Effect of lactate therapy upon cognitive deficits after traumatic brain injury in the rat.

BACKGROUND: In previous studies, it has been shown that intravenous lactate therapy can improve brain neurochemistry, adenosine triphosphate (ATP) generation and outcome after traumatic brain injury (TBI) in rats. In this study, we examined: (1) four L-lactate concentrations to determine the optimal therapeutic dose post TBI in terms of cognitive function; (2) ATP production after TBI for the L-lactate concentration found to be the optimal dose; (3) the possible production of lactic acidosis with the highest L-lactate concentration tested. METHODS: Thirty minutes following a fluid percussion injury (FPI) over the left cerebral hemisphere, the animals received an intravenous infusion of 10, 28, 100, or 280 mM L-lactate (n = 10 for each group) for 3 h at a rate of 0.65 ml/h. Shams and control injured animals received a saline infusion. At 11-15 days post injury, cognitive deficits were examined using the Morris Water Maze (MWM) test. Three groups of rats were used for ATP analysis: shams, injured + saline infusion, and injury + the optimal lactate dose as determined by the MWM (n = 4/group). Additionally, a group receiving 280 mM L-lactate (n = 5) and one receiving a saline infusion (n = 3) were monitored for arterial blood variables and blood pressures. FINDINGS: In the MWM test, only the 100 mM L-lactate-treated injured animals showed a significant reduction in cognitive deficits when compared to saline-treated injured animals (p

Neurobehavioral assessment of outcome following traumatic brain injury in rats: an evaluation of selected measures.

Neurobehavioral assessment of outcome has played an integral part in traumatic brain injury (TBI) research. Given the fundamental role of neurobehavioral measurement, it is critical that the tasks used are of the highest psychometric quality. The purpose of this paper is to evaluate several, commonly used neurobehavioral measures along the dimensions of reliability, sensitivity, and validity. Using both the midline and lateral fluid-percussion injury models, nine neurobehavioral measures were evaluated that assessed three different neurobehavioral constructs. Reflex suppression was measured by the duration of the suppression of the pinna, corneal, and righting reflexes. Vestibulomotor function was assessed with the beam-balance, beam-walking, and rotorod tasks. Cognitive function was evaluated by three measures of Morris water maze performance (goal latency, path length, cumulative distance). The evaluation of the reliability of the nine neurobehavioral measures found that all had acceptably high reliability coefficients (0.79 or higher). The analysis of each measure's sensitivity to injury found that all measures were capable of detecting injury-induced impairments. However, there were some substantial differences in the sensitivity of the measures of vestibulomotor and maze performance: the rotorod was the most sensitive vestibulomotor measure and goal latency and path length were equally sensitive measures of maze performance. In the assessment of validity, the results of a factor analysis supported the convergent and discriminative validity of the measures. And in cases in which the preclinical and clinical research have assessed the same construct, the animal model neurobehavioral measures had predictive (or external) validity. Thus, according to the psychometric standards by which measurement instruments are evaluated, the results indicated that these measures provide a valid assessment of neurobehavioral function after fluid percussion TBI.

Differential effects of delta 9-THC on spatial reference and working memory in mice.

RATIONALE: Marijuana remains the most widely used illicit drug in the U.S., and recent attention has been given to putative therapeutic uses of marijuana and cannabinoid derivatives. Thus, developing a better understanding of delta9-THC (tetrahydrocannabinol)-induced mnemonic deficits is of critical importance. OBJECTIVES: These experiments were conducted to determine whether delta9-THC has differential effects on spatial reference and working memory tasks, to investigate its receptor mechanism of action, and to compare these effects with those produced by two other compounds--scopolamine and phencyclidine--known to produce mnemonic deficits. In addition, the potency of delta9-THC in these memory tasks was compared with its potency in other pharmacological effects traditionally associated with cannabinoid activity. METHODS: Two different versions of the Morris water maze were employed: a working memory task and a reference memory task. Other effects of delta9-THC were assessed using standard tests of hypomotility, antinociception, catalepsy, and hypothermia. RESULTS: delta9-THC disrupted performance of the working memory task (3.0 mg/kg) at doses lower than those required to disrupt performance of the reference memory task (100 mg/kg), or elicit hypomotility, antinociception, catalepsy, and hypothermia. These performance deficits were reversed by SR 141716A. The effects of delta9-THC resembled those of scopolamine, which also selectively disrupted the working maze task. Conversely, phencyclidine disrupted both tasks only at a dose that also produced motor deficits. CONCLUSIONS: These data indicate that delta9-THC selectively impairs performance of a working memory task through a CB, receptor mechanism of action and that these memory disruptions are more sensitive than other pharmacological effects of delta9-THC.

Nefiracetam improves Morris water maze performance following traumatic brain injury in rats.

Nefiracetam, a pyrrolidone derivative, is a nootropic agent that has facilitated cognitive function in a wide variety of animal models of cognitive dysfunction. The purpose of this study was to investigate the efficacy of the chronic postinjury administration of nefiracetam (DM-9384) in improving cognitive performance following central fluid percussion brain injury in rats. Twenty-four hours following surgical preparation, a sham injury or a moderate fluid percussive injury (2.1 atm) was delivered. Nefiracetam was administered chronically (0 or 9 mg/kg, po, for sham animals and 0, 3, or 9 mg/kg for injured animals) on postinjury days 1-15. Cognitive performance was assessed using the Morris water maze (MWM) on postinjury days 11-15. Chronic administration of 3 and 9 mg/kg nefiracetam attenuated MWM deficits produced by central fluid percussive brain injury. Importantly, the MWM performance of the injured animals treated with 9 mg/kg did not significantly differ from uninjured, sham animals. The 9-mg/kg dose of nefiracetam did not have a positive or negative effect on MWM performance of uninjured animals. The results of the present experiment suggest that a nootropic such as nefiracetam may be an appropriate treatment for trauma-induced cognitive dysfunction.

Subtle alterations in NMDA-stimulated cyclic GMP levels following lateral fluid percussion brain injury.

This study examined whether NMDA-stimulated cyclic GMP levels were altered at two different time points following lateral fluid percussion injury. At 60 min and 15 days postinjury, the left and right hippocampi were dissected and chopped into mini-prisms. Each hippocampus was divided into five equal parts and incubated with either the phosphodiesterase inhibitor IBMX (3-isobutyl-1-methylxanthine, 500 microM) alone, IBMX and N-methyl-D-aspartic acid (NMDA) OR IBMX, NMDA, and glycine (10 MM). Two concentrations of NMDA were used: 500 or 1,000 microM. Tissues were then assayed for levels of cyclic GMP. Results indicated that there were no changes in basal levels of cyclic GMP at either postinjury time point. At 60 min postinjury, there were no significant main effects for injury or drug concentration. There was a significant injury x side interaction effect with increased levels of NMDA-stimulated cyclic GMP in the hippocampus ipsilateral to the injury impact and decreased cyclic GMP levels in the contralateral hippocampus. There were no significant alterations in NMDA-stimulated cyclic GMP levels at 15 days postinjury. The data from this study indicated that NMDA-stimulated cyclic GMP accumulation is differentially altered in the hippocampus ipsilateral and contralateral to the site of the injury at 1 h after injury, but is normalized by 15 days postinjury. These findings implicate NMDA-mediated intracellular signaling processes in the acute excitotoxic response to injury.

Postinjury administration of L-deprenyl improves cognitive function and enhances neuroplasticity after traumatic brain injury.

The rat model of combined central fluid percussion traumatic brain injury (TBI) and bilateral entorhinal cortical lesion (BEC) produces profound, persistent cognitive deficits, sequelae associated with human TBI. In contrast to percussive TBI alone, this combined injury induces maladaptive hippocampal plasticity. Recent reports suggest a potential role for dopamine in CNS plasticity after trauma. We have examined the effect of the dopamine enhancer l-deprenyl on cognitive function and neuroplasticity following TBI. Rats received fluid percussion TBI, BEC alone, or combined TBI + BEC lesion and were treated once daily for 7 days with l-deprenyl, beginning 24 h after TBI alone and 15 min after BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl treatment. Cognitive performance was assessed on days 11-15 postinjury and brains from the same cases examined for dopamine beta-hydroxylase immunoreactivity (DBH-IR) and acetylcholinesterase (AChE) histochemistry. Significant cognitive improvement relative to untreated injured cases was observed in both TBI groups following l-deprenyl treatment; however, no drug effects were seen with BEC alone. l-Deprenyl attenuated injury-induced loss in DBH-IR over CA1 and CA3 after TBI alone. However, after combined TBI + BEC, l-deprenyl was only effective in protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with l-deprenyl in both injury models. After TBI + BEC, l-deprenyl also increased AChE in the dentate molecular layer relative to untreated injured cases. These results suggest that dopaminergic/noradrenergic enhancement facilitates cognitive recovery after brain injury and that noradrenergic fiber integrity is correlated with enhanced synaptic plasticity in the injured hippocampus.

Positive and negative modulation of the GABA(A) receptor and outcome after traumatic brain injury in rats.

Glutamate-mediated excitotoxicity has been shown to contribute to cellular dysfunction following traumatic brain injury (TBI). Increasing inhibitory function through stimulation of gamma-aminobutyric acid (GABA(A)) receptors may attenuate excitotoxic effects and improve outcome. The present experiment examined the effects of diazepam, a positive modulator at the GABA(A) receptor, on survival and cognitive performance in traumatically brain-injured animals. In experiment 1, 15 min prior to central fluid percussion brain injury, rats (n=8 per group) were injected (i.p.) with saline or diazepam (5 mg/kg or 10 mg/kg). Additional rats (n=8) were surgically prepared but not injured (sham-injury). Rats pre-treated with the 5 mg/kg dose of diazepam had significantly lower mortality (0%) than injured, saline-treated rats (53%). Also, diazepam-treated (5 mg/kg) rats had significantly shorter latencies to reach the goal platform in the Morris water maze test performed 11-15 days post-injury. In experiment 2, at 15 min post-injury, rats were given either saline (n=5) or 5 mg/kg diazepam (n=6). Rats treated with diazepam did not differ in mortality from injured rats treated with vehicle. However, rats treated with diazepam at 15 min post-injury had significantly shorter latencies to reach the goal platform in the Morris water maze than injured, vehicle-treated rats. In experiment 3, the post-injury administration of bicuculline (1.5 mg/kg, n=8), a GABA(A) antagonist, increased Morris water maze goal latencies compared to injured animals treated with saline (n=8). These results suggest that enhancing inhibitory function during the acute post-injury period produces beneficial effects on both survival and outcome following experimental TBI.

Status epilepticus causes long-term NMDA receptor-dependent behavioral changes and cognitive deficits.

PURPOSE: The role of N-methyl-D-aspartate (NMDA)-receptor activation on behavioral and cognitive changes after status epilepticus (SE) is unknown. In this study, behavioral and cognitive changes after SE were evaluated in the short and long term and in rats in which the NMDA receptor was inactivated during SE. METHODS: Pilocarpine (350 mg/kg) was injected to induce SE. Inhibition of the NMDA receptor during SE was achieved with MK-801 (4 mg/kg). Seizure intensity during SE was monitored by electroencephalography (EEG). After SE, behavioral studies were performed to identify abnormal behavior by using behavioral tests adapted from Moser's functional observational battery. Cognitive changes were assessed by using the Morris Water Maze (MWM). RESULTS: Pilocarpine-treated animals scored significantly higher on two of the behavioral tests: the Touch test and the Pick-Up test. These behavioral changes occurred very soon after SE, with the earliest changes observed 2 days after SE and persisting for the life of the animal. Inhibition of the NMDA receptor with MK-801 completely inhibited these behavioral changes under conditions that did not alter the duration of SE. In addition, pilocarpine-treated animals exhibited cognitive deficits as determined by using the MWM. Six weeks after SE, the animals displayed significantly longer latencies to locate the hidden platform on this test. The impaired performance on the MWM also occurred as early as 5 days after SE. These cognitive deficits were prevented in animals treated with MK-801 during SE. CONCLUSIONS: The results indicate that behavioral and cognitive changes occur soon after SE, are permanent, and are dependent on NMDA-receptor activation during SE. NMDA-receptor activation may play an important role in causing cognitive and behavioral morbidity after recovery from SE.

Glutamate antagonism during secondary deafferentation enhances cognition and axo-dendritic integrity after traumatic brain injury.

The combination of central fluid percussion traumatic brain injury (TBI) followed 24 h later by a bilateral entorhinal cortical deafferentation (BEC) produces profound cognitive morbidity. We recently showed that MK-801 given prior to TBI in this insult improved spatial memory for up to 15 days. In the present study we examine whether MK-801 treatment of the BEC component in the combined insult model affects cognitive recovery. Two strategies for drug treatment were tested. Fifteen minutes prior to the BEC lesion in the combined insult, rats were given i.p. doses of either 3 mg/kg (acute group) or 1 mg/kg (chronic group) MK-801. The acute group received no further injections, whereas the chronic group received 1 mg/kg MK-801 i.p. twice a day for 2 days post-BEC lesion. Two additional groups of animals received BEC lesion alone and either acute or chronic MK-801 treatment identical with the combined insult cases. Each group was then assessed for spatial memory deficits with the Morris water maze at days 11-15 and 60-64 postinjury. Both acute and chronic MK-801 treatment in the combined insult group significantly reduced spatial memory deficits at 15 days postinjury relative to untreated injured cases (P < .01). This reduction appeared more robust at 15 days and persisted for up to 64 days in the chronically treated group (P < .05). By contrast, neither acute nor chronic MK-801 treatment affected memory performance with the BEC insult alone. Immunocytochemical localization of parvalbumin showed that chronic administration of MK-801 in the combined insult cases attenuated the injury-induced dendritic atrophy of inhibitory neurons in the dentate gyrus and area CA1. Synaptophysin immunobinding revealed that chronic MK-801 treatment of the BEC component of the combined insult normalized the distribution of presynaptic terminals within the dentate gyrus. These results suggest that cognitive deficits produced by head trauma involving both neuroexcitation and deafferentation can be attenuated with chronic application of glutamatergic antagonists during the period of deafferentation injury and that this attenuation is correlated with axo-dendritic integrity.

Chronic administration of a partial muscarinic M1 receptor agonist attenuates decreases in forebrain choline acetyltransferase immunoreactivity following experimental brain trauma.

Lu 25-109-T is a partial muscarinic M1 receptor agonist with antagonistic effects at presynaptic M2 autoreceptors and has been shown to improve cognitive function following traumatic brain injury (TBI) in rats. This investigation examined the effects of TBI on basal forebrain choline acetyltransferase immunoreactivity (ChAT-IR) following daily administration of saline or 15 mumol/kg Lu 25-109-T. Rats received a moderate (2.1 +/- 0.1 atm) level of central fluid percussion TBI or were surgically prepared but not injured and were injected (sc) with saline or drug on Days 1-15 postinjury. Rats were sacrificed following the last daily injection, and sections were collected through the basal forebrain and processed for ChAT-IR. TBI caused a significant reduction in ChAT-IR neuronal density in saline- and Lu 25-109-T-treated rats with a 13% and 5% decrease in the medial septal nucleus (MSN), a 48 and 23% decrease in the vertical limb nucleus of the diagonal band (VDB), and a 51 and 28% decrease in the nucleus basalis magnocellularis (NBM), respectively. However, Lu 25-109-T significantly attenuated the injury-induced reductions in ChAT-IR. Loss in ChAT-IR neuronal density is not thought to result from cell death as parallel cresyl violet-stained sections indicated no decrease in neuronal cell density in the MSN, VDB, or NBM. These results support the hypothesis that increasing cholinergic tone during the recovery period after TBI will restore cholinergic function impaired by brain trauma.

Activating the posttraumatic cholinergic system for the treatment of cognitive impairment following traumatic brain injury.

Cognitive impairment after traumatic brain injury (TBI) is correlated with decreased cholinergic markers of neuronal viability. The purpose of this experiment was to test the hypothesis that pharmacological activation of the muscarinic cholinergic system during the recovery period after TBI will improve cognitive performance. LU 25-109-T is a partial muscarinic M1 agonist that also acts as an antagonist at presynaptic M2 autoreceptors (thus increasing ACh release). Injured rats were injected subcutaneously daily for 15 days with either 0.0, 3.6, or 15 mumol/kg of LU 25-109-T beginning 24 h after a receiving a moderate (2.1 +/- 0.1 atm) level of central fluid percussion brain injury. Cognitive performance was assessed on days 11-15 postinjury in a Morris water maze (MWM). Injured rats treated with 15 mumol/kg, but not those treated with 3.6 mumol/kg, showed a significant improvement (p < 0.01) in MWM performance as compared with injured vehicle-treated rats. This result supports the hypotheses that a decrease in posttraumatic cholinergic neurotransmission contributes to TBI-induced cognitive deficits and that increasing cholinergic tone during the recovery period following TBI will improve cognitive performance.

Effect of prior receptor antagonism on behavioral morbidity produced by combined fluid percussion injury and entorhinal cortical lesion.

We have used an animal model of traumatic brain injury (TBI) that incorporates both the neurotransmitter toxicity of fluid percussion TBI and deafferentation of bilateral entorhinal cortical (BEC) lesion to explore whether administration of muscarinic cholinergic or N-methyl-D-aspartate glutamatergic antagonists prior to injury ameliorates cognitive morbidity. Fifteen minutes prior to moderate central fluid percussion TBI, rats were given intraperitoneal injections of either scopolamine (1.0 mg/kg) or MK-801 (0.3 mg/kg) and 24 hr later underwent BEC lesion. Body weight was followed for 5 days postinjury, as was beam balance and beam walk performance to assure motor recovery prior to spatial memory testing. Each group was assessed for spatial memory deficits with the Morris water maze at short term (days 11-15) and long-term (60-64 days) postinjury intervals and then compared with untreated combined insult and sham-injured controls. Results showed that each drug significantly elevated body weight relative to untreated injured cases. Both scopolamine and MK-801 reduced beam balance deficits, whereas neither drug had a significant effect on beam walk deficits. Interestingly, short-term cognitive deficits assessed on days 11-15 were differentially affected by the two drugs: MK-801 pretreatment enhanced the recovery of spatial memory performance, whereas scopolamine pretreatment did not. Long-term (days 60-64) deficits in spatial memory were not altered by pretreatment with either drug. Our results suggest that, unlike fluid percussion TBI alone, behavioral impairment may require more select intervention when deafferentation is part of the head trauma pathology.

The effects of traumatic brain injury on inhibition in the hippocampus and dentate gyrus.

Changes in inhibitory neuronal functioning may contribute to morbidity following traumatic brain injury (TBI). Evoked responses to orthodromic paired-pulse stimulation were examined in the hippocampus and dentate gyrus at 2 and 15 days following lateral fluid percussion TBI in adult rats. The relative strength of inhibition was estimated by measuring evoked paired pulses in three afferent systems: the CA3 commissural input to the CA1 region of the hippocampus; the entorhinal cortical input to the ipsilateral CA1 area (temporoammonic system); and the entorhinal input to the ipsilateral dentate gyrus (perforant path). In addition to quantitative electrophysiological estimates of inhibitory efficacy, levels of gamma-aminobutyric acid (GABA) were qualitatively examined with immunohistochemical techniques. Effects of TBI on paired-pulse responses were pathway-specific, and dependent on time postinjury. At 2 days following TBI, inhibition of population spikes was significantly reduced in the CA3 commissural input to CA1, which contrasted with injury-induced increases in inhibition in the dentate gyrus seen at both 2 and 15 days postinjury. Low-level stimulation, subthreshold for population spikes, also revealed changes in paired-pulse facilitation of field extracellular postsynaptic potentials (fEPSPs), which depended on fiber pathway and time postinjury. Significant injury-induced electrophysiological changes were almost entirely confined to the hemisphere ipsilateral to injury. Intensity of GABA immunobinding exhibited a regional association with electrophysiological indices of inhibition, with the most pronounced increases in GABA levels and inhibition found in the dentate gyrus. TBI-induced effects showed a regional pattern within the hippocampus which corresponds closely to inhibitory changes reported to follow ischemia and kindling. This degree of similarity in outcome following dissimilar injuries may indicate common mechanisms in the nervous system response to injury.

Inhibition of nitric oxide synthase potentiates hypertension and increases mortality in traumatically brain-injured rats.

We examined the effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), on mortality, morbidity, and cardiovascular parameters following traumatic brain injury (TBI) in the rat. Rats were anesthetized with 2% isoflurane prior to moderate (2.0 atmosphere), central fluid percussion TBI. Temporalis muscle temperature was maintained at 37 +/- 0.5 degrees C. L-NAME (10 mg/kg iv) was administered once at either 5 min before, 5 min after, or 15 min after TBI. Sensorimotor deficits and spatial learning/ memory deficits were assessed after injury. Separate groups of rats were monitored for cardiovascular parameters. Preinjury administration of L-NAME significantly increased mortality from 13 (vehicle) to 70% (associated with pulmonary edema), whereas postinjury, L-NAME had no effect on mortality (14 and 25%). L-NAME administered at 5 or 15 min after injury had no significant effect on motor performance or cognitive performance deficits associated with TBI. L-NAME in uninjured rats increased arterial blood pressure by 25 mmHg within 2 min. L-NAME injected 5 min before TBI greatly prolonged the hypertensive episode associated with TBI (1 min in vehicle vs 60 min in L-NAME). L-NAME injected 5 min after TBI caused a sustained 35 mmHg increase in blood pressure. These findings suggest that acute inhibition of NOS has detrimental consequences on mortality that may be owing to its cardiovascular effects.

Effect of tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental brain injury.

An emerging literature exists in support of deficits in cholinergic neurotransmission days to weeks following experimental traumatic brain injury (TBI). In addition, novel cholinomimetic therapeutics have been demonstrated to improve cognitive outcome following TBI in rats. We examined the effects of repeated postinjury administration of a cholinesterase inhibitor, tetrahydroaminoacridine (THA), on cognitive performance following experimental TBI. Rats were either injured at a moderate level of central fluid percussion TBI (2.1+/-0.1 atm) or were surgically prepared but not delivered a fluid pulse (sham injury). Beginning 24 h after TBI or sham injury, rats were injected (IP) daily for 15 days with an equal volume (1.0 ml/kg) of either 0.0, 1.0, 3.0, or 9.0 mg/kg THA (TBI: n = 8, 8, 10, and 7, respectively, and Sham: n = 5, 7, 8, 7, respectively). Cognitive performance was assessed on Days 11-15 after injury in a Morris water maze (MWM). Analysis of maze latencies over days indicated that chronic administration of THA produced a dose-related impairment in MWM performance in both the injured and sham groups, with the 9.0 mg/kg dose producing the largest deficit. The 1.0 and 3.0 mg/kg doses of THA impaired MWM performance without affecting swimming speeds. Thus, the results of this investigation do not support the use of THA as a cholinomimetic therapeutic for the treatment of cognitive deficits following TBI.

Chronic, post-injury administration of D-cycloserine, an NMDA partial agonist, enhances cognitive performance following experimental brain injury.

The purpose of this study was to determine the effect of augmenting NMDA receptor activation on cognitive deficits produced by traumatic brain injury (TBI). Specifically, D-cycloserine (DCS), a partial agonist of the NMDA-associated glycine site, was tested as a potential cognitive enhancer. Rats were injured using lateral fluid percussion TBI (2.8 +/- .10 atm). On days 1-15 post-injury, animals were injected (i.p.) with vehicle (n = 8), 10 mg/kg (n = 9), or 30 mg/kg (n = 8) of DCS. Sham-injured animals treated with either vehicle (n = 8) or 30 mg/kg of DCS (n = 8) were used for comparison. On days 11-15 post-injury, cognitive function was assessed using the Morris water maze (MWM). Results indicate that the 30 mg/kg dose of DCS significantly attenuated memory deficits as compared to injured vehicle-treated animals (P < 0.01). Analysis also revealed that performance of the injured-DCS (30 mg/kg) group was not significantly different from sham-injured animals treated with vehicle (P > 0.10). In contrast, the 10 mg/kg dose of DCS was ineffective in reducing injury-induced memory deficits. DCS (30 mg/kg) also significantly improved the spatial memory of sham-injured animals when compared with sham-injured animals treated with vehicle (P < 0.05). In conclusion, chronic, post-injury enhancement of the NMDA receptor is an effective strategy for ameliorating TBI-associated cognitive deficits.

Voltage-dependent Na+/K+ ion channel blockade fails to ameliorate behavioral deficits after traumatic brain injury in the rat.

Traumatic brain injury (TBI) induces massive, transient ion flux, after impact. This may be via agonist gated channels, such as the muscarinic, cholinergic or NMDA receptor, or via voltage-dependent channels. Pharmacological blockade of the former, is neuroprotective in most TBI models, but the role of voltage-dependent Na+/K+ channels has not been tested. We have therefore tested the hypothesis that intraventricular tetrodotoxin (TTX) (20 microliters, 5 mM) induced blockade of post-TBI ion flux will prevent cytotoxic cell swelling, Na+ and K+ flux, and behavioral deficit. Microdialysis demonstrated blockade of [K+]d flux in the TTX group compared to controls. Behavioral evaluation of motor (days 1-5) and memory function (days 11-15) after TBI revealed no beneficial effect in the TTX group compared to controls. Thus, although evidence of reduced ionic flux was demonstrated in the TTX group, memory and behavior were unaffected, suggesting that agonist-operated channel-mediated ion flux is more important after TBI.

Working memory deficits following traumatic brain injury in the rat.

This study was designed to examine working memory following fluid-percussion traumatic brain injury (TBI) using the Morris water maze (MWM). Rats were injured (n = 9) at a moderate level of central fluid percussion injury (2.1 atm) or were prepared for injury but did not receive a fluid pulse (sham injury) (n = 10). On days 11-15 postinjury, working memory was assessed using the MWM. Each animal received 8 pairs of trials per day. For each pair of trials, animals were randomly assigned to one of four possible starting points and one of four possible escape platform positions. On the first trial of each pair, rats were placed in the maze facing the wall and were given 120 sec to locate the hidden escape platform. After remaining on the goal platform for 10 sec, they were placed back into the maze for the second trial of the pair. The platform position and the start position remained unchanged on this trial. After the second trial, the animal was given a 4 min intertrial rest. Between pairs of trials, both the start position and the goal location were changed. Analyses of the latency to reach the goal platform indicated that sham-injured animals performed significantly better on the second trial than on the first trial of each pair. However, injured animals did not significantly differ between first and second trial goal latencies on any day. These results indicate that injured animals have a profound and enduring deficit in spatial working memory function on days 11-15 after TBI.

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.

Reduced sensorimotor reactivity following traumatic brain injury in rats.

The present study examined sensorimotor reactivity in rats following traumatic brain injury (TBI). Moderate injury was induced with midline fluid percussion in some of the rats. Others received identical surgery, but were not injured (sham-injured rats), or received neither surgery nor injury (naive rats). All rats were evaluated in acoustic and/or tactile startle procedures. At 8 days post-injury, the sensorimotor reactivity of TBI rats to acoustic stimuli was severely reduced compared to that of sham-injured rats. This TBI-induced deficit was enduring (> 30 days). In a separate experiment, greater sensorimotor reactivity was observed with tactile (vs. acoustic) stimulation in both TBI and naive rats although startle amplitudes for the TBI rats were lower than control levels for both types of stimuli. These results suggest that sensorimotor reactivity is altered by TBI and that the startle procedure is a promising method for investigation of information processing alterations following TBI.