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PubMed2004

Comparison of behavioral deficits and acute neuronal degeneration in rat lateral fluid percussion and weight-drop brain injury models.

The behavioral and histological effects of the lateral fluid percussion (LFP) brain injury model were compared with the weight drop impact-acceleration model with 10 min of secondary hypoxia (WDIA + H). LFP injury resulted in significant motor deficits on the beam walk and inclined plane, and memory deficits on the radial arm maze and Morris water maze. Motor deficits following LFP remained throughout 6 weeks of behavioral testing. WDIA + H injury produced significant motor deficits on the beam walk and inclined plane immediately following injury, but these effects were transient and recovered by 14 days post-injury. In contrast to the LFP injury, the WDIA + H injured animals showed no memory deficits on the radial arm maze and Morris water maze. In order to determine if the differences in behavioral outcome between models were due to differences in injury mechanism or injury severity, 10 LFP-injured animals were matched with 10 WDIA-injured animals based on injury severity (i.e., time to regain righting reflex after brain injury). The LFP-matched injury group showed greater impairment than the WDIA + H matched injury group on the radial arm maze and Morris water maze. Histological examination of LFP-injured brains with Fluoro-Jade staining 24 h, 48 h, and 7 days post-injury revealed degenerating neurons in the cortex, thalamus, hippocampus, caudate-putamen, brainstem, and cerebellum, with degenerating fibers tracts in the corpus callosum and other major tracts throughout the brain. Fluoro-Jade staining following WDIA+H injury revealed damage to fibers in the optic tract, lateral olfactory tract, corpus callosum, anterior commissure, caudate-putamen, brain stem, and cerebellum. While both models produce reliable and characteristic behavioral and neuronal pathologies, their differences are important to consider when choosing a brain injury model.

Animals↗
PubMed2004

Intraventricular infusion of the neurotrophic protein S100B improves cognitive recovery after fluid percussion injury in the rat.

Elevated serum S100B levels have been shown to be a predictor of poor outcome after traumatic brain injury (TBI). Experimental data, on the other hand, demonstrate a neuroprotective and neurotrophic effect of this calcium-binding protein. The purpose of this study was to examine the role of increased S100B levels on functional outcome after TBI. Following lateral fluid percussion or sham injury in male Sprague Dawley rats (n = 56), we infused S100B (50 ng/h) or vehicle into the cerebrospinal fluid of the ipsilateral ventricle for 7 days using an osmotic mini-pump. Assessment of cognitive performance by the Morris water maze on days 30-34 after injury revealed an improved performance of injured animals after S100B infusion (p < 0.05), when compared to vehicle infusion. Blood samples for analysis of clinical markers of brain damage, S100B and neuron specific enolase, taken at 30 min, 3 h, 4 h, 2 days, or 5 days showed a typical peak 3 h after injury (p < 0.01), and higher serum levels correlated significantly with an impaired cognitive recovery (p < 0.01). The correlation of higher serum S100B levels with poor water maze performance may result from injury induced opening of the blood-brain barrier, allowing the passage of S100B into serum. Thus while higher serum levels of S100B seem to reflect the degree of blood-brain barrier opening and severity of injury, a beneficial effect of intraventricular S100B administration on long-term functional recovery after TBI has been demonstrated for the first time. The exact mechanism by which S100B exerts its neuroprotective or neurotrophic influence remains unknown and needs to be elucidated by further investigation.

Animals↗
PubMed2006

Comparison of lung deposition of amikacin by intrapulmonary percussive ventilation and jet nebulization by urinary monitoring.

The intrapulmonary percussive ventilation (IPV), frequently coupled with a nebulizer, is increasingly used as a physiotherapy technique; however, its physiologic and clinical values have been poorly studied. The aim of this study was to compare lung deposition of amikacin by the nebulizer of the IPV device (Percussionaire; Percussionaire Corporation; Sandpoint, ID) and that of standard jet nebulization (SST; SideStream; Medic-Aid; West Sussex, UK). Amikacin was nebulized with both devices in a group of five healthy subjects during spontaneous breathing. The deposition of amikacin was measured by urinary monitoring. Drug output of both devices was measured. Respiratory frequency (RF) was significantly lower when comparing the IPV device with SST (8.2 +/- 1.6 breaths/min vs. 12.6 +/- 2.5 breaths/min, p < 0.05). The total daily amount of amikacin excreted in the urine was significantly lower with IPV than with SST (0.8% initial dose vs. 5.6% initial dose, p < 0.001). Elimination halflife was identical with both devices. Drug output was lower with IPV than with SST. The amount of amikacin delivered to the lung is sixfold lower with IPV than with SST, although a lower respiratory frequency was adopted by the subjects with the IPV. Therefore, the IPV seems unfavorable for the nebulization of antibiotics.

Administration, Inhalation↗
PubMed1989

Effect of D, alpha-tocopheryl succinate and polyethylene glycol on performance tests after fluid percussion brain injury.

One hundred and one rats were administered either D, alpha-tocopheryl succinate plus polyethylene glycol (PEG), PEG, or saline 30 min prior to or 5 min after moderate fluid percussion brain injury. Mortality rates, performance on beam balance and beam-walking tasks, and body weight were assessed daily for 10 days. With preinjury administration, mortality rate was reduced from 31% with saline to 9% with PEG and 9% with D, alpha-tocopheryl succinate plus PEG. With postinjury administration, mortality rate was reduced from 36% with saline to 20% with PEG and to 10% with the D, alpha-tocopheryl succinate plus PEG combination. With administration prior to injury, PEG and D, alpha-tocopheryl succinate plus PEG reduced the deficits seen on beam balance testing on days 1-3 after injury. On beam walking, PEG and D, alpha-tocopheryl succinate plus PEG reduced deficits compared to those in saline-injected animals on days 1 and 2 and on day 1 after injury, respectively. A strongly protective effect of PEG and of D, alpha-tocopheryl succinate plus PEG was seen with preinjury administration. With postinjury administration, D, alpha-tocopheryl succinate plus PEG reduced deficits on beam balance testing compared to animals receiving both saline and PEG on days 1-3 after injury. On beam-walking latencies, D, alpha-tocopheryl succinate plus PEG reduced deficits on days 1 and 2 after injury compared to saline and to PEG. Both PEG and D, alpha-tocopheryl succinate plus PEG reduced weight loss after injury compared to saline. The protective effects of these agents and their relatively low toxicity and high lipid solubility give them potential for the treatment of human head injury.

Animals↗
PubMed1992

Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. Part 1: Distribution and time course of protein extravasation.

Experimental brain injury is associated with marked vasogenic edema, as evidenced by an increase in brain water content. This prominent and widespread response raises questions about the vulnerability of microvasculature in the brain to injury. In the present report we further characterize the vascular response by evaluating the integrity of the blood-brain barrier to circulating proteins. Vascular permeability to endogenous immunoglobulins (IgG) and to the protein horseradish peroxidase (HRP) was examined after a lateral, fluid percussive brain injury in the rat. In study 1 IgG was immunolocalized in brain sections 1-24 hr after injury. In studies 2 and 3 HRP was given intravenously either before impact (study 2) or 10 min before sacrifice (study 3). Permeability to this protein was assessed at 1-6 hr (study 2) or at 1-72 hr (study 3) after injury. In studies 1 and 2 the extravascular accumulation of proteins was evaluated. Pronounced abnormal permeability to IgG and HRP occurred within the first hour after injury and was widespread throughout both hemispheres. The intensity of immunostaining for IgG increased with time up to 24 hr after injury. In contrast, maximal extravascular accumulation of HRP occurred within the first hour after injury. In study 3 the time course for re-establishment of the blood-brain barrier to HRP was determined. Maximal permeability occurred at 1 hr after injury. At 24 hr abnormal permeability was restricted to the impact site and this area remained permeable up to 72 hr after injury. In summary this study demonstrates that breakdown of the blood-brain barrier to plasma proteins is a prominent feature of experimental brain injury. This abnormal permeability is characterized by its transient expression and widespread distribution. The time course for re-establishment of the blood-brain barrier to circulating proteins is most delayed at the impact site.

Animals↗
PubMed1993

Regional patterns of blood-brain barrier breakdown following central and lateral fluid percussion injury in rodents.

In order to determine how fluid percussion injury (FPI) effect is distributed throughout the brain, and to assess the extent to which individual brain nuclei and regions are affected, the pattern of blood-brain barrier (BBB) breakdown was determined in groups with different injury cannula locations. Injury cannulas were placed either at midline, or 2 or 4 mm to the side. One hour following FPI, animals were given horseradish peroxidase (HRP) and the brains were stained using the TMB method. The distribution of HRP leakage varied considerably depending upon the location of the injury cannula, however, there were also common sites of leakage among these groups. Locally the cortex and hippocampus under and adjacent to the injury cannula were heavily affected, with a clear asymmetric effect in the lateral cannula groups. Common sites of leakage included the dorsal thalamus, septal area, pontine tegmentum, periaqueductal gray, substantia nigra, and narrow zones adjacent to ventricular or cisternal surfaces. The hippocampus tended to be involved at greater distances than the cerebral cortex. The cervicomedullary junction proved to be especially vulnerable to FPI with extensive HRP leakage, and petechial hemorrhage ranging from minor to fatal coalescent hemorrhage. A very narrow threshold separated these outcomes. Neurologic impairment of the animals correlated most directly with the extent of cervico-medullary junction injury. Thus FPI produces a mix of local and diffuse effects on the BBB. Injury at the cervicomedullary junction is a prominent effect and is the limiting factor in trying to establish more severe diffuse injury.

Animals↗
PubMed1993

Effect of U74006F on neurologic function and brain edema after fluid percussion injury in rats.

The effect of the 21-aminosteroid U74006F, an inhibitor of iron-dependent lipid peroxidation, on neurologic outcome and cerebral edema was evaluated in adult male Sprague-Dawley rats subjected to a fluid percussion temporal brain injury followed by 45 min of hypoxia (PaO2 = 30.0 mm Hg). The rats were divided randomly into five groups. Bolus injections of a control drug or U74006F (1.0, 3.0, 10.0, or 30.0 mg/kg) were given 3 min and 3 h after the injury. Twenty-four hours after the injury, the neurologic status was evaluated, the rats were killed, and brain water content was determined by microgravimetry. U74006F did not significantly reduce brain water content at any dose level, nor did it affect rotorod walking or activity scores. However, rats treated with U74006F at a dose of 10.0 mg/kg had significantly better motor function scores (p < 0.05) than rats in the control group. These findings demonstrate the usefulness of U74006F as a cerebroprotective agent in this model of experimental head injury.

Animals↗
PubMed1994

Fluid percussion injury causes loss of forebrain choline acetyltransferase and nerve growth factor receptor immunoreactive cells in the rat.

Memory dysfunction is a common sequela of human traumatic brain injury (TBI). Cholinergic forebrain neurons are recognized for their role in memory. We tested the hypothesis that forebrain cholinergic neurons are vulnerable to fluid percussion injury (FPI), a model of human TBI. Rodents were subjected to a moderate parasagittal FPI, sham injury, or fimbria/fornix axotomy and then killed 10 days after the procedure. Additional animals underwent FPI or sham injury and were killed 7, 14, and 28 days after the procedure. Neurons in the medial septal nucleus and vertical limb of the nucleus of the diagonal band of Broca were identified and quantitated using choline acetyltransferase (ChAT) and low affinity nerve growth factor receptor (NGF-R) immunohistochemistry. Our results showed a significant decrease in ChAT (17% +/- 5%) and NGF-R (24% +/- 8%) immunoreactive cells in FPI animals killed after 10 days when compared to sham-injured animals. Animals undergoing fimbria/fornix axotomy showed a greater reduction in ChAT (53% +/- 13%) and NGF-R (55% +/- 5%) immunoreactive cells 10 days postaxotomy. The number of ChAT and NGF-R immunoreactive neurons was reduced at all time points. However, statistical significance was present 10 and 14 days postinjury for ChAT immunoreactive neurons and 10 days only for NGF-R immunoreactive neurons. These studies have shown that FPI produces transient loss of ChAT and NGF-R immunoreactive neurons.

Animals↗
PubMed1995

The blood-brain barrier disruption to circulating proteins in the early period after fluid percussion brain injury in rats.

Breakdown of the blood-brain barrier (BBB) immediately after traumatic brain injury is not clearly understood. In the present study we focused on the integrity of the BBB to circulating proteins within the first hour after injury. For this purpose, vascular permeability to endogenous albumin and to the exogenous protein tracer horseradish peroxidase (HRP) was examined after a lateral fluid percussion brain injury in rats. Albumin was immunolocalized in brain sections at 3 and 60 min after impact. This distribution was compared with the histochemical localization of HRP given before impact at the same time points. In a separate experiment HRP was given prior to sacrifice to determine the time course for the barrier disruption. Permeability to this protein was assessed at 13, 30, and 60 min after impact. Prominent extravasation of albumin occurred within 3 min of injury and was present in multiple foci within the injured hemisphere. At 60 min the extravasated albumin was present in the same sites, where it was widely distributed. Throughout the related brain parenchyma, little difference was found between the extravascular distribution of albumin and HRP. In the delayed administration paradigm breakdown of the BBB was noted in the impact site, hemorrhagic site in the deep cortical layer, hippocampus, thalamus, and midbrain at 13 min after injury. This injured barrier was restored in most regions by 30 min. However, the impact site and hemorrhagic site remained permeable up to 60 min postinjury. In addition, newly developed barrier disruption to HRP occurred in the parasagittal cortex at 30 and 60 min. In conclusion, widespread breakdown of the BBB to circulating proteins occurred within a few minutes after traumatic brain injury. The time course for this barrier disruption is characterized by three different patterns: (1) transient, (2) prolonged, and (3) delayed opening. This variation in the development of barrier disruption may be related to the secondary barrier failure as well as the primary opening after injury.

Animals↗
PubMed1995

Effect of hypoxia or hyperbaric oxygen on cerebral edema following moderate fluid percussion or cortical impact injury in rats.

This study was designed to evaluate the production of cerebral edema [as measured by tissue specific gravity (SpG)] following moderate fluid percussion (FP) and cortical impact (CI) injury in rodents. To determine the effects of a secondary systemic insult, hypoxia (13% oxygen for 30 min) was added to some experimental groups immediately after head injury. To determine the effects of hyperbaric oxygen (HBO) on injured cortical tissue, additional animal groups were exposed to HBO (1.5 atm, for 60 min), beginning 4 h after head trauma. Both injury models produced equal amounts of tissue edema at the site of injury (mean SpG +/- SEM = 1.035 +/- 0.001), when measured 6 h posttrauma. There was no significant edema at the tissue sites immediately adjacent to the trauma sites. The addition of hypoxia to either injury system did not increase edema formation beyond that produced by injury alone. HBO reduced the water content of the trauma site in animals that had received FP, but not in animals receiving CI. We conclude that with the injury parameters used in this protocol, both FP and CI appear to produce focal cerebral edema at the site of trauma. Hypoxia does not worsen edema. HBO appears to reduce edema produced by FP, but not by CI.

Animals↗
PubMed1995

The effect of acute cocaine or lidocaine on behavioral function following fluid percussion brain injury in rats.

One of the goals of our laboratory is to examine how the presence of drugs of abuse will influence traumatic brain injury. Previous studies in our laboratory have shown that cocaine or lidocaine treatment before experimental fluid percussion brain injury in rats reduces the cortical hypoperfusion normally found in the early posttraumatic period. The purpose of the current study was to determine if pretreatment with cocaine or lidocaine is also associated with changes in trauma-induced suppression of reflexes and motor and cognitive dysfunction that occurs following traumatic brain injury (TBI). Twenty-four hours after surgical preparation, rats were randomly assigned to a saline or drug pretreatment group, cocaine (0.5, 2, or 5 mg/kg) or lidocaine (2 mg/kg), which was injected via the tail vein. None of the drug pretreatments worsened injury. Lidocaine and cocaine decreased the duration of suppression of some neurological reflexes and reduced posttraumatic body weight losses. Lidocaine and cocaine both decreased postinjury motor deficits. Lidocaine and cocaine did not affect cognitive function on days 11-15 postinjury. The mechanism by which lidocaine improves acute neurological and motor function following brain injury is unknown, but may involve improved posttraumatic cortical blood flow, as seen in our previous study. Our results, along with other studies showing lidocaine to be neuroprotective in animal models of ischemia, suggest that studies of the effect of posttraumatic administration of lidocaine are warranted.

Animals↗
PubMed1996

Laser-Doppler flowmetry measurements of subcortical blood flow changes after fluid percussion brain injury in rats.

Laser-Doppler flowmetry (LDF) was used to record subcortical cerebral blood flow in hippocampus and striatum immediately following parasaggital fluid percussion brain injuries of mild to moderate severity (2.58 +/- 0.09 atm, 10-11 msec duration) in spontaneously breathing anesthetized rats. At 5 min postinjury, mean blood flow decreased bilaterally by 20-30% in both brain structures, and remained significantly reduced during the remainder of the 60 min postinjury recording interval. Blood flow did not change in the sham-injured rats. Subsequent beam-walk, beam-balance, and rope-hang assessments revealed significant neurological impairments in the injured rats but not in the sham controls. The magnitude of the blood flow changes and the severity of the ensuing neurological impairment were significantly correlated. Histopathological assessments revealed hemorrhagic contusions within ipsilateral cortical regions, occasional neuronal necrosis within underlying thalamus and CA3 and CA4 sectors of the hippocampus, and neuronal cell loss in the hilus of the dentate gyrus. In a second series of experiments, radiolabeled microspheres were used to validate the LDF blood flow measurements. The microsphere measurements revealed that the preinjury baseline and postinjury right hippocampal blood flow changes were not significantly altered by the intrahippocampal presence of an LDF probe, verifying that the LDF probe was not by itself an unacceptably disruptive influence on local cerebrovascular reactivity. Moreover, when right hippocampal blood flow was simultaneously evaluated in injured rats by both techniques, the relative blood flow changes were significantly correlated. These results indicate that laser-Doppler flowmetry provides a potentially useful means to appreciate acute regional cerebrovascular changes relative to other measures of outcome after brain trauma.

Animals↗
PubMed1996

The effect of postinjury administration of polyethylene glycol-conjugated superoxide dismutase (pegorgotein, Dismutec) or lidocaine on behavioral function following fluid-percussion brain injury in rats.

Previous studies in our laboratory have shown that polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) or lidocaine treatment before experimental fluid-percussion brain injury in rats reduces the cortical hypoperfusion normally found in the early posttraumatic period. The purpose of the current study was to determine if posttreatment with PEG-SOD or lidocaine is also associated with changes in the trauma-induced suppression of motor and cognitive function that occurs following traumatic brain injury (TBI). Twenty-four hours after surgical preparation, rats were randomly assigned to a saline or drug posttreatment group, PEG-SOD (pegorgotein, Dismutec 10,000 IU/kg) or lidocaine (2 mg/kg), which was injected iv 30 min after moderate injury. PEG-SOD completely prevented beam walk deficits on days 1-5 postinjury while lidocaine similarly prevented beam walk deficits on days 2 through 5 postinjury. Both drugs produced a statistically insignificant trend for a decrease in beam balance duration deficits on days 1-5 postinjury and had no effect on cognitive function, as assessed by the Morris water maze, on days 11 through 15 postinjury. The mechanism by which PEG-SOD and lidocaine reduce posttraumatic motor deficits may be related to their free radical scavenging effect or previously reported effects on posttraumatic cerebral blood flow. To our knowledge, this is the first report of the effectiveness of these two agents in laboratory animals when administered after traumatic injury.

Anesthetics, Local↗
PubMed1997

Lack of delayed effects of amphetamine, methoxamine, and prazosin (adrenergic drugs) on behavioral outcome after lateral fluid percussion brain injury in the rat.

This study examined the delayed effects of the administration of d-amphetamine, methoxamine (an alpha1-adrenergic receptor agonist), and prazosin (an alpha1-adrenergic receptor antagonist) on the behavioral outcome of lateral fluid-percussion (FP) brain injury. Rats trained to perform a beam-walking task were subjected to brain injury of moderate severity (2.1 to 2.2 atm). Twenty-four hours after injury, rats were treated with amphetamine, methoxamine, or prazosin at two or three different dose levels. Amphetamine-treated animals displayed no significant improvement in beam-walking ability either during or after drug intoxication (from days 3 to 5 after brain injury). Similarly, neither methoxamine nor prazosin significantly affected beam-walking ability during or after drug intoxication. Neither amphetamine treatment at three different doses nor treatment with methoxamine or prazosin at two different doses affected the spatial learning disabilities of brain-injured animals. These results suggest that (1) unlike amphetamine administration after sensorimotor cortex (SMC) ablation or contusion brain injury models, amphetamine administration at 24 h after concussive FP brain injury does not improve beam-walking performance; (2) unlike amphetamine administration 10 min after concussive FP brain injury amphetamine administration 24 h after injury does not improve cognitive function; and (3) unlike prazosin administration after SMC ablation brain injury, prazosin administration 24 h after concussive FP brain injury does not effect beam-walking performance.

Amphetamine↗
PubMed1997

Extracellular release of serotonin following fluid-percussion brain injury in rats.

Serotonin has been implicated in the pathobiology of central nervous system trauma. Using microdialysis techniques, we performed measurements of extracellular serotonin release within the traumatized cerebral cortex of rats subjected to moderate fluid-percussion (F-P) brain injury. Twenty-four hours prior to TBI, a F-P interface was positioned parasagitally over the right cerebral cortex. On the second day, fasted rats were anesthetized with 70% nitrous oxide, 1% halothane and 30% oxygen. Under controlled physiological conditions and normothermic brain temperature (37-37.5 degrees C), rats were injured (n = 6) with a F-P pulse ranging from 1.8 to 2.0 atm. Following trauma, brain temperature was maintained for 4 h at 37 degrees C. Sham trauma animals (n = 7) were treated in an identical manner. Brain trauma induced acute elevations in the extracellular levels of serotonin (p < 0.01, ANOVA) compared to sham-operated controls. For example, serotonin levels increased from 18.85 +/- 7.12 pm/mL (mean +/- SD) in baseline samples to 65.78 +/- 11.36 in the first 10 min after trauma. The levels of serotonin remained significantly higher than control for the first 90-min sampling period. In parallel to the increase in serotonin levels after TBI, a significant 71.1% decrease (i.e., 182.29 +/- 30.08 vs 52.75 +/- 16.92) in extracellular 5-hydroxyindoleacetic acid (5-HIAA) levels was observed during the first 10 min after TBI. These data indicate that TBI is followed by a prompt increase in the extracellular levels of serotonin in cortical regions adjacent to the impact site. These neurochemical findings indicate that serotonin may play a significant role in the pathophysiology of TBI.

Animals↗
PubMed1998

Adaptation of the fluid percussion injury model to the mouse.

Fluid percussion injury (FPI) is a well-characterized experimental model of traumatic brain injury (TBI) in the rat. Many pathophysiologic consequences and mechanisms of recovery after TBI rely on neurochemical pathways that can be examined in genetically altered mice. Therefore, FPI applied to mice may be a useful experimental tool to investigate TBI at the molecular level. In the present study, we establish FPI as a viable model of TBI in the mouse by characterizing acute neurological, histopathological, and behavioral changes. Right-sided parasagittal FPI or sham treatment was administered in male C57BL/6 mice. Acute neurological evaluation revealed righting reflexes in the injured animals (p < 0.001). Deficits in spatial learning and memory were observed in the Morris water maze (MWM) 5 and 6 days after injury. A novel MWM data analysis protocol is described. The injured group (n = 18) demonstrated impaired performance in the MWM during acquisition (p < 0.05) and probe trials (p < 0.025) compared to sham animals (n = 16). At 7 days postinjury, glial fibrillary acidic protein immunohistochemistry revealed intense cortical, callosal, and hippocampal gliosis. The modified Gallyas silver degeneration stain consistently labeled cell bodies and terminals throughout the ipsilateral cortex, axons in the gray matter-white matter interface above the corpus callosum and within the corpus callosum bilaterally, and terminals and fibers in the thalamus bilaterally. Additionally, the mouse FPI model described is immediately employable in labs already using the FPI rat model with no modifications to a pre-existing FPI apparatus.

Animals↗
PubMed1998

The 21-aminosteroid U-74389G reduces cerebral superoxide anion concentration following fluid percussion injury of the brain.

We examined the effects of the 21-aminosteroid antioxidant U-74389G (16-desmethyl-tirilazad) on the concentration of extracellular superoxide anion following fluid percussion traumatic brain injury (TBI) measured by a cytochrome c-coated electrode and on local cerebral perfusion (CBFld) measured by laser Doppler flowmetry (LDF). U-74389G in a dose of 3 mg/kg reduced superoxide anion concentrations 60 min after TBI significantly but had no significant effect on CBFld. These results indicate that reduction of CBF after TBI can be dissociated from superoxide anion production. Persistent ischemia may limit neuroprotection efficacy and may contribute to divergent outcome results in clinical and animal trials using agents to modify reactive oxygen species.

Animals↗
PubMed1998

Effects of moderate, central fluid percussion traumatic brain injury on nitric oxide synthase activity in rats.

Experimental traumatic brain injury (TBI) damages cerebral vascular endothelium and reduces cerebral blood flow (CBF). The nitric oxide synthase (NOS) substrate, L-arginine, prevents CBF reductions after TBI, but the mechanism is not known. This study examined the possibility that post-traumatic hypoperfusion is due to reductions in the substrate sensitivity of NOS which are overcome by L-arginine. Isoflurane-anesthetized rats were prepared for TBI (midline fluid-percussion, 2.2 atm), sham-TBI, or no surgery (control), and were decapitated 30 min after injury or sham injury. The brains were removed and homogenized or minced for measurements of crude soluble or cell-dependent stimulated NOS activity, respectively. Baseline arterial oxygen, carbon dioxide, pH, or hemoglobin levels did not differ among control, sham, or TBI groups. Total cortical soluble NOS activity in TBI-treated rats was not significantly different from either untreated or sham groups when 0.45 microM or 1.5 microM L-arginine was added. Also, there were no differences in cell-dependent NOS activity among the three groups stimulated by 300 microM N-methyl-D-aspartate, 50 mM K+, or 10 microM ionomycin. These data suggest that TBI reduces CBF by a mechanism other than altering the substrate specificity or activation of nNOS.

Analysis of Variance↗