Neuroprotective effect of ceftriaxone on the penumbra in a rat venous ischemia model.

OBJECTIVE: Glutamate transporter-1 (GLT-1) maintains low concentrations of extracellular glutamate by removing glutamate from the extracellular space. It is controversial, however, whether upregulation of GLT-1 is neuroprotective under all ischemic/hypoxic conditions. Recently, a neuroprotective effect of preconditioning with a ß-lactam antibiotic ceftriaxone (CTX) that increases expression of GLT-1 has been reported in animal models of focal ischemia. On the other hand, it is said that CTX does not play a neuroprotective role in an in vitro study. Thus, we examined the effect of CTX on ischemic injury in a rat model of two-vein occlusion (2VO). This model mimics venous ischemia during, e.g. tumor surgery, a clinical situation that is best suitable for pretreatment with CTX. METHODS: CTX (100mg/kg, 200mg/kg per day) or vehicle (0.9% NaCl) was intraperitoneally injected into Wistar rats for 5days before venous ischemia (n=57). Then, animals were prepared for occlusion of two adjacent cortical veins (2VO) by photothrombosis with rose bengal that was followed by KCl-induced cortical spreading depression (CSD). Infarct volume was evaluated with hematoxylin and eosin (H&E) staining 2days after venous occlusion. [(3)H]MK-801, [(3)H]AMPA and [(3)H]Muscimol ligand binding were examined autoradiographically in additional two groups without 2VO (n=5/group). Animals were injected either with NaCl (vehicle) or CTX 200mg/kg for 5days in order to evaluate whether NMDA, AMPA and GABAA ligand binding densities were affected. RESULTS: CTX pretreatment reduced infarct volume compared to vehicle pretreatment (p<0.05). The effect of CTX pretreatment was attenuated by administration of the GLT-1 inhibitor, dihydrokainate (DHK) 30min before 2VO. CTX had no effect on the number of spontaneous spreading depressions after 2VO. Analysis of quantitative receptor autoradiography showed no statistically significant difference between rats after administration with CTX compared to control rats. CONCLUSIONS: Pretreatment with CTX has neuroprotective potential without effect on NMDA, AMPA and GABAA receptor density and spontaneous spreading depression. This effect can be abolished by GLT-1 inhibition, indicating that upregulation of GLT-1 is an important mechanism for neuroprotective action in penumbra-like conditions, e.g. if neurosurgeons plan to occlude cerebral veins during tumor surgery.

Erythropoietin neuroprotection is enhanced by direct cortical application following subdural blood evacuation in a rat model of acute subdural hematoma.

Recombinant human erythropoietin (EPO) has been successfully tested as neuroprotectant in brain injury models. The first large clinical trial with stroke patients, however, revealed negative results. Reasons are manifold and may include side-effects such as thrombotic complications or interactions with other medication, EPO concentration, penetration of the blood-brain-barrier and/or route of application. The latter is restricted to systemic application. Here we hypothesize that EPO is neuroprotective in a rat model of acute subdural hemorrhage (ASDH) and that direct cortical application is a feasible route of application in this injury type. The subdural hematoma was surgically evacuated and EPO was applied directly onto the surface of the brain. We injected NaCl, 200, 2000 or 20,000IU EPO per rat i.v. at 15min post-ASDH (400µl autologous venous blood) or NaCl, 0.02, 0.2 or 2IU per rat onto the cortical surface after removal of the subdurally infused blood t at 70min post-ASDH. Arterial blood pressure (MAP), blood chemistry, intracranial pressure (ICP), cerebral blood flow (CBF) and brain tissue oxygen (ptiO2) were assessed during the first hour and lesion volume at 2days after ASDH. EPO 20,000IU/rat (i.v.) elevated ICP significantly. EPO at 200 and 2000IU reduced lesion volume from 38.2±0.6mm(3) (NaCl-treated group) to 28.5±0.9 and 22.2±1.3mm(3) (all p<0.05 vs. NaCl). Cortical application of 0.02IU EPO after ASDH evacuation reduced injury from 36.0±5.2 to 11.2±2.1mm(3) (p=0.007), whereas 0.2IU had no effect (38.0±9.0mm(3)). The highest dose of both application routes (i.v. 20,000IU; cortical 2IU) enlarged the ASDH-induced damage significantly to 46.5±1.7 and 67.9±10.4mm(3) (all p<0.05 vs. NaCl). In order to test whether Tween-20, a solvent of EPO formulation 'NeoRecomon®' was responsible for adverse effects two groups were treated with NaCl or Tween-20 after the evacuation of ASDH, but no difference in lesion volume was detected. In conclusion, EPO is neuroprotective in a model of ASDH in rats and was most efficacious at a very low dose in combination with subdural blood removal. High systemic and topically applied concentrations caused adverse effects on lesion size which were partially due to increased ICP. Thus, patients with traumatic ASDH could be treated with cortically applied EPO but with caution concerning concentration.

Spontaneous cortical spreading depression and intracranial pressure following acute subdural hematoma in a rat.

Acute subdural hemorrhage (ASDH) is a frequent and devastating consequence of traumatic brain injury. Tissue damage develops rapidly and makes treatment even more difficult. Management of increased intracranial pressure (ICP) due to extravasated blood volume and brain swelling is often insufficient to control all adverse effects of ASDH. In addition to sheer volume, spontaneously triggered cortical spreading depression (CSD) that leads to cell death following ischemia or trauma may contribute to injury development after ASDH. Therefore, we explored the occurrence of CSD by tissue impedance (IMP) measurement in a rat model subjected to ASDH. IMP and intraventricular and mean arterial pressure were monitored before (baseline), during (blood infusion), and after ASDH for 3 h.Tissue impedance increased by around 203% of baseline during subdural infusion of 300 µl of autologous, venous blood and dropped back to baseline within 22 min. Fifty-six minutes after the start of ASDH a cluster of four short-lasting (3-3.5 min; 140-160% of baseline) IMP increases started that reflected spontaneous CSDs. This pattern presumes that CSD occurs early after ASDH and therefore may contribute to the rapid lesion development in this disease.

Effects of a small acute subdural hematoma following traumatic brain injury on neuromonitoring, brain swelling and histology in pigs.

An acute subdural hematoma (ASDH) induces pathomechanisms which worsen outcome after traumatic brain injury, even after a small hemorrhage. Synergistic effects of a small ASDH on brain damage are poorly understood, and were studied here using neuromonitoring for 10 h in an injury model of controlled cortical impact (CCI) and ASDH. Pigs (n = 32) were assigned to 4 groups: sham, CCI (2.5 m/s), ASDH (2 ml) and CCI + ASDH. Intracranial pressure was significantly increased above sham levels by all injuries with no difference between groups. CCI and ASDH reduced ptiO(2) by a maximum of 36 ± 9 and 26 ± 11%, respectively. The combination caused a 31 ± 11% drop. ASDH alone and in combination with CCI caused a significant elevation in extracellular glutamate, which remained increased longer for CCI + ASDH. The same two groups had significantly higher peak lactate levels compared to sham. Somatosensory evoked potential (SSEP) amplitude was persistently reduced by combined injury. These effects translated into significantly elevated brain water content and histological damage in all injury groups. Thus, combined injury had stronger effects on glutamate and SSEP when compared to CCI and ASDH, but no clear-cut synergistic effects of 2 ml ASDH on trauma were observed. We speculate that this was partially due to the CCI injury severity.

The effect of a gap-junction blocker, carbenoxolone, on ischemic brain injury and cortical spreading depression.

Cortical spreading depression (CSD) has been shown to cause secondary cell loss in experimental models of brain injury and in patients, and blocking of CSD is a potential neuroprotective strategy. Here we tested the hypothesis that gap junctions affect CSD under physiological conditions as well as infarct development in a rat two-vein occlusion model suited to study pathophysiology of the penumbra (n = 71). We applied the gap junction blocker carbenoxolone (CBX) or saline intra-ventricularly. Interestingly, CBX temporarily increased systemic blood pressure and cortical blood flow (41% and 53%, 15 min after 250 µg CBX). We induced CSD with cortical microinjection of potassium chloride (KCl), counted how many spontaneous CSDs after CSD induction were elicited and measured the propagation velocity. After 250 µg CBX administration, significant 37.5 ± 6.5 additional CSDs were seen. CSD velocity increased significantly after 50 µg and 250 µg CBX. Occlusion of two adjacent cortical veins using Rose Bengal dye and fiberoptic illumination followed by 250 µg CBX or saline showed a significant more than doubling of infarct volumes 7 days after CBX. The current experiments provide evidence that CBX can accelerate the initiation and propagation of CSD suggesting opening of gap junctions is not required for CSD propagation. Blocking gap junctions worsens outcome from focal cerebral ischemia. Hence, measures intended to improve spatial buffering via astroglial gap junctions could have therapeutic potential in disease processes involving CSD.

Caspase-dependent cell death involved in brain damage after acute subdural hematoma in rats.

Traumatic brain injury is associated with acute subdural hematoma (ASDH) that worsens outcome. Although early removal of blood can reduce mortality, patients still die or remain disabled after surgery and additional treatments are needed. The blood mass and extravasated blood induce pathomechanisms such as high intracranial pressure (ICP), ischemia, apoptosis and inflammation which lead to acute as well as delayed cell death. Only little is known about the basis of delayed cell death in this type of injury. Thus, the purpose of the study was to investigate to which extent caspase-dependent intracellular processes are involved in the lesion development after ASDH in rats. A volume of 300microL blood was infused into the subdural space under monitoring of ICP and tissue oxygen concentration. To asses delayed cell death mechanisms, DNA fragmentation was measured 1, 2, 4 and 7 days after ASDH by TUNEL staining, and the effect of the pan-caspase inhibitor zVADfmk on lesion volume was assessed 7 days post-ASDH. A peak of TUNEL-positive cells was found in the injured cortex at day 2 after blood infusion (53.4+/-11.6 cells/mm(2)). zVADfmk (160ng), applied by intracerebroventricular injection before ASDH, reduced lesion volume significantly by more than 50% (vehicle: 23.79+/-7.62mm(3); zVADfmk: 9.06+/-4.08). The data show for the first time that apoptotic processes are evident following ASDH and that caspase-dependent mechanisms play a crucial role in the lesion development caused by the blood effect on brain tissue.

Brain oxygen monitoring: in-vitro accuracy, long-term drift and response-time of Licox- and Neurotrend sensors.

BACKGROUND: Oxygen tension sensors have been used to monitor tissue oxygenation in human brain for several years. The working principals of the most frequently used sensors, the Licox (LX) and Neurotrend (NT), are different, and they have never been validated independently for correct measurement in vitro. Therefore, we tried to clarify if the two currently available sensors provide sufficient accuracy and stability. METHOD: 12 LX oxygen tension sensors and NT sensors were placed into a liquid-filled tonometer chamber. The solution was kept at 37 +/- 0.2 degrees C and equilibrated with five calibration gases containing different O(2)- and CO(2)-concentrations. After equilibration, readings were taken for each gas concentration (accuracy test). Afterwards, the sensors were left in 3% O(2) and 9% CO(2) and readings were taken after 24, 48, 72, 96 and 120 hours (drift test). Thereafter, a 90% response time test was performed transferring sensors from 1% to 5% oxygen concentration and back, using pre-equilibrated tonometers. FINDINGS: All Licox oxygen probes [12] were used for this study. Two of 14 Neurotrend sensors did not calibrate, revealing a failure rate of 14% for NT. Oxygen tension during the accuracy test was measured as follows: 1% O(2) (7.1 mmHg): LX 6.5 +/- 0.4, NT 5.3 +/- 2.3 mmHg, 2% O(2) (14.2 mmHg): LX 12.9 +/- 0.6, NT 12.1 +/- 2.2 mmHg, 3% O(2) (21.4 mmHg): LX 19.8 +/- 0.7, NT 19.4 +/- 2.4 mmHg, 5% O(2) (35.8 mmHg): LX 33.4 +/- 1.0 mmHg, NT 33.5 +/- 2.9 mmHg, 8% O(2) (57.0 mmHg): 53.8 +/- 1.5, NT 53.6 +/- 3.3 mmHg. After 120 hours in 3% O(2) (21 mmHg), LX measured 19.8 +/- 1.9 mmHg, NT 17.9 +/- 4.7 mmHg. 90% response time from 1% to 5%/5% to 1% oxygen concentration was 129 +/- 27/174 +/- 26 sec for LX, 55 +/- 19/98 +/- 39 sec for NT. CONCLUSIONS: Both systems are measuring oxygen tension sufficiently, but more accurately with LX probes. NT sensors read significantly lower pO(2) in 1% O(2) and show an increasing deviation with higher oxygen concentrations which was due to two of twelve probes. A slight drift towards lower oxygen tension readings for both sensors but more pronounced for the NT does not impair long-term use. NT measures pCO(2) and pH very accurately.

Effects of hypertonic/hyperoncotic treatment after rat cortical vein occlusion.

OBJECTIVE: To examine the effects of hypertonic/hyperoncotic treatment on physiologic variables and regional cerebral blood flow and to test its neuroprotective efficiency in a model of permanent venous ischemia. DESIGN: Randomized prospective study. SETTING: University research institute. SUBJECTS: Adult male Wistar rats, weighing 359 +/- 54 g (n = 38). INTERVENTIONS: Rats were subjected to photochemical occlusion of two adjacent cortical veins. A randomized infusion with vehicle (0.9% NaCl), 10% hydroxyethyl starch 200,000 (HES), or 7.5% saline plus 10% hydroxyethyl starch 200,000 (HHES) was started 30 mins after two-vein occlusion. Effects on physiologic variables and regional cerebral blood flow (assessed by laser Doppler flowmetry) were studied up to 120 mins after two-vein occlusion. Two days after occlusion, the brains were removed for histologic evaluation. MEASUREMENTS AND MAIN RESULTS: After occlusion, regional cerebral blood flow decreased by 50%, significantly in all groups (from 47.3 +/- 3 to 22.2 +/- 2.2 laser Doppler units). In the vehicle and HES groups, regional cerebral blood flow further decreased to 12.9 +/- 1.9 and 17.8 +/- 2.3 laser Doppler units, respectively. HHES improved regional cerebral blood flow significantly to 27.3 +/- 3.5 laser Doppler units, particularly by reducing no-flow/low-flow areas and reducing infarct size. CONCLUSION: We found that HHES reduced infarct size as a consequence of an improved regional cerebral blood flow and reduced no-flow/low-flow areas in the tissue at risk in the two-vein occlusion model.

Lactate administration attenuates cognitive deficits following traumatic brain injury.

Moderately head injured patients often suffer long term neurological sequelae. There is no therapy for brain trauma and current treatments aim only to minimize secondary damage. These secondary effects are often triggered by the inability to re-establish ionic homeostasis after injury, due to large energy demands. Recent reports have demonstrated that neurons are capable of utilizing lactate as an energy source, thus this report examines the usefulness of lactate administration in the attenuation of behavioural deficits following a moderate brain injury. Lactate infusion (i.v.) was started 30 min after lateral fluid percussion injury and continued for 3 h. Cognitive deficits were determined using the Morris water maze. Lactate infused injured animals demonstrated significantly less cognitive deficits than saline infused injured animals. Thus, lactate infusion attenuated the cognitive deficits normally observed in this model, and therefore may provide moderately head injured patients with a treatment to help ameliorate the sequelae.

Lactate reduces glutamate-induced neurotoxicity in rat cortex.

Experiments were carried out to test the hypothesis that lactate reduces the neurotoxicity of glutamate in vivo. MAP2 immunohistochemistry was used to measure lesion size, and microdialysis to measure the changes in glucose and lactate in the extracellular compartment. After implantation of a microdialysis probe 100 mM glutamate with or without 6 mM lactate was added to the perfusion medium and infused into the cortex of unanesthetized rats. Infusion of 100 mM glutamate for a period of 30 min produced a lesion of 6.05 +/- 0.64 mm(3), an increase in lactate of 124 +/- 19% above basal and a 21 +/- 9% reduction of glucose below basal level. When 6mM L-lactate was perfused together with 100 mM glutamate there was a significant reduction in the size of the lesion and there was no reduction in dialysate glucose. When L-lactate was replaced with D-lactate the lesion size and the increase in dialysate lactate were greater than after glutamate alone. The neuroprotective role of L-lactate is attributed to its ability to meet the increased energy demands of neurones exposed to high concentrations of glutamate.

Extracellular levels of glucose and lactate measured by quantitative microdialysis in the human brain.

The aim of this study was to use quantitative microdialysis to estimate the true extracellular concentrations of glucose and lactate in minimally disturbed human brain. These values are important as criteria for microdialytical monitoring in critical care patients and for determining therapy. Microdialysis procedures were carried out during tumor operations, the probe being inserted distant from the site of manipulation in minimally disturbed tissue. Two methods were used: 1. The zero net flux method of Lönnroth. 2. The low flow method (10 mm membrane length, flow rate 0.3 microliter min-1, high in vivo recovery). Both methods gave similar values of about 2000 microM for lactate and slightly less for glucose (1700 microM). Glucose levels correspond with those measured by other methods in humans, allowing for the fact that our patients were anesthetised. Extracellular glucose levels were positively correlated with blood glucose values measured before the operation, and with extracellular lactate. Results confirm that extracellular glucose is zero when blood glucose is about 2 mM.

Acute and late changes in N-acetyl-aspartate following diffuse axonal injury in rats: an MRI spectroscopy and microdialysis study.

N-acetyl-aspartate (NAA) measured by proton nuclear magnetic resonance spectroscopy (1H-NMR) has been used as a marker of neuronal injury in many cerebral pathologies. Therefore, we evaluate the roles of microdialysis vs. 1H-NMR as techniques to assess NAA (NAAd; NAA/Creatine ratio) in the living brain, and compare the results with whole brain NAA (NAAw), analyzed by HPLC after diffuse traumatic brain injury (TBI). Acute (4 h post-injury survival) and late (48 h survival) changes were studied in a sham-operated group (Sham, n = 4), and two injured groups (TBI/4 h, n = 8; TBI/48 h, n = 7). Baseline NAAd was 8.17 +/- 1 microM, and there was no significant difference between groups. There was only a small (twice of control), but transient increase in NAAd in the TBI/4 h group after trauma. Baseline NAA/Cr ratio was 1.35 +/- 0.2, which did not change significantly between baseline, 1, 2, 3, 4 and 48 h or between groups after TBI. Whole brain NAAw (baseline 8.5 +/- 0.5 mmol kg-1 wet weight) did not differ significantly between groups before and after TBI. Diffuse TBI did not produce long-term changes in NAA, assessed by three different methods. These results may indicate that NAA is not a sensitive marker of the severity of diffuse axonal damage. However, further studies are needed to evaluate whether confounding factors such as microdialysis probe, voxel position and non-regional tissue homogenization might have influenced our data.

Chronic effects of an aminosteroid on microdialytically measured parameters after experimental middle cerebral artery occlusion in the rat.

The effects of the neuroprotective aminosteroid U74006F (tirilazad mesylate, Freedox) were monitored microdialytically in rat cortex during three 4h periods beginning immediately, 25h and 49h after permanent middle cerebral artery occlusion. Either U74006F or vehicle only was administered 15 min, 2h, 6h, 12h and 24h after operation. The dialysate was analysed for on-line pH, ascorbic acid, uric acid, glucose and lactate. The efficacy of post-ischaemic treatment was shown by: a) lesion volume 53h after operation was significantly smaller in U74006F-treated animals; b) microdialytic findings were very similar to those found previously with pre-ischaemic drug application (reduction in release of ascorbic acid, uric acid and lactate, increased pH); c) an effect of U74006F on lactate release could still be seen on days 2 and 3; and d) increases in uric acid on days 2 and 3, possibly reflecting delayed cell death, were smaller in aminosteroid treated animals.

Extracellular N-acetyl-aspartate as a biochemical marker of the severity of neuronal damage following experimental acute traumatic brain injury.

We evaluated the acute changes in interstitial and whole brain N-acetyl-aspartate (NAA) measured by high-performance liquid chromatography in animal models of isolated traumatic brain injury (TBI) and TBI combined with secondary insult (hypotension-hypoxia [HH]). The Marmarou impact-acceleration model was used. Four groups were studied: (1) sham-operated control, (2) TBI alone (TBI 500 gm, 2 m), (3) TBI plus 30 min of hypoxia (PaO2, approximately 40 mm Hg) and hypotension (mean arterial blood pressure, approximately 40 mm Hg) (THH), and (4) HH alone. The baseline value for dialysate NAA (NAAd) in the rats was 8.17+/-1 microM. No significant difference between groups was found for this baseline value. The TBI group had a modest (100%) transient increase in NAAd after isolated TBI. The HH group had a transient (500%) increase in NAAd at 1 h, sustained for 2 h. In the THH group, there was a persistent increase in NAAd (800%) that peaked at 2.5 h. The whole brain NAA (NAAw) concentration in controls was 8.5+/-0.5 mmol/kg wet weight. There was no significant difference between TBI and controls; however, there was a significant decrease in NAAw in the THH and HH group compared to controls. Thus, in this animal model of TBI and TBI with secondary insult, we found that persistent, marked elevation in NAA is associated with TBI and secondary ischemic/hypoxic insult, but not with isolated TBI alone.

Fluid percussion injury transiently increases then decreases brain oxygen consumption in the rat.

The oxygen consumption (VO2 microL/h/mg) of sham and of traumatized rat brains within 30 min and 6 h after a lateral fluid percussion injury (FPI) was measured with the Cartesian microrespirometer. Brain slices were cut at the plain of injury and site-specific 20-60-microg cores of tissue were transferred to the microrespirometer. In sham brains, the cortical VO2 (CVO2) was 13.78+/-0.64 and the hippocampal VO2 (HPVO2) was 11.20+/-0.58 microL/h/mg (p<0.05). Within 30 min of the injury, the respective values of 16.89+/-0.55 and 14.91+/-0.06 were significantly increased (p<0.05). The combined VO2 (CVO2, HPVO2) of 12.49+/-0.06 microL/h/mg in shams was significantly less than the combined VO2 of 15.90+/-0.59 microL/h/mg at 30 min post FPI (p<0.001). The maximal CVO2 of 19.49+/-1.10 microL/h/mg and the maximal HPVO2 of 15.98+/-0.99 microL/h/mg were both obtained from the ipsilateral side of the injury. Whereas the contralateral cortical value for injured brains was not significantly different from that of the shams, both ipsilateral and contralateral hippocampal values were significantly greater than that of the shams in response to injury (p<0.05). By 6 h postinjury, the combined VO2 had dropped to 10.01+/-0.84 microL/h/mg but was not significantly lower than the sham values. The data indicate that normal CVO2 is greater than normal HPVO2. The FPI produces significant increases in both CVO2 and HPVO2. Also, while the immediate increase in CVO2 appears to be injury-site dependent, that is, regional, the increase in HPVO2 appears to be global.

Comparison of NAA measures by MRS and HPLC.

This work investigates the accuracy of an in vivo estimation of absolute N-acetyl aspartate (NAA) concentrations by magnetic resonance spectroscopy (MRS) using cerebral water as an internal reference standard. Single-voxel, proton spectroscopy was carried out in two groups of rats (normal and diffuse head injury), using a PRESS sequence with TR = 3 s, TE = 135 ms. Fully relaxed water spectra and water-suppressed proton spectra were obtained from a 7 x 5 x 5 mm3 volume of tissue. MRI-based brain water content measurements were also performed. Following MRS, HPLC determinations of NAA were carried out. In the normal rats the MRS yielded 10.98 +/- 0.83 mmol/kg w.w. vs 10.76 +/- 0.76 for HPLC with a mean absolute difference of 0.8. In the injured rats the corresponding results were 9.41 +/- 1.78 (MRS) and 8.16 +/- 0.77 (HPLC) with a mean absolute difference of 1.66. The in vivo absolute method accurately documented the temporal NAA changes compared to the NAA/Cr approach.

Low extracellular (ECF) glucose affects the neurochemical profile in severe head-injured patients.

Glucose (Gluc) is the main energy source for the brain. After severe head-injury energy demand is massively increased and supply is often decreased. In pilot microdialysis studies, many patients with severe head-injury had undetectable glucose concentrations, probably reflecting changes in metabolism and/or reduced supply. We therefore investigated whether patients with low ECF glucose (criterion: < 50 microM for > or = 5 hrs), LOWgluc, differ from patients with higher glucose levels (NORMALgluc) We also tested the interrelationships between other parameters such as lactate, glutamate, K+, brain O2 and CO2, ICP, CPP, and CBF in these two groups. We found that patients with low ECF glucose, LOWgluc, have significantly lower lactate concentrations than patients with "normal" glucose, NORMALgluc, levels do. Spearman correlations between glucose and most other parameters were similar in both patient groups. However, glutamate correlated positively with glucose, lactate, brain CO2 and negatively with brain O2 in the NORMALgluc patient group, whereas glutamate did not significantly correlate with any of these parameters in the LOWgluc group. There was also no correlation between outcome and the dialysate glucose. The results indicate that low ECF glucose is almost always present in severe head-injury. Moreover, the lack of correlation between low glucose and outcome, however, suggests that other energy substrates, such as lactate, are important after TBI.

The neuroprotective effect of a new serotonin receptor agonist, BAY X3702, upon focal ischemic brain damage caused by acute subdural hematoma in the rat.

We tested the neuroprotective effect of a novel, high affinity serotonin (5-HT1A) agonist, BAY X3702, in a rat model of acute subdural hematoma (ASDH). Animals were treated with 0.01 mg/kg (n=8), 0.003 mg/kg (n=8) BAY X3702 or vehicle (n=4) 15 min before (i.v.) and after (continuous infusion) injection of 400 microl of autologous blood into the subdural space. The ischemic brain damage at 4 h after ASDH was 59.01+/-39 and 60.8+/-49 mm(3) for the low- and high-dose BAY X3702 group, respectively, which was significantly smaller compared to the vehicle-treated ASDH group (106.2+/-33 mm(3)). The result indicates that this novel, high affinity 5-HT(1A) agonist, BAY X3702, is neuroprotective in this model.

Detection of ultra-early brain damage after acute subdural hematoma in the rat by magnetic resonance imaging.

We measured serial changes in diffusion-weighted magnetic resonance imaging (DW) and in apparent diffusion coefficient (ADC) 1 to 3 hours after induction of acute subdural hematoma (ASDH) in rats, to assess the rate of development of cytotoxic edema and ischemic brain damage observed in this model. Cortical ADC values underneath the hematoma in ASDH rats (n = 12) were significantly lower than those in sham-operated rats (n = 5) at 1 hour. By 3 hours, the area of ADC abnormality had further increased. The lesion areas, as percentage of hemispheric areas on 1- and 3-hour ADC maps, correlated significantly with those on the histologic sections stained with hematoxylin and eosin. The results indicate that DWI with ADC mapping may provide a valuable diagnostic tool for monitoring of early pathologic changes following subdural hematoma in head-injured patients.

Reducing hemoglobin oxygen affinity does not increase hydroxyl radicals after acute subdural hematoma in the rat.

Extensive evidence is available to show the importance of ischemia after severe human head injury. We have previously shown that pharmacologically increasing the release of oxygen in brain tissue where the local oxygen pressure is low reduces infarct size in animal models. To study the possible negative effects of this strategy, we tested the effect of an allosteric modifier of hemoglobin (RSR13) on free radical production in the rat acute subdural hematoma (ASDH) model, both under normoxic as well as under hyperoxic, normobaric conditions. When compared to baseline, induction of ASDH resulted in a significant increase (p < 0.05) in 2,3-DHBA (2,3 dihydroxybenzoic acid, produced from salicylate after attack by hydroxyl radicals) at 30 and 60 min postinduction, both for the control group (39% and 91%) as well as the RSR13-treated group (41% and 62%). The 2,5-DHBA also increased significantly (p < 0.05) in the drug-treated animals at the 30- and 60-min time points when compared to baseline (49% and 77%). At all time points, except the 30-min, the increase in 2,3-DHBA was less marked in the RSR13 animals than in the control group. Similarly, the 2,5-DHBA increase after ASDH was lower at all time points except for the 30-min time point in the RSR13-treated group. These results indicate that enhanced tissue oxygen release by the allosteric modifier of hemoglobin RSR13 does not increase hydroxyl radical production after ASDH. Clinical trials are needed to test this compound in humans after severe head injury.