phosphocreatine and Brain-Injuries

In this study, the concentrations of creatine (Cr), creatine phosphate (CrP), N-acetylaspartate (NAA), ATP, ADP and phosphatidylcholine (PC) were measured at different time intervals after mild traumatic brain injury (mTBI) in whole brain homogenates of rats. Anaesthetized animals underwent to the closed-head impact acceleration "weight-drop" model (450 g delivered from 1 m height = mild traumatic brain injury) and were killed at 2, 6, 24, 48 and 120 h after the insult (n = 6 for each time point). Sham-operated rats (n = 6) were used as controls. Compounds of interest were synchronously measured by HPLC in organic solvent deproteinized whole brain homogenates. A reversible decrease of all metabolites but PC was observed, with minimal values recorded at 24 h post-injury (minimum of CrP = 48 h after impact). In particular, Cr and NAA showed a decrease of 44.5 and 29.5%, respectively, at this time point. When measuring NAA in relation to other metabolites, as it is commonly carried out in "in vivo" (1)H-magnetic resonance spectroscopy ((1)H-MRS), an increase in the NAA/Cr ratio and a decrease in the NAA/PC ratio was observed. Besides confirming a transient alteration of NAA homeostasis and ATP imbalance, our results clearly show significant changes in the cerebral concentration of Cr and CrP after mTBI. This suggests a careful use of the NAA/Cr ratio to measure NAA by (1)H-MRS in conditions of altered cerebral energy metabolism. Viceversa, the NAA/PC ratio appears to be a better indicator of actual NAA levels during energy metabolism impairment. Furthermore, our data suggest that, under pathological conditions affecting the brain energetic, the Cr-CrP system is not a suitable tool to buffer possible ATP depletion in the brain, thus supporting the growing indications for alternative roles of cerebral Cr.

Topics: Adenosine Triphosphate; Animals; Aspartic Acid; Brain Chemistry; Brain Injuries; Creatine; Energy Metabolism; Kinetics; Phosphates; Phosphocreatine; Rats

Single-voxel proton magnetic resonance imaging ((1)H-MRS) and proton MR spectroscopic imaging ((1)H-MRSI) were used to compare brain metabolite levels in semi-acute mild traumatic brain injury (mTBI) patients (n = 10) and matched healthy controls (n = 9). The (1)H-MRS voxel was positioned in the splenium, a region known to be susceptible to axonal injury in TBI, and a single (1)H-MRSI slice was positioned above the lateral ventricles. To increase sensitivity to the glutamate (Glu) and the combined glutamate-glutamine (Glx) signal, an inter-pulse echo time shown to emphasize the major Glu signals was used along with an analysis method that reduces partial volume errors by using water as a concentration standard. Our preliminary findings indicate significantly lower levels of gray matter Glx and higher levels of white matter creatine-phosphocreatine (Cr) in mTBI subjects relative to healthy controls. Furthermore, Cr levels were predictive of executive function and emotional distress in the combined groups. These results suggest that perturbations in Cr, a critical component of the brain's energy metabolism, and Glu, the brain's major neurotransmitter, may occur following mTBI. Moreover, the different pattern of results for gray and white matter suggests tissue-specific metabolic responses to mTBI.

Topics: Adult; Affective Symptoms; Axons; Biomarkers; Body Water; Brain; Brain Injuries; Cognition Disorders; Corpus Callosum; Creatine; Diffuse Axonal Injury; Energy Metabolism; Female; Glutamic Acid; Glutamine; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Spectroscopy; Male; Middle Aged; Nerve Fibers, Myelinated; Phosphocreatine; Young Adult

Proton MR spectroscopy (1H-MRS) has been previously used to monitor metabolic changes in areas of diffuse brain injury. We studied metabolism in the close vicinity of experimental traumatic brain contusions and remote on the contralateral side from 1h to 28d post-injury. Changes of creatine and phosphocreatine (Cr&PCr), N-acetylaspartate (NAA), choline (Cho), inositol (Ino), taurine (Tau), glutamate (Glu), and lactate (Lac) were assessed and compared to neuronal, glial and inflammatory changes in histology. In the pericontusional zone Cr&PCr, NAA, and Glu decreased immediately after trauma by -35%, -60%, and -37%, respectively, related to primary cell disintegration and secondary perturbations as reflected in histology. These metabolites partially recovered at 7d (-15%, -37%, and -21% respectively), in parallel to indicators of repair in immunhistochemistry. Control levels were not regained at 28d, in correlation to a decrease of viable neurons. Cho and Ino, initially lowered by -26% and -31% respectively, increased at 7d by +74% and 31%, reflecting glial activation and proliferation. The signal including the lactate resonance increased by >1000% with a maximum at 7d, possibly related to energy failure, inflammation and glial activation. A partial contribution of lipids to this signal cannot be fully excluded. The contralateral side showed mild astroglial activation in histology, but no changes in 1H-MRS. The study demonstrates the feasibility of volume selective 1H-MRS using the LCModel (Linear Combination of Model in vitro spectra of metabolites solutions) to monitor metabolic changes close to focal traumatic lesions and suggests how metabolic alterations can be differentiated in cause.

Topics: Animals; Aspartic Acid; Biomarkers; Brain Injuries; Choline; Creatine; Functional Laterality; Glutamic Acid; Immunohistochemistry; Inositol; Lactic Acid; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Protons; Rats; Rats, Sprague-Dawley; Taurine; Time Factors

In a Sham-controlled study we applied proton magnetic resonance spectroscopy (1H-MRS) at 4.7 T to a model of experimental traumatic brain contusion. The time course of cerebral metabolite changes was monitored in serial investigation in 14 Sprague Dawley rats up to 4 weeks after trauma. 6 animals served as controls. 1H-MRS spectra were acquired from a voxel covering the hippocampus/basal ganglia ipsi and contralateral to the lesion. Metabolites ratios of the injured hemisphere were compared to those ipsilateral in Sham animals and to those of the contralateral side in the trauma animals. NAA/Cr ratio and Glu/Cr ratio, possible markers of neuronal loss, persistently decreased after trauma to a minimum of -40% and -20% versus controls, respectively. One week after trauma Cho/Cr ratio was strongly increased by 73%. This might indicate a high inflammatory activity at that time. Lac/Cr ratio showed long-lasting and continuing increases up to 2000% versus controls as a sign of permanently shifted posttraumatic energy metabolism. 1H-MRS proved to be a useful non-invasive method for in-vivo monitoring of posttraumatic metabolism also in models of brain contusion. In single cases however, accompanying haemorrhage can potentially prevent useful data acquisition.

Topics: Animals; Aspartic Acid; Basal Ganglia; Biomarkers; Brain; Brain Injuries; Disease Models, Animal; Functional Laterality; Glutamic Acid; Hippocampus; Lactates; Magnetic Resonance Imaging; Male; Monitoring, Physiologic; Phosphocreatine; Rats; Rats, Sprague-Dawley; Reference Values; Taurine; Time Factors

Experimental studies have reported early reductions in pH, phosphocreatine, and free intracellular magnesium following traumatic brain injury using phosphorus magnetic resonance spectroscopy. Paradoxically, in clinical studies there is some evidence for an increase in the pH in the subacute stage following traumatic brain injury. We therefore performed phosphorus magnetic resonance spectroscopy on seven patients in the subacute stage (mean 9 days postinjury) following traumatic brain injury to assess cellular metabolism. In areas of normal-appearing white matter, the pH was significantly alkaline (patients 7.09 +/- 0.04 [mean +/- SD], controls 7.01 +/- 0.04, p = 0.008), the phosphocreatine to inorganic phosphate ratio (PCr/Pi) was significantly increased (patients 4.03 +/- 1.18, controls 2.64 +/- 0.71, p = 0.03), the inorganic phosphate to adenosine triphosphate ratio (Pi/ATP) was significantly reduced (patients 0.37 +/- 0.10, controls 0.56 +/- 0.19, p = 0.04), and the PCr/ATP ratio was nonsignificantly increased (patients 1.53 +/- 0.29, controls 1.34 +/- 0.19, p = 0.14) in patients compared to controls. Furthermore, the calculated free intracellular magnesium was significantly increased in the patients compared to the controls (patients 0.33 +/- 0.09 mM, controls 0.22 +/- 0.09 mM, p = 0.03)). Proton spectra, acquired from similar regions showed a significant reduction in N-acetylaspartate (patients 9.64 +/- 2.49 units, controls 12.84 +/- 2.35 units, p = 0.03) and a significant increase in choline compounds (patients 7.96 +/- 1.02, controls 6.67 +/- 1.01 units, p = 0.03). No lactate was visible in any patient or control spectrum. The alterations in metabolism observed in these patients could not be explained by ongoing ischemia but might be secondary to a loss of normal cellular homeostasis or a relative alteration in the cellular population, in particular an increase in the glial cell density, in these regions.

Topics: Adenosine Triphosphate; Adolescent; Adult; Aspartic Acid; Brain; Brain Injuries; Choline; Creatine; Female; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphates; Phosphocreatine

Mimicking in rats the reduced level of dietary magnesium (Mg) intake, seen in present-day Western World populations, short-term (4 weeks) restriction of Mg intake (30-35% normal) resulted in a 40% loss in brain intracellular free Mg2+ ions ([Mg2+]i) and significant rises in brain intracellular pH (pHi) and phosphocreatine ([PCr]) but no change in [ATP] or [Pi] as measured by 31P-NMR spectroscopy. Such Mg-deficient animals (serum Mg fell 65%), when given ED40 stroke doses of ethanol, demonstrated a 100% stroke mortality. These findings indicate that: 1) moderate, short-term Mg deficiency makes the brain vulnerable to hypoxic-lethal stroke insults induced by alcohol administration, and 2) brain [Mg2+]i appears to play an important role in finely regulating brain pHi and [PCr].

Topics: Animals; Brain; Brain Injuries; Cerebrovascular Disorders; Diet; Ethanol; Hydrogen-Ion Concentration; Magnesium; Magnesium Deficiency; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Rats; Rats, Wistar

The authors previously demonstrated, in a large-animal intracerebral hemorrhage (ICH) model, that markedly edematous ("translucent") white matter regions (> 10% increases in water contents) containing high levels of clot-derived plasma proteins rapidly develop adjacent to hematomas. The goal of the present study was to determine the concentrations of high-energy phosphate, carbohydrate substrate, and lactate in these and other perihematomal white and gray matter regions during the early hours following experimental ICH.. The authors infused autologous blood (1.7 ml) into frontal lobe white matter in a physiologically controlled model in pigs (weighing approximately 7 kg each) and froze their brains in situ at 1, 3, 5, or 8 hours postinfusion. Adenosine triphosphate (ATP), phosphocreatine (PCr), glycogen, glucose, lactate, and water contents were then measured in white and gray matter located ipsi- and contralateral to the hematomas, and metabolite concentrations in edematous brain regions were corrected for dilution. In markedly edematous white matter, glycogen and glucose concentrations increased two- to fivefold compared with control during 8 hours postinfusion. Similarly, PCr levels increased several-fold by 5 hours, whereas, except for a moderate decrease at 1 hour, ATP remained unchanged. Lactate was markedly increased (approximately 20 micromol/g) at all times. In gyral gray matter overlying the hematoma, water contents and glycogen levels were significantly increased at 5 and 8 hours, whereas lactate levels were increased two- to fourfold at all times.. These results, which demonstrate normal to increased high-energy phosphate and carbohydrate substrate concentrations in edematous perihematomal regions during the early hours following ICH, are qualitatively similar to findings in other brain injury models in which a reduction in metabolic rate develops. Because an energy deficit is not present, lactate accumulation in edematous white matter is not caused by stimulated anaerobic glycolysis. Instead, because glutamate concentrations in the blood entering the brain's extracellular space during ICH are several-fold higher than normal levels, the authors speculate, on the basis of work reported by Pellerin and Magistretti, that glutamate uptake by astrocytes leads to enhanced aerobic glycolysis and lactate is generated at a rate that exceeds utilization.

Topics: Adenosine Triphosphate; Aerobiosis; Animals; Astrocytes; Blood Proteins; Body Water; Brain Edema; Brain Injuries; Cerebral Hemorrhage; Disease Models, Animal; Energy Metabolism; Extracellular Space; Frontal Lobe; Glucose; Glutamates; Glycogen; Glycolysis; Hematoma; Lactates; Phosphocreatine; Swine; Time Factors

The acute metabolic events linked to the evolution of selective axonal pathology in the white matter following diffuse brain injury have not previously been evaluated due to the paucity of relevant experimental models. Here, we utilized a new model of inertial brain injury in the pig that selectively damages axons in the white matter, and applied proton and phosphorous magnetic resonance spectroscopy (MRS) to noninvasively monitor the temporal course of metabolic changes following trauma. Evaluating four pigs with MRS prior to injury, within 1 h and 3 and 7 days postinjury, we found that widespread axonal injury was produced in the absence of changes in pH, PCr/Pi, or the concentrations of ATP, and lactate. However, we did observe an acute 60% loss of intracellular Mg2+ levels, which gradually resolved by 7 days postinjury. In addition, we found that the levels of the neuron marker, N-acetylaspartate (NAA), acutely dropped 20% and remained persistently decreased for at least 7 days postinjury. Moreover, the changes in Mg2+ and NAA were found with MRS in the absence of abnormalities with conventional magnetic resonance imaging (MRI). These results show that (1) profound alterations in intracellular metabolism occur acutely following diffuse axonal pathology in the white matter, but in the absence of indicators of ischemia, and (2) axonal pathology may be evaluated with high sensitivity utilizing noninvasive MRS techniques.

Topics: Adenosine Triphosphate; Animals; Aspartic Acid; Axons; Behavior, Animal; Brain Chemistry; Brain Injuries; Female; Lactic Acid; Magnesium; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Phosphorus; Protons; Swine; Swine, Miniature

To evaluate the usefulness of proton magnetic resonance (MR) spectroscopy in predicting 6-12-month neurologic outcome in children after central nervous system injuries.. Localized single-voxel, 20-msec-echo-time MR spectra (including N-acetylaspartate [NAA], choline [Ch], creatine and phosphocreatine [Cr]) were obtained in the occipital gray matter in 82 patients and 24 control patients. Patient age groups were defined as neonates (< or = 1 month [n = 23]), infants (1-18 months [n = 31]), and children (> or = 18 months [n = 28]). Metabolite ratios and the presence of lactate were determined. Linear discriminant analysis-with admission clinical data, proton MR spectroscopy findings, and MR imaging score (three-point scale based on severity of structural neuroimaging changes)-was performed to help predict outcome in each patient. Findings were then compared with the actual 6-12-month outcome assigned by a pediatric neurologist.. Outcome on the basis of proton MR spectroscopy findings combined with clinical data and MR imaging score was predicted correctly in 91% of neonates and in 100% of infants and children. Outcome on the basis of clinical data and MR imaging score alone was 83% in neonates, 84% in infants, and 93% in children. The presence of lactate was significantly higher in patients with poor outcome than in patients with good-moderate outcomes in all three age groups (neonates, 38% vs 5%; infants, 87% vs 5%; children, 64% vs 10% [chi 2 test, P < .02]). In children with poor outcomes, NAA/Cr ratios were significantly lower in infants (P = .006) and children (P < .001), and NAA/Ch ratios were significantly lower in infants (P = .001) and neonates (P = .05).. Findings at proton MR spectroscopy helped predict long-term neurologic outcomes in children after central nervous system injury.

Topics: Adolescent; Aspartic Acid; Brain; Brain Diseases; Brain Injuries; Child; Choline; Discriminant Analysis; Female; Humans; Infant; Infant, Newborn; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Predictive Value of Tests; Prognosis

The effects of 6 weeks of chronic ethanol administration on the lateral fluid percussion (FP) brain injury-induced regional accumulation of lactate and on the levels of total high-energy phosphates were examined in rats. In both the chronic ethanol diet (ethanol diet) and pair-fed isocaloric sucrose control diet (control diet) groups, tissue concentrations of lactate were elevated in the cortices and hippocampi of both the ipsilateral and contralateral hemispheres at 5 min after brain injury. In both diet groups, concentrations of lactate were elevated only in the injured left cortex and the ipsilateral hippocampus at 20 min after FP brain injury. No significant differences were found in the levels of lactate in the cortices and hippocampi of sham animals and brain-injured animals between the ethanol and control diet groups at 5 min and 20 min after injury. In the ethanol and control diet groups, tissue concentrations of total high-energy phosphates (ATP + PCr) were not affected in the cortices and hippocampi at 5 min and 20 min after lateral FP brain injury. No significant differences were found in the levels of total high-energy phosphates in the cortices and hippocampi of the sham and brain-injured animals between the ethanol and control diet groups at 5 min and 20 min after injury. Histologic studies revealed a similar extent of damage in the cortex and in the CA3 region of the ipsilateral hippocampus in both diet groups at 14 days after lateral FP brain injury. These findings suggest that 6 weeks of chronic ethanol administration does not alter brain injury-induced accumulation of lactate, levels of total high energy phosphates, and extent of morphological damage.

Topics: Adenosine Triphosphate; Animals; Body Weight; Brain; Brain Injuries; Central Nervous System Depressants; Ethanol; Lactic Acid; Male; Phosphocreatine; Rats; Rats, Sprague-Dawley

We studied nine infants and children, aged 1 week to 42 months, with severe acute central nervous system injuries associated with cardiac disease or corrective operations by means of single-voxel proton magnetic resonance spectroscopy to determine whether this technique would be useful in predicting neurologic outcome. Proton magnetic resonance spectroscopic data were acquired from the occipital gray and parietal white matter (8 cm3 volume, stimulated echo-acquisition mode sequence with echo time of 20 msec and repetition time of 3.0 seconds) a median of 9 days after operation (range 3 to 42 days). Data were expressed as ratios of areas under metabolite peaks, including N-acetyl compounds, choline-containing compounds, creatine and phosphocreatine, and lactate. Four patients had cerebral insults before operation, one had both a preoperative and a perioperative insult, three had perioperative insults, and one had a prolonged cardiac arrest 2 days after operation. Outcomes (Glasgow Outcome Scale scores) were assigned at discharge and 6 to 12 months after injury. Six patients were in a vegetative state or had severe impairment at discharge, and two still had severe impairment at 6- to 12-month follow-up. Proton magnetic resonance spectroscopy showed lactate in these two patients, along with markedly reduced ratios of N-acetyl compounds to creatine compounds. The other four patients with severe impairment recovered to a level of mild disability at follow-up. Proton magnetic resonance spectroscopy showed no lactate in these four patients; however, one patient showed moderately reduced ratio of N-acetyl compounds to creatine compounds. The three patients who had mild or moderate impairment at discharge showed no lactate and mild or no changes in metabolite ratios; follow-up revealed normal or mild outcomes. Overall, we found that the presence of lactate and markedly reduced ratios of N-acetyl compounds to creatine compounds were predictive of severe outcomes at discharge and long-term follow-up, whereas no lactate and mild or no changes in ratios suggested potential for recovery with at least a mild disability. Continuing investigations are in progress to determine the optimal selection of candidates and timing of proton magnetic resonance spectroscopic studies.

Topics: Aspartic Acid; Brain; Brain Injuries; Cardiopulmonary Bypass; Case-Control Studies; Child, Preschool; Choline; Coma; Creatine; Follow-Up Studies; Forecasting; Glasgow Coma Scale; Heart Arrest; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Lactates; Magnetic Resonance Spectroscopy; Neurologic Examination; Patient Discharge; Phosphocreatine; Protons; Treatment Outcome

The aim of the present study was to determine the effects of a hyperosmotic agent, 10% glycerol, on both brain energy metabolism and intracellular pH (pHi) in experimental vasogenic brain edema. Vasogenic brain edema was induced by cold injury applied to bilateral parietal portions in 13 mongrel dogs (7 glycerol, 6 control) while, 3 dogs were used as control. Before and at 24 hours after the injury, sequential phosphorous-31 magnetic resonance spectroscopy (31P-MRS) was performed for 2 hours in order to determine phosphocreatine (PCr), beta-adenosine triphosphate (beta-ATP), inorganic phosphate (Pi) levels and pHi. At 24 hours following cold injury, both PCr/Pi and ATP/Pi ratios significantly decreased from 7.75 to 3.97 and from 2.26 to 1.25, respectively. Furthermore, a moderate decrease in pHi of 7.16 to 7.01 was significantly demonstrated during the same experimental period. Administration of glycerol for 30 minutes significantly increased PCr/Pi from 3.97 to 5.06 and ATP/Pi from 1.25 to 1.72, respectively. Also, glycerol administration caused a significant increase in pHi from 7.01 to 7.11. This study indicates that cryogenic injury, in which formation and expansion of vasogenic brain edema a known to occur, results in disturbed brain energy metabolism and in intracellular acidosis; moreover, the administration of glycerol can ameliorate either or both of these derangements.

Topics: Acid-Base Equilibrium; Adenosine Triphosphate; Animals; Brain Edema; Brain Injuries; Dogs; Energy Metabolism; Freezing; Glycerol; Intracellular Fluid; Magnetic Resonance Spectroscopy; Parietal Lobe; Phosphates; Phosphocreatine; Water-Electrolyte Balance

The goal of this study was to introduce a new method inducing an experimental brain injury model using ESWL(Extracorporeal Shock Wave Lithotripsy) and to evaluate findings of localized lesions on 1H MR imaging and the response of cerebral energy metabolism using a 31P MR spectroscope to the ESWL brain injury in cats. This study also examined effects of cerebral protective drugs. 1) There were no statistically significant changes in pH at all measurement points. 2) In the trauma group, initial decrease of PCr/Pi was seen at 30 to 60 minutes with return to control levels by 2 hours after injury(P < 0.05), followed by a second decline at 4 hours which lasted until 8 hours after injury. 3) Significant recovery in PCr/Pi(P < 0.05) was observed in both the THAM and dexamethasone treated groups at all measurement points and in the mannitol treated group only temporary recovery at 30 and 60 minutes (P < 0.05). 4) High intensity signals were seen on 1H MR imaging in traumatized animals. This study demonstrated the immediate and persistent recovery of cerebral energy metabolism using THAM or dexamethasone and an immediate but transient effect with mannitol in traumatized animals.

Topics: Adenosine Triphosphate; Animals; Brain; Brain Injuries; Cats; Dexamethasone; Disease Models, Animal; Energy Metabolism; Hydrogen-Ion Concentration; Lithotripsy; Magnetic Resonance Spectroscopy; Phosphates; Phosphocreatine; Random Allocation; Tromethamine

The recently developed controlled cortical impact model of brain injury in rats may be an excellent tool by which to attempt to understand the neurochemical mechanisms mediating the pathophysiology of traumatic brain injury. In this study, rats were subjected to lateral controlled cortical impact brain injury of low grade severity; their brains were frozen in situ at various times after injury to measure regional levels of lactate, high energy phosphates, and norepinephrine. Tissue lactate concentration in the injury site left cortex was increased in injured animals by sixfold at 30 min and twofold at 2.5 h and 24 h after injury (p < 0.05). At all postinjury times, lactate concentration was also increased in injured animals by about twofold in the cortex and hippocampus adjacent to the injury site (p < 0.05). No significant changes occurred in the levels of ATP and phosphocreatine in most of the brain regions of injured animals. However, in the primary site of injury (left cortex), phosphocreatine concentration was decreased by 40% in injured animals at 30 min after injury (p < 0.05). The norepinephrine concentration was decreased in the injury site left cortex of injured animals by 38% at 30 min, 29% at 2.5 h, and 30% at 24 h after injury (p < 0.05). The level of norepinephrine was also reduced by approximately 20% in the cortex adjacent to the injury site in injured animals. The present results suggest that controlled cortical impact brain injury produces disorder in the neuronal oxidative and norepinephrine metabolism.

Topics: Adenosine Triphosphate; Animals; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Freezing; Hippocampus; Lactates; Lactic Acid; Male; Norepinephrine; Phosphates; Phosphocreatine; Rats; Rats, Inbred F344; Tissue Distribution

Treatment with opioid receptor antagonists improves outcome after experimental brain trauma, although the mechanisms underlying the protective actions of these compounds remain speculative. We have proposed that endogenous opioids contribute to the pathophysiology of traumatic brain injury through actions at kappa-opioid receptors, possibly by affecting cellular bioenergetic state. In the present study, the effects of the kappa-selective opioid-receptor antagonist nor-binaltorphimine (nor-BNI) were examined after fluid percussion brain injury in rats. Metabolic changes were evaluated by 31P magnetic resonance spectroscopy; the same animals were subsequently followed over 2 wk to evaluate neurological recovery. Nor-BNI, administered intravenously as a 10 or 20 mg/kg bolus at 30 min after injury, significantly improved neurological outcome at 2 wk posttrauma compared with controls. Animals treated with nor-BNI showed significantly greater recovery of intracellular free magnesium concentrations and cytosolic phosphorylation potentials during the first 4 h after injury compared with saline-treated controls. The improvement in cytosolic phosphorylation potential was significantly correlated to neurological outcome. These data support the hypothesis that kappa-opioid receptors mediate pathophysiological changes after traumatic brain injury and that the beneficial effects of opioid-receptor antagonist may result from improvement of posttraumatic cellular bioenergetics.

Topics: Animals; Blood Pressure; Brain Injuries; Magnesium; Magnetic Resonance Spectroscopy; Male; Naltrexone; Narcotic Antagonists; Phosphates; Phosphocreatine; Phosphorylation; Rats; Rats, Inbred Strains; Receptors, Opioid, kappa

Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global and focal ischemia and hypoglycemia, and improves neurological outcome after experimental spinal cord injury. The present study examined the effects of the noncompetitive N-methyl-D-aspartate receptor blocker MK-801 on neurochemical sequelae following experimental fluid-percussion brain injury in the rat. Fifteen minutes after fluid-percussion brain injury (2.8 atmospheres), animals received either MK-801 (1 mg/kg, i.v.) or saline. MK-801 treatment significantly attenuated the development of focal brain edema at the site of injury 48 h after brain injury, significantly reduced the increase in tissue sodium, and prevented the localized decline in total tissue magnesium that was observed in injured tissue of saline-treated animals. Using phosphorus nuclear magnetic resonance spectroscopy, we also observed that MK-801 treatment improved brain metabolic status and promoted a significant recovery of intracellular free magnesium concentrations that fell precipitously after brain injury. These results suggest that excitatory amino acid neurotransmitters may be involved in the pathophysiological sequelae of traumatic brain injury and that noncompetitive N-methyl-D-aspartate receptor antagonists may effectively attenuate some of the potentially deleterious neurochemical sequelae of brain injury.

Topics: Adenosine Triphosphate; Animals; Anticonvulsants; Body Water; Brain; Brain Edema; Brain Injuries; Carbon Dioxide; Cations; Dibenzocycloheptenes; Dizocilpine Maleate; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Oxygen; Phosphates; Phosphocreatine; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Reference Values

Treatment of CNS trauma with the opiate antagonist naloxone improves outcome, though the mechanisms of action remain speculative. Nalmefene is another opiate-receptor antagonist, but it has substantially greater potency and duration of action than naloxone. It also has increased activity at kappa opiate receptors and has recently been shown to limit histological changes and neurological dysfunction after traumatic spinal cord injury. The present study examined the effects of treatment with nalmefene on outcome after fluid-percussion-induced traumatic brain injury in rats, using magnetic resonance spectroscopy to monitor acute metabolic changes and behavioral tests to determine chronic neurological recovery. Single-dose treatment with nalmefene (100 micrograms/kg, i.v.) at 30 min after trauma significantly improved (p less than 0.05) neurological outcome (up to 4 weeks) as compared to saline-treated controls. Early changes in intracellular free-magnesium concentration, adenosine diphosphate concentration, and cytosolic phosphorylation potential were all significantly improved by nalmefene treatment, reflecting improved bioenergetic state. We suggest that the ability of nalmefene to improve cellular bioenergetics after trauma may in part account for the neuroprotective effects of this and related compounds.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Brain Injuries; Disease Models, Animal; Energy Metabolism; Magnesium; Magnetic Resonance Spectroscopy; Male; Motor Activity; Naltrexone; Narcotic Antagonists; Phosphates; Phosphocreatine; Phosphorus; Rats; Rats, Inbred Strains

Six patients who had suffered severe non-penetrating high velocity head injuries were investigated with phosphorus (31P) magnetic resonance spectroscopy (MRS) to determine, non-invasively, long-term alteration in intracellular biochemistry. The normal subjects were found to have a constant intracellular pH (pHi, 7.03 +/- 0.03) with depth into the brain. The adenosine triphosphate (ATP, 3.46 +/- 0.66 mmol/L of brain tissue), inorganic phosphate (Pi, 1.15 +/- 0.41 mmol/L) and phosphomonester (PME, 2.76 +/- 1.0 mmol/L) tissue concentrations did not alter significantly with depth into normal brain. The phosphocreatine (PCr, 2 cm = 5.21 +/- 1.25, 5 cm = 4.85 +/- 1.49 mmol/L) was slightly reduced, whilst phosphodiesters (PDE, 2 cm = 9.53 +/- 2.6, 5 cm = 14.41 +/- 4.2 mmol/L) rose significantly between tissue comprising mainly of gray (2 cm) and white matter (5 cm). In comparison the contra-lateral hemisphere to the side of worst spasticity showed significant changes a considerable time after injury (6-18 months). The intracellular metabolite tissue concentrations were all reduced by 30% (ATP 2.53 +/- 1.0 mmol/L, PCr 3.44 +/- 0.8 mmol/L) with PDE reduced most significantly at depth (5 cm = 8.4 +/- 3.4 mmol/L), compatible with the cerebral atrophy seen in these patients. In white matter the pHi also decreased with depth (2 cm = 7.03 +/- 0.03, 5 cm = 6.89 +/- 0.05). The reduction in pHi so long after injury is difficult to explain in these steady-state conditions. A structural abnormality, such as a disorder in the blood brain barrier or accumulation of large acidic lysosomes, could cause these pHi changes. There may also be a failure in blood flow regulation, with near critical fluctuations in blood flow both with time and space.

Topics: Accidents, Traffic; Adenosine Triphosphate; Adult; Brain; Brain Injuries; Functional Laterality; Humans; Magnetic Resonance Spectroscopy; Organophosphorus Compounds; Phosphates; Phosphocreatine; Phosphorus; Reference Values; Wounds, Penetrating

Brain injury induced by fluid percussion in rats caused a marked elevation in extracellular glutamate and aspartate adjacent to the trauma site. This increase in excitatory amino acids was related to the severity of the injury and was associated with a reduction in cellular bioenergetic state and intracellular free magnesium. Treatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrophan or the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid limited the resultant neurological dysfunction; dextrorphan treatment also improved the bioenergetic state after trauma and increased the intracellular free magnesium. Thus, excitatory amino acids contribute to delayed tissue damage after brain trauma; NMDA antagonists may be of benefit in treating acute head injury.

Topics: Animals; Aspartic Acid; Binding, Competitive; Brain; Brain Injuries; Dextrorphan; Glutamates; Glutamic Acid; Magnesium; Magnetic Resonance Spectroscopy; Male; N-Methylaspartate; Phosphates; Phosphocreatine; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

Cats were subjected to a 3.5-atm fluid percussion impact administered to the cerebral cortex. Near-infrared spectrophotometry (NIRS) was used to measure the quantity of oxyhemoglobin and total hemoglobin in the illuminated tissue as well as the cytochrome a, a3 redox state. Corroborative data were obtained by freezing brains with liquid nitrogen and measuring cortical concentrations of ATP, creatine phosphate (CP), and lactate. Immediately postimpact there was a rise in mean arterial pressure with a 38% increase of highly oxygenated blood and a shift toward oxidation in the cytochrome a, a3 redox state. By 4 hours postimpact, cytochrome a, a3 was becoming progressively reduced despite the persistence of hyperemia. This was associated with a significant (p less than 0.01) decrease in ATP and CP concentration. Additional studies in which a 0.5-sec, 100-v electrical seizure was induced before and after fluid percussion demonstrated significant differences in seizure response, indicating a failure of autoregulation.

Topics: Adenosine Triphosphate; Animals; Brain Chemistry; Brain Injuries; Cats; Electron Transport Complex IV; Hemoglobins; Homeostasis; Lactates; Oxidation-Reduction; Oxyhemoglobins; Phosphocreatine; Seizures; Spectrophotometry, Infrared

Topics: Adenosine Triphosphate; Animals; Brain; Brain Injuries; Energy Metabolism; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Rats; Thyrotropin-Releasing Hormone

To clarify the effect of hypovolemic hypotension on high-energy phosphate metabolism in head injury, sequential changes in in vivo phosphorus-31 magnetic resonance (31P MR) spectra were compared in 35 rats after impact injury with and without hypotension. Fourteen rats were subjected to hypotension alone (mean arterial blood pressure (MABP) of either 40 or 30 mm Hg for 60 minutes), seven to fluid-percussion impact injury (4 to 5 atm) alone, and 14 to impact injury and hypotension (MABP of 40 to 30 mm Hg). Impact injury alone caused a transient decrease in the phosphocreatine (PCr) level and an increase in the inorganic phosphate (Pi) value. While hypotension alone produced only small changes on 31P MR spectra, impact injury plus hypotension caused pronounced changes. Impact injury and an MABP of 40 mm Hg caused a 50% decrease in PCr concentration and an approximately twofold increase in Pi level, which were significantly greater than values in rats with impact injury alone. Impact injury and an MABP of 30 mm Hg also caused a significant decrease in adenosine triphosphate value, which was not observed in rats with impact injury alone or with an MABP of 30 mm Hg alone. Decreases in intracellular pH were greater in rats with impact injury and hypotension. After traumatic injury, the brain is extremely vulnerable to hypovolemic hypotension, as reflected in the loss of high-energy phosphates in brain.

Topics: Animals; Brain; Brain Injuries; Hypotension; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Rats; Rats, Inbred Strains; Time Factors

The effect of different degrees of hypoxia on phosphate metabolism in the brains of impact-injured rats was studied using in vivo phosphorus-31 magnetic resonance (P-31 MR) spectroscopy. Sequential changes in P-31 MR spectra within 60 minutes of insult were compared among rats with hypoxia alone, impact injury alone, or a combined impact-hypoxic insult. Hypoxia alone (PaO2 of 40 mm Hg for 30 minutes) caused no remarkable changes in phosphorus spectra except a decrease in intracellular pH. In impact-injured rats, the concentration of inorganic phosphate (Pi) increased, but signals for phosphocreatine (PCr) and beta-adenosine triphosphate (beta-ATP) did not change, and the ratio of PCr/Pi changed only slightly to 7% below control value. When rats with a fluid percussion impact injury of 5 atm were subjected to hypoxic conditions of a PaO2 of 40 mm Hg for 15 minutes, the PCr/Pi ratio decreased by 14%, a value significantly below that of the impact alone group (P less than 0.05). After longer periods of hypoxia (PaO2 of 40 mm Hg for 30 minutes) in impact-injured rats, there were marked increases of Pi and significant decreases in signals for PCr and beta-ATP, which caused a marked decrease in the PCr/Pi ratio to 39% below control values (P less than 0.001). Milder hypoxia (PaO2 of 50 mm Hg for 30 minutes) plus impact injury caused smaller changes in high energy metabolite concentrations, and the PCr/Pi ratio decreased to 15% below control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Brain; Brain Injuries; Hydrogen-Ion Concentration; Hypoxia, Brain; Male; Phosphates; Phosphocreatine; Rats; Rats, Inbred Strains

A Remington humane stunner was used to deliver a blow to the left side of the surgically-exposed skull in ketamine-anesthetized cats. At 15 minutes after the trauma, brain tissue was frozen in situ. In animals without visible tissue hemorrhage (Grade 0) and in those with unilateral cerebral contusions involving the cerebral cortex and white matter (Grade 2), regional cerebral metabolite concentrations were measured by enzymatic-fluorometric techniques and edema was tested with an organic gradient. No substantial changes in cerebral metabolite concentrations were observed in head-injured animals without cerebral contusions. In animals with unilateral contusions, the white matter neighboring the tissue hemorrhage had an increase in lactic acid and a decrease in phosphocreatine as compared to values from corresponding areas on the contralateral side, and in control and Grade 0 animals. The cerebral cortex adjacent to tissue hemorrhage had a variable response that ranged from metabolite concentrations within normal ranges to marked decreases in high-energy phosphates and increases in lactic acid. Metabolites of the cortex and white matter contralateral as well as distant to contusion were not statistically different from values of control animals. Changes in several metabolites correlated well with the magnitude of edema. It is concluded that focal metabolic alterations can occur shortly after severe blunt head injury, and that these events may contribute to acute traumatic cerebral edema.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Brain Edema; Brain Injuries; Cats; Glucose; Glycogen; Lactates; Phosphocreatine; Wounds, Nonpenetrating

Glucose, adenosine triphosphate, phosphocreatine, and lactate levels in the cortex, striatum, diencephalon, hippocampus, cerebellum, and brain stem were measured in cats 1 hour after they were subjected to low-level (2 atm) fluid-percussion injury. Following injury, there was a mild but significant increase in lactate levels in the majority of regions studied. The hippocampus exhibited the highest percentage increase in lactate (fourfold). The cortical area directly under the trauma device showed a threefold lactate increase, while there was a twofold increase in other brain regions studied. Although there were consistent decreases in phosphocreatine levels, these decreases were significant only in the hippocampus (p less than 0.05). Glucose levels in all brain regions studied were no different from control levels at the time of study. The unchanged glucose levels, together with previous studies of identically injured cats showing that cerebral blood flow was unimpaired, suggest that excess lactate was not a consequence of cerebral ischemia. Rather, the increase in lactate levels may indicate that concussive injury can produce a mild derangement of brain energy metabolism in the absence of substrate limitations. This derangement may reflect altered mitochondrial function.

Topics: Adenosine Triphosphate; Animals; Brain; Brain Chemistry; Brain Injuries; Brain Stem; Cats; Energy Metabolism; Female; Glucose; Hippocampus; Lactates; Male; Mitochondria; Phosphocreatine

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Circulation Time; Blood Pressure; Brain; Brain Chemistry; Brain Injuries; Brain Stem; Carotid Arteries; Cerebral Angiography; Cerebral Cortex; Cerebrovascular Circulation; Energy Metabolism; Heart Rate; Ischemia; Male; Phosphocreatine; Pulse; Rats; Subarachnoid Hemorrhage

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adenosine Triphosphate; Amphetamine; Animals; Brain; Brain Injuries; Brain Stem; Cerebellum; Cerebral Cortex; Female; Male; Mitochondria; Oxidative Phosphorylation; Phosphocreatine; Rabbits; Skull Fractures; Urethane

Topics: Acid-Base Equilibrium; Adenine Nucleotides; Animals; Brain Injuries; Humans; Hypercapnia; Hyperventilation; Hypoxia; Intracranial Pressure; Lactates; Phosphocreatine; Pyruvates; Rats; Time Factors

Topics: Adenine Nucleotides; Adenosine Monophosphate; Adenosine Triphosphate; Biomedical Research; Brain; Brain Injuries; Creatine; Creatinine; Humans; Phosphates; Phosphocreatine; Urinalysis

Topics: Adenine Nucleotides; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Brain; Brain Injuries; Coenzymes; Phosphates; Phosphocreatine; Rats