nitrone;STAZN, stilbazu-lenyl-bis-nitrone;LY341122, 2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethyl-phenyloxy)ethyl)oxazole;7-NI,7-nitroindazole;SIN-1, 3-morpholino-sydnonimine;L-NAME, N(G)-nitro-L-arginine methyl ester;AG, Aminoguanidine hydrogencarbonate;IGF-1, insulin-like growth factor-1; NGF, nerve growth factor; BDNF, brain-derived growth factor; BFGF, basic fibro-blast growth factor; Z-DEVD-FMK, N-benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethyl ketone;1-ARA-35b(35b), 57a,4(5)NO2 TRH, 2,4 diiodo TRH, and 2-ARA-53a are analogues and derivates of thyrotropin-releasing hormone;YM-14673, N al-pha-[(S)-4-oxo-2-azetidinyl)-carbonyl]-L-histidyl-L-prolinamide dihydrate;D-phe CRH, d-Phe(12),Nle(21,38),alpha-Me-Leu(37))-corticotrophin-releasing hormone (12-41);Emopamil, [(2s)-2-isopropyl-5-(methylphenylamino)-2-phenylvaleronitrilehydrochloride];LOE 908, (R,S)-(3,4-dihydro-6,7-dimethoxy-isochinolin-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]acetamid mesylate;BMS-204352, 3S)-(�)-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one)(MaxiPost);AK295, Z-Leu-aminobutyric acid-CONH(CH2)3-morpholine.

References to Table 3: 42Knoblach and Faden, J. Neurotrauma, 2002. 43Toulmond and Rothwell, Brain Res., 1995. 44Sandersonet al., J. Cereb. Blood Flow Metab, 1999. 45Knoblach and Faden, Neurosci. Lett., 2000. 46Knoblach and Faden, Exp. Neurol., 1998.47Marklund et al., Restor. Neurol. Neurosci., 2004. 48Knoblach et al., J. Neuroimmunol., 1999. 49Grady et al., J. Neurotrauma, 1999.50Bentzer et al., J. Neurotrauma, 2003. 51Bentzer et al., J. Neurotrauma, 2001. 52Alessandri et al., J. Neurotrauma, 2002. 53Riess etal., Restor. Neurol. Neurosci., 2001. 54Hicks et al., J. Neurotrauma, 2002. 55McIntosh et al., J. Neurotrauma, 1992. 56McIntosh et al.,Acta Neurochir. Suppl (Wien.), 1990. 57Sanada et al., J. Neurotrauma, 1993. 58Hamm et al., J. Neurotrauma, 1996. 59Petty et al.,Eur. J. Pharmacol., 1996. 60Marklund et al., J. Neurotrauma, 2001. 61Belayev et al., J. Neurosurg., 2002. 62Wada et al.,Neurosurgery, 1999. 63Wada et al., J. Neurotrauma, 1999. 64Wada et al., J. Neurosurg., 1998. 65Lu et al., Neuropharmacology, 2003.66Lu et al., Neurosci. Lett., 2003. 67Wada et al., Neurosurgery, 1998. 68Saatman et al., Exp. Neurol., 1997. 69Sinson et al., J.Neurochem., 1995. 70Sinson et al., J. Neurosurg., 1997. 71Blaha et al., Neuroscience, 2000. 72McDermott et al., J. Neurotrauma,1997. 73Dietrich et al., J. Neurotrauma, 1996. 74Yakovlev et al., J. Neurosci., 1997. 75Faden et al., J. Cereb. Blood Flow Metab,2003. 76Faden et al., Ann. N. Y. Acad. Sci., 1999. 77McIntosh et al., J. Neurotrauma, 1993. 78Faden et al., J. Neurotrauma, 1993.79Faden et al., Am. J. Physiol, 1999. 80Roe et al., Eur. J. Neurosci., 1998. 81Emerson et al., Brain Res., 1993. 82Okiyama et al., J.Neurosurg., 1992. 83Cheney et al., J. Neurotrauma, 2000. 84Cheney et al., J. Cereb. Blood Flow Metab, 2001. 85Saatman et al., Proc.Natl. Acad. Sci. U. S. A, 1996. 86Saatman et al., J. Cereb. Blood Flow Metab, 2000.

prove neurological motor function after LFP (Toulmondet al., 1993b; Belayev et al., 2001; Mignani et al., 2002)(Table 2). The administration of magnesium post-injuryattenuates behavioral deficits and histological alterations(Bareyre et al., 1999; Saatman et al., 2001) (Table 2).Magnesium administration is currently being studied in asingle-center NIH-sponsored clinical trial to evaluate itseffects to reduce post-traumatic epilepsy in TBI patients.Other glycine-site NMDA receptor antagonists shown tobe effective in the LFP model (e.g., KYNA, I2CA; Table2) have not been developed for clinical trials.

Activation of Group I mGluR receptors can potentiateneuronal excitation and exacerbate excitotoxic cell death(Mukhin et al., 1996), whereas Group II and III agonistsreduce excitation and may provide neuroprotection afterLFP brain injury (Faden et al., 2001). Group 1 metabotropic

anatagonists (MCPG, AIDA and MPEP) improve neuro-logical motor deficits, cortical lesion volume and cognitiveperformance after LFP (Gong et al., 1995; Mukhin et al.,1996; Faden et al., 2001; Lyeth et al., 2001; Movsesyan etal., 2001a). Group II metabotropic agonists (LY 354740and DCG-IV) can attenuate neurological motor deficits, andreduce the number of degenerating hippocampal neurons(Allen et al., 1999; Zwienenberg et al., 2001) (Table 2).

Of interest, several reports have demonstrated benefi-cial actions of glutamate and glutamate receptor activa-tion. For example, the NMDA agonist D-cycloserine im-proved cognitive performance 24 h after LFP (Temple etal., 1996) (Table 1). Although the attenuation of excito-toxicity presents a promising treatment strategy, the in-herent neuronal functions served by glutamate receptoractivation must be considered carefully.

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TABLE 4. MISCELLANEOUS COMPOUNDS EVALUATED AFTER LATERAL FLUID PERCUSSION BRAIN INJURY

Drug and Time and routereference of administrationa Outcome

Miscellaneous treatment approachesLidocaine58, 87 58Iv, 30 min; 87Iv, pre 58MWM ↑, 58NS →, 87NS ↑, 87MWM →Naloxone77 Iv, 30 min NS ↑Nalmefene12, 88 12Iv, 30 min; 88Iv, 30 min NS ↑Haloperidol89 Ip, 24h MWM ↓Olanzapine89 Ip, 24h MWM →Amphetamine90 Ip, 24h BW →, MWM →Methoxamine90 Ip, 24h BW →, MWM →Prazosin90 Ip, 24h BW →, MWM →Enoxaparin91 Iv, 2h Edema ↓, MWM ↓, NS ↓Lactate92 Iv, 30 min MWM ↑, CA3/CA1 →GPI 615093 Ip, 30 min LV ↓, TUNEL� ↓Topiramate94 Ip, 30 min LV →, CA3 →, Edema →,

memory →, MWM ↓, NS ↑, RP ↑TPCK95 Icv, 15 min MWM →, NS ↓BMY-2150296 Sc, 7 days MWM ↑ (injured), MWM ↓ (sham)High-fat sucrose diet97 P.o., pre MWM ↓Suritozole98 Ip, 24h or 11 days early: MWM ↑, delayed: MWM →Albumin99 Iv, 15 min NS ↑, LV ↓Diazepam100 Ip, pre or 15 min MWM ↑, pre: Mort ↓, post: Mort→Bicuculline100 Ip, 15 min MWM ↓Fluoxetine101 Ip, 24h MWM ↑S100B102 Icv, 10 min MWM ↑

Abbreviations for compounds in Table 4: GPI 6150, 1,11b-dihydro-[2H]benzopyrano [4,3,2-de]isoquinolin-3-one;Topiramate, 2,3:4,5-di-O-(1-isopropylidene)-B-D-fructopyranose sulfamate;TPCK, N-Tosyl-L-phenylalanyl-chloromethyl ke-tone;BMY-21502, 1-[[1-[2-trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2-pyrroli dinone;Suritozole, MDL 26,479, 5-aryl-1,2,4-triazole.

References to Table 4: 87Muir et al., J. Neurotrauma, 1995. 88Vink et al., J. Neurosci., 1990. 89Wilson et al., Am. J. Phys. Med.Rehabil., 2003. 90Dose et al., J. Neurotrauma, 1997. 91Wahl et al., J. Neurotrauma, 2000. 92Rice et al., Brain Res., 2002. 93LaPlacaet al., J. Neurotrauma, 2001. 94Hoover et al., J. Neurotrauma, 2004. 95Movsesyan et al., Exp. Neurol., 2001. 96Pierce et al., BrainRes., 1993. 97Wu et al., Neuroscience, 2003. 98O’Dell and Hamm, J. Neurosurg., 1995. 99Belayev et al., J. Neurotrauma, 1999.100O’Dell et al., Brain Res., 2000. 101Wilson and Hamm, Am. J. Phys. Med. Rehabil., 2002. 102Kleindienst et al., J. Neurotrauma,2004.

Anti-Inflammatory Agents

After LFP, the secondary injury includes an acute in-flammatory response with breakdown of the blood-brainbarrier (BBB), edema formation, infiltration of periph-eral blood cells, activation of resident immunocompetentcells and intrathecal release of immune mediators suchas cytokines (Toulmond et al., 1995; Soares et al., 1995a;Philips et al., 2001; Morganti-Kossmann et al., 2002). Al-though the detrimental CNS inflammation can cause sus-tained functional impairment and cell death, inflamma-tory pathways now may be crucial to regenerativeresponses. In particular, inflammation following injury isbelieved to be detrimental, but after days or weeks maycontribute to restoration and repair (Philips et al., 2001;Lenzlinger et al., 2001a). Therefore mixed results fol-low inhibition of the inflammatory cascade, includ-ing the blockade of ICAM-1, TNF-a, IL-6, IL-10, andprostaglandin actions (Table 3). Furthermore, global sup-pression of inflammatory responses with cyclosporin orvaccinia virus complement control protein (VCP) de-pends on route, duration and dose of administration forefficacy (Table 3). Currently, the nature of inflammationafter TBI remains elusive, not to mention the need forcautious clinical anti-inflammatory administration, par-ticularly in light of multiple organ damage and infection(pneumonia/sepsis) (Griffin et al., 1994; Riess et al.,2001).

REACTIVE OXYGEN SPECIES. Despite a short half-life inbiological tissue, oxygen radicals (reactive oxygenspecies [ROS]), in particular superoxide anion (O2��, hy-droxyl radical (OH�), peroxynitrite (ONOO�), and nitricoxide, cause tissue pathology due to high reactivity(Lewen et al., 2000). Brain tissue is susceptible to ox-idative damage because of its high rate of oxidative me-tabolism, low antioxidant defenses, low repair mecha-nism activity, and the high membrane surface tocytoplasm ratio (Tyurin et al., 2000; Marklund et al.,2001a). Predominantly, oxidative damage after LFP man-ifests as lipid peroxidation. Varying degrees of successhave been reported with inhibitors of lipid peroxidationevaluated after LFP, including the vitamin E (�-toco-pherol) analogue MDL 74,180 and LY341122 (Petty etal., 1996; Wada et al., 1999a) (Table 3). Conjugated poly-ethylene glycol-superoxide dismutase (PEG-SOD, pego-gortein, Dismutec) attenuated neurological motor andcognitive deficits after LFP brain injury of moderateseverity (Hamm et al., 1996) (Table 3). The initial resultsof a randomized, phase III multi-center clinical trial ofDismutec in severely brain-injured patients revealed atrend towards more favorable outcomes and less disabil-ity at three months post-injury (Muizelaar et al., 1993).However, a follow-up randomized, multi-center clinical

trial of Dismutec did not demonstrate therapeutic effi-cacy (Young et al., 1996). Additionally, the 21-aminos-teroid Tirilazad mesylate also was shown to reduce brainwater content, post-injury mortality and improve motorfunction after LFP (McIntosh et al., 1992; Sanada et al.,1993) (Table 2). However, Tirilizad administered to se-verely, not moderately, head-injured patients of all types(not just those where edema was a primary response toinjury) showed no benefit on outcomes in over 2300 pa-tients worldwide (Marshall et al., 1998).

The spin-trapping agent �-phenyl-tert-N-butyl nitrone(PBN) and its sulfonated derivative, sodium 2-sul-fophenyl-N-tert-butyl nitrone (S-PBN) provide neuro-protection in the LFP model through the formation of sta-ble adducts with ROS (Oliver et al., 1990; Marklund etal., 2001b) (Table 3). Additionally, nitroxides (stilbazu-lenyl nitrone, STAZN) are stable free radicals serving ascell permeable antioxidants that improve neurologicalmotor function and reduce lesion volume after LFP (Be-layev et al., 2002) (Table 3). Inhibition of nitric oxidesynthase (NOS) after LFP has demonstrated a role for ni-tric oxide in the post-injury free radical pathology, butneither 3-bromo-7-nitroindazole (7-NI), a relatively spe-cific inhibitor of neuronal NOS, nor nitro-L-arginine-methyl ester (L-NAME) and aminoguanidine, an iNOSinhibitor, substantially improved functional or anatomi-cal outcome (Wada et al., 1998a,b) (Table 3).

NEUROTROPHIC FACTORS. The peptide growth factors(e.g., nerve growth factor [NGF], basic fibroblast growthfactor [bFGF], brain-derived neurotrophic factor [BDNF],insulin-like growth factor [IGF-1], neurotrophin-4/5 [NT-4/5]) function to support neuronal survival, induce sprout-ing of neurites (neuronal plasticity), and facilitate axonguidance (Conte et al., 2003). In addition, neurotrophinsdelay apoptosis, prevent atrophy of axotomized neurons,and enhance the expression of growth-associated genes(Fournier et al., 1997; Kobayashi et al., 1997; Bregmanet al., 1998; Broude et al., 1999).

After LFP, marked changes in neurotrophin mRNAand protein expression have been reported in vulnerablebrain regions (O’Dell et al., 2000c; Royo et al., 2002;Shimizu et al., 2002). Further pharmacological augmen-tation of the inherent post-injury NGF increase improvedmemory function and reduced apoptotic cell death, butnot motor function or hippocampal cell loss (Sinson etal., 1995; Sinson et al., 1997) (Table 3). IGF-1 adminis-tration improves learning and neuromotor function, whilepost-injury bFGF administration reduces lesion volume,necrotic cortical neurons, and memory dysfunction in theLFP model (Dietrich et al., 1996; McDermott et al., 1997;Saatman et al., 1997) (Table 3). Yet, the combined se-quential administration of bFGF and magnesium chloride

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diminished the neuromotor improvement observed withmagnesium treatment alone (Guluma et al., 1999). Pro-longed administration of NT-4/5 attenuates hippocampalcell loss, without affecting cortical lesion volume (Royoet al., 2002). Alternatively, no improvement in either cog-nitive function or histological preservation are observedafter BDNF infusion (Blaha et al., 2000). Neurotrophinadministration promises to be a potential clinical therapydue to extended treatment windows.

INHIBITORS OF APOPTOSIS. Despite the extensive re-search establishing the apoptotic pathways that contributeto the pathology of LFP brain injury, sparse interventionsto divert cell death signaling exist (Yakovlev et al., 1997).Future interventions aimed at pro-apoptotic and anti-apoptotic gene expression, caspase activation, mitochon-drial preservation, and the inhibitors of apoptosis maylimit tissue pathology.

ENDOCRINOLOGICAL TARGETS. Neuroendocrinologial ab-normalities and their pharmacological restoration havebeen explored in LFP brain injury (Yuan et al., 1991;Childers et al., 1998). For example, analogues of thy-rotropin-releasing hormone (TRH) consistently improveneuromotor function (Faden, 1996; Faden et al., 2003)(Table 3). In addition, pre-injury treatment with estrogenimproves neurological motor function after LFP brain in-jury (Emerson et al., 1993; Bramlett et al., 2001).

CATION CHANNEL BLOCKERS AND CALPAIN INHIBITORS.The marked ionic disturbance after LFP results in down-stream activation of calcium-dependent enzymes. Severalcompounds that target the acute post-traumatic ionic dis-turbance have shown improved behavioral outcome andinclude the calcium channel blocker emopamil, thebroad-spectrum cation channel blocker LOE 908, and thepotassium channel opener BMS-204352 (Cheney et al.,2001) (Table 3). Likewise, the selective calpain inhibitorAK295 attenuates motor and cognitive dysfunction afterLFP brain injury, without affecting lesion volume, apop-totic cell number, or spectrin degradation (Saatman et al.,1996, 2000) (Table 3). To date, these compounds wereadministered shortly post-injury, and more delayed ad-ministration paradigms are needed to establish their clin-ical utility.

MISCELLANEOUS THERAPEUTIC STRATEGIES. Compoundsoutside the categories discussed above have been evaluatedin the LFP model (Table 4). Miscellaneous compounds tar-get specific neurotransmitter systems (dopamine, GABA,serotonin) and/or include various anesthetics and dietarychanges.

CAVEATS AND RECOMMENDATIONS FOR PHARMACOLOGI-CAL STUDY DESIGN USING THE LFP MODEL. To date, nu-

merous treatment targets have been explored in the LFPbrain injury model and ongoing strategies (Tables 2–4)are being developed and studied routinely. However, fewevaluations have explored the extent of the efficacioustime-window to improve applicability to the clinical set-ting. Furthermore, numerous experimental studies haveemployed routes of administration that may not be ac-cessible in mild or moderate clinical TBI. Moreover, sin-gle high-dose treatment in the laboratory contrasts withthe clinical setting, where continuous infusions controldrug concentrations and minimize adverse effects. Theobservation times for treatment efficacy are commonlyshort, usually a few weeks, whereas clinical outcomes are6 months post-injury or longer. Again, we challenge theTBI research community to adopt long-term behavioraland histological outcome measures to increase the clini-cal relevance of pre-clinical studies.

HYPOTHERMIA. The treatment strategy to induce hy-pothermia following LFP brain injury slows cellularprocesses to provide substantial neuroprotection, asdemonstrated by attenuated neural injury (Dietrich et al.,1994a; Bramlett et al., 1995, 1997a; Chatzipanteli et al.,2000; Matsushita et al., 2001a). Post-injury hypothermiareduced cortical contusion volume and the number ofnecrotic cortical neurons compared to normothermic con-trols (Bramlett et al., 1997a). Additional efficacy in neu-romotor and cognitive functioning in animals treated withhypothermia have been reported (Bramlett et al., 1995).When the positive findings from the LFP model weretranslated to human studies, preliminary results were pos-itive (Marion et al., 1997). However, a subsequent NIH-sponsored multi-center trial showed no statistical im-provement in outcome (Clifton et al., 2001), with minortime and age-dependent treatment effects (Clifton et al.,2002).

TRANSPLANTATION. Since cell loss is a hallmark of TBI,cellular transplantation may replace lost cells or aid self-repair mechanisms in damaged tissue (Schouten et al.,2004). In the first transplantation studies, the transplan-tation window for fetal cortical tissue in adult non-im-munosuppressed rats was 2 weeks after LFP brain injury,where cognitive and motor function can recover in LFP-injured rats after transplantation alone or in combinationwith locally infused NGF (Soares et al., 1991, 1995b;Sinson et al., 1996) (Table 5). Later studies with post-mitotic human neurons (hNT) demonstrated substantialintegration between the injured cortex and the graft; how-ever, no behavioral improvements were found up to 2weeks post-transplantation (Philips et al., 1999; Muir etal., 1999) (Table 5).

Transplantation of immortalized progenitor cells im-prove outcome after LFP and provide a limitless supply

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TABLE 5. SUMMARY OF TRANSPLANTATION STUDIES AFTER LATERAL FLUID PERCUSSION BRAIN INJURY

Transplantation Transplantation HistologicalCell type time (post-injury) location time point Reference

Fetal cortical E16 2d, 1wk, Ipsi. cortex 4wk Soares and McIntosh, J. Neural2wk, 4wk Transplant. Plast., 1991

E16 2d Ipsi. cortex 4wk Soares et al., J. Neurotrauma, 1995E16 (with NGF) 24h Ipsi. cortex 72h, 1wk, 2wk Sinson et al., J. Neurosurg., 1996hNT 24h Ipsi. cortex 2wk Muir et al., J. Neurotrauma, 1999hNT 24h Ipsi. cortex 2wk, 4wk Philips et al., J. Neurosurg., 1999HiB5 (NGF) 24h Ipsi. cortex 1wk Philips et al., J. Neurosurg., 2001MHP 36 48h Ipsi. and contra. cortex 4wks Lenzlinger et al., J. Neurotrauma, 2001C17.2 48h Ipsi. and contra. 72h, 2wk Boockvar et al., Neurosurgery, 2005

corpus callosum

of transplant material. Significant neuromotor and cog-nitive improvements, as well as a reduction in hip-pocampal (CA3) cell death, were afforded by HiB5 celltransplantation with NGF at 24 h post-injury (Philips etal., 2001). Similarly, detailed evaluation of neural stemcell survival, migration and terminal differentiation in theinjured brain after transplantation demonstrate the utilityof cell replacement as a viable therapy for TBI (Boock-var et al., 2005). To date, none of these transplantationtherapies is available for human clinical trial in TBI, butthe LFP model has proven useful for examining poten-tial therapies, graft/brain interaction, and cellular repara-tion post-injury (Table 5).

Predictive Validity

The LFP brain injury model is the most commonlyused model for preclinical evaluation of pharmacologictherapies (Bullock et al., 1999). Although several com-pounds, have shown efficacy in the LFP model, the trans-lation to the bedside was unsuccessful (Bullock et al.,1999). We posit that both the inability of any experi-mental model to reproduce all types of clinical TBI andissues with study design using severely brain-injured pa-tients contributed to the relatively poor success rate ofpast clinical trials. Preclinical studies employing LFP in-jury of moderate severity have been translated to clinicaltrials involving severely head-injured patients. In fact, in-jury levels classified as moderate severity typically resultin mortality rates approaching 20%. The expectations thatthe LFP model would have full predictive validity for anytrial involving severe TBI clearly are unreasonably high.

Optimal clinical trial design should be based on ap-propriate dosing regimens and patient population for thespecific therapy (Bullock et al., 1999; Statler et al., 2001).Administration paradigms in laboratory studies are basedtypically on animal body weight, whereas clinical trialsestablish a single dose for all enrolled patients, regardless

of body weight (Bullock et al., 1999). Reciprocally, pre-clinical designs can be designed to include various dos-ing strategies, multiple severity levels within a single braininjury model, incorporating secondary insults evident inhuman TBI, or more than one model of TBI (Narayan etal., 2002). Compounds likely to be brought to clinical tri-als should be evaluated in the laboratory using models likeLFP to better mimic the clinical situation.

Construct Validity

Construct validity assesses the degree to which the LFPmodel can unambiguously be interpreted to mimic theclinical condition (Jenck et al., 1995; Willner, 1997;Hamm, 2001). Additionally, the internal workings of themodel should respond in a similar manner to experi-mental manipulations (i.e., injury severity, physiologicalfluctuations) as the clinical condition. High construct va-lidity in the LFP model is afforded by the reproductionof human TBI contusion, diffuse white matter injury, andvarying severity (Laurer et al., 2000). Additionally, thepersistent neuromotor and cognitive deficits up to oneyear after severe LFP brain injury, with the concomitanttemporal pattern of cellular death add construct validityto the model (Smith et al., 1997a; Pierce et al., 1998;Bramlett et al., 2002).

The anesthesia necessary for LFP surgery, in additionto the required craniectomy, introduces factors that dis-rupt the congruent relationship between the model andwhat is being modeled. However, LFP clearly is not amodel of open or penetrating TBI, as some have sug-gested. Histological examination after LFP shows whitematter tissue tears that are very similar if not identical tothe shearing injury seen in human closed head injury(Graham et al., 2000b). Moreover, the patterns of celldeath after LFP predict those later observed in post-mortem tissue (Rink et al., 1995; Smith et al., 2000).Brain regions, in particular white matter versus grey mat-

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ter, are known to respond differently after either humanTBI or LFP (Yakovlev et al., 1997; Conti et al., 1998;Williams et al., 2001; Wilson et al., 2004). The active,progressive enlargement of the cortical contusion andventricles after LFP (Smith et al., 1997a; Bramlett et al.,1997b; Pierce et al., 1998) also parallels that seen afterhuman head injury (Shiozaki et al., 2001).

IS LFP A RELEVANT MODEL OF HUMAN TBI?

As an experimental model of closed head injury, lat-eral fluid percussion has provided the consistency, re-producibility and reliability required of a laboratorymodel. In contrast to human TBI, LFP necessitates prioranesthesia and craniotomy, which presents some poten-tial confounds to the ability of this (or any) model to re-produce the clinical condition. But, based on mortality,physiological alterations, and neurological impairments,the model achieves face validity. Due to finite laboratoryresources, the construct validity with regard to mild andmoderate traumatic brain injury in the young adult hu-man male population has been achieved. However, cer-tain restrictions on the model somewhat limit the pre-dictive validity of LFP and preclinical therapies tested inthis experimental model have yet to translate to effectiveclinical interventions. By expanding the lateral fluid per-cussion model to include additional aspects of the clini-cal presentation, both construct and predictive validity ofthe model likely can be maximized.

Combined Experimental Models May AffordAdditional Construct Validity

Head injured patients often present with additionalcomplications, such as hypotensive or hypoxic episodes,which occur acutely for prolonged intervals in severelyhead-injured patients (Ananda et al., 1999; Robertson etal., 1999). In order to transfer the true clinical conditionto animal models, clinically relevant TBI pathophysiol-ogy (hemorrhage, hypotension, ischemia, or hypoxia) canbe integrated into the existing model (Statler et al., 2001).Several studies have incorporated ischemia (Dietrich etal., 1998; Perez-Pinzon et al., 1999), hemorrhage (Lawet al., 1996; Stover et al., 2002), hypoxia (Tanno et al.,1992; Nida et al., 1995; Dave et al., 1997; Bramlett etal., 1999a,b; Bauman et al., 2000; Matsushita et al.,2000), hyperglycemia (Kinoshita et al., 2002) or hy-potension (Matsushita et al., 2001b) after LFP to assessthe contributions to brain injury pathology of these sec-ondary insults. Furthermore, posttraumatic coma, a com-mon clinical indicator for morbidity and mortality(Gennarelli, 1983), has proven difficult to induce in small

animal models. Rodents are lissencephalic, have smallerbrain mass, and lack cortical gyri, which may provideprotection from injury, limiting the mechanical inductionof coma (Statler et al., 2001). Animals can cope with theposttraumatic secondary episodes without further dam-age to CNS structures or exacerbation of behavioral im-pairments, as long as the secondary episodes are moder-ated in terms of severity and duration. When the durationor severity exceeds a threshold, injury-induced pathologysubstantially increases.

Although a smaller fraction of the clinical TBI patientpopulation, women remain an understudied componentof basic science studies. Susceptibility to brain injury isgreater in female rats, which may be related to levels offree magnesium (Emerson et al., 1992). However, en-dogenous circulating hormones in the female rats sur-viving brain injury after LFP provide histopathologicalprotection after injury compared to males or ovariec-tomized females (Bramlett et al., 2001; Suzuki et al.,2003). Yet, posttraumatic hypothermia therapy remainsan effective treatment in male, but not female, brain-in-jured animals (Suzuki et al., 2003). Without further in-vestigation, the paradoxes between gender and treatmentefficacy cannot be resolved.

Age is one of the most important predictors of out-come after human traumatic brain injury (Hukkelhovenet al., 2003). Substantial age-dependent injury-induceddifferences in aging-associated and regeneration-relatedgene expression in the hippocampus may contribute tothe increased vulnerability of the aged brain to injury(Shimamura et al., 2004). However, behavioral dysfunc-tion and vulnerability to injury have not been exploredin aged animals after LFP. Moreover, the metabolic stressand free radical cascades after injury can establish con-ditions that promote aging-associated mitochondrialDNA deletion and oxidation, suggesting that the under-lying pathology between TBI and aging may be similar(Lifshitz et al., 2003b). In fact, clinical and preclinicallinks between Alzheimer’s pathology and TBI have beenexplored using the LFP model (Pierce et al., 1996; Kayet al., 2003) and may be crucial to treating the survivingpopulation of TBI patients.

Traumatic brain injury (TBI) is the leading cause ofinjury-related death and disability among children underthe age of 15 years in the United States (Prins et al.,2003). The biomechanical and physiological data indi-cate that reproducible traumatic brain injuries can be gen-erated using the LFP model in developing animals, wherephysiological responses increase with injury severity.Compared to adult animals, young or developing animalsexhibit pronounced hypotension associated with excita-tory amino acid–induced pial dilation (Armstead et al.,1994; Prins et al., 1996; Armstead, 1999a; Armstead,

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2000). An injury-induced premature elevation of NMDAreceptor subunits inhibits experience-dependent develop-mental plasticity, cortical thickening, and dendritic ar-borization (Fineman et al., 2000; Giza et al., 2002; Ip etal., 2002). The LFP brain injury further disrupts the co-ordinated expression of age-dependent genes in the hip-pocampus (Giza et al., 2002; Griesbach et al., 2002) thatmay have deleterious consequences for the developinganimal. Despite the blunted neuronal damage and pre-served blood–brain barrier in young injured animals, anacute hyperglycolytic period is compounded by biphasicregional calcium accumulation and an enhanced mi-croglial/macrophage infiltration (Thomas et al., 2000;Osteen et al., 2001). Yet, developing animals that surviveLFP brain injury show intact cognitive function com-pared to older injured animals (Prins et al., 1998; Prinset al., 2001). Within developing animals, the newborn re-mains more sensitive to post-traumatic vascular, as pre-sumably other, components of the injury compared withjuvenile animals (Armstead, 1999a). Age-related differ-ences in the response to TBI reinforce the hypothesis thatoutcomes and therapies for head-injured patients may beage-dependent (Prins et al., 2003).

Incorporating additional components of the clinicalpresentation of traumatic brain injury into the LFP modelwould add additional construct validity. Gender, old age,and developing animals complete the description of trau-matic brain injury in the laboratory and permit clinicallyrelevant therapies to be pursued.

Redirection of the LFP Model: Mild Versus Severe TBI

The clinical classification of TBI encompasses a broadspectrum of dysfunction, ranging from patients who re-main in a coma from the moment of injury until death,to those who are mildly impaired after the injury and re-cover over time. With the increased use of safety equip-ment and restraints, the previously large population of se-verely brain-injured patients has been inflated by a newpopulation of mild and moderately brain-injured patients.Although the classical histopathological damage of LFPis more consistent with severe human TBI, the absenceof coma, intravenous fluids, ICP management, nursingcare, or vegetative state mandates that the focus of ani-mal brain injury models remains on mild-moderate in-jury severity. Moreover, the LFP model resembles mildhuman TBI in its acute pathobiology and behavioral re-covery. Redirecting the basic science focus of the LFPbrain injury model to mild TBI will help ensure the ap-propriate translation of pharmacological, behavioral andhistopathological findings to the clinical setting (Hicks etal., 1993; Sick et al., 1998; Saatman et al., 1998; Raghu-

pathi et al., 2002; Griesbach et al., 2002). The predictivevalidity of the model is enhanced and directed towards asignificantly larger population of traumatic brain injuredpatients. As such, the LFP injury model has sufficientoverall validity and can provide a strong basis for trans-lational research as part of a well-designed program ofresearch for mild to moderate traumatic brain injury.

CONCLUSION

It is possible to gain new insight into clinical problemseven if full construct or other validity cannot be estab-lished from use of an animal model. The true power ofa model does not lie exclusively in its validity, but in its“productive generativity” (Shapiro, 1998), defined as theamount of new information discovered or new hypothe-ses generated about the disease or condition from the an-imal model. The productive generativity of the LFP in-jury model over the past 15 years has been extensive, andincludes information regarding gene and protein expres-sion, mechanisms of cell death, the inflammatory re-sponse, and potential therapeutic strategies, rehabilitationstrategies (e.g., exercise) and cellular transplantation intothe injured brain. The amassed literature on LFP braininjury, which has helped to refine clinical trials in humanhead injury and vice versa, authenticates that sometimes“you get what you need.”

ACKNOWLEDGMENTS

We are grateful to David G. LeBold and Diego M.Morales for compiling literature for several sections ofthis review. Some studies in this review and the prepa-ration of this manuscript were supported by T32-NS043126, NS-08803, NS-40478, and VA Merit Review.

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Address reprint requests to:Jonathan Lifshitz, Ph.D.

Anatomy and NeurobiologyVirginia Commonwealth University

Medical College of Virginia CampusP.O. Box 980709

Richmond, VA 23298-0709

E-mail: JLIFSHITZ@vcu.edu

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