scholarly journals Factors affecting excitatory amino acid release following severe human head injury

1998 ◽  
Vol 5 (2) ◽  
pp. E1
Author(s):  
Ross Bullock ◽  
Alois Zauner ◽  
John J. Woodward ◽  
John Myseros ◽  
Sung C. Choi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Brain Injury ◽  
Head Injury ◽  
Excitatory Amino Acid ◽  
Neuronal Damage ◽  
Cell Swelling ◽  
Microdialysis Probe ◽  
Glutamate Antagonists

Recent animal studies demonstrate that excitatory amino acids (EAAs) play a major role in neuronal damage after brain trauma and ischemia. However, the role of EAAs in patients who have suffered severe head injury is not understood. Excess quantities of glutamate in the extracellular space may lead to uncontrolled shifts of sodium, potassium, and calcium, disrupting ionic homeostasis, which may lead to severe cell swelling and cell death. The authors evaluated the role of EEAs in human traumatic brain injury. In 80 consecutive severely head injured patients, a microdialysis probe was placed into the gray matter along with a ventriculostomy catheter or an intracranial pressure (ICP) monitor for 4 days. Levels of EAAs and structural amino acids were analyzed using high-performance liquid chromatography. Multifactorial analysis of the amino acid pattern was performed and its correlations with clinical parameters and outcome were tested. The levels of EAAs were increased up to 50 times normal in 30% of the patients and were significantly correlated to levels of structural amino acids both in each patient and across the whole group (p < 0.01). Secondary ischemic brain injury and focal contusions were most strongly associated with high EAA levels (27 ± 22 μmol/L). Sustained high ICP and poor outcome were significantly correlated to high levels of EAAs (glutamate > 20 μmol/L; p < 0.01). The release of EAAs is closely linked to the release of structural amino acids and may thus reflect nonspecific development of membrane micropores, rather than presynaptic neuronal vesicular exocytosis. The magnitude of EAA release in patients with focal contusions and ischemic events may be sufficient to exacerbate neuronal damage, and these patients may be the best candidates for treatment with glutamate antagonists in the future.

Factors affecting excitatory amino acid release following severe human head injury

1998 ◽  
Vol 89 (4) ◽  
pp. 507-518 ◽  
Author(s):  
Ross Bullock ◽  
Alois Zauner ◽  
John J. Woodward ◽  
John Myseros ◽  
Sung C. Choi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Brain Injury ◽  
Head Injury ◽  
Neuronal Damage ◽  
Cell Swelling ◽  
Glutamate Antagonists ◽  
Content Type ◽  
Fine Print

Object. Recent animal studies demonstrate that excitatory amino acids (EAAs) play a major role in neuronal damage after brain trauma and ischemia. However, the role of EAAs in patients who have suffered severe head injury is not understood. Excess quantities of glutamate in the extracellular space may lead to uncontrolled shifts of sodium, potassium, and calcium, disrupting ionic homeostasis, which may lead to severe cell swelling and cell death. The authors evaluated the role of EEAs in human traumatic brain injury. Methods. In 80 consecutive severely head injured patients, a microdialysis probe was placed into the gray matter along with a ventriculostomy catheter or an intracranial pressure (ICP) monitor for 4 days. Levels of EAAs and structural amino acids were analyzed using high-performance liquid chromatography. Multifactorial analysis of the amino acid pattern was performed and its correlations with clinical parameters and outcome were tested. The levels of EAAs were increased up to 50 times normal in 30% of the patients and were significantly correlated to levels of structural amino acids both in each patient and across the whole group (p < 0.01). Secondary ischemic brain injury and focal contusions were most strongly associated with high EAA levels (27 ± 22 µmol/L). Sustained high ICP and poor outcome were significantly correlated to high levels of EAAs (glutamate > 20 µmol/L; p < 0.01). Conclusions. The release of EAAs is closely linked to the release of structural amino acids and may thus reflect nonspecific development of membrane micropores, rather than presynaptic neuronal vesicular exocytosis. The magnitude of EAA release in patients with focal contusions and ischemic events may be sufficient to exacerbate neuronal damage, and these patients may be the best candidates for treatment with glutamate antagonists in the future.

Excitatory amino acids in cerebrospinal fluid following traumatic brain injury in humans

1993 ◽  
Vol 79 (3) ◽  
pp. 369-372 ◽  
Author(s):  
Andrew J. Baker ◽  
Richard J. Moulton ◽  
Vernon H. MacMillan ◽  
Peter M. Shedden
Keyword(s):  
Amino Acids ◽  
Traumatic Brain Injury ◽  
Cerebrospinal Fluid ◽  
Amino Acid ◽  
Brain Injury ◽  
Excitatory Amino Acids ◽  
Excitatory Amino Acid ◽  
Neuronal Damage ◽  
Control Group ◽  
Injured Patients

✓ Evidence from models of traumatic brain injury implicates excitotoxicity as an integral process in the ultimate neuronal damage that follows. Concentrations of the excitatory amino acid glutamate were serially measured in the cerebrospinal fluid (CSF) of patients with traumatic brain injuries and in control patients for comparison. The purpose of the study was to determine whether glutamate concentrations were significantly elevated following traumatic brain injury and, if so, whether they were elevated in a time frame that would allow the use of antagonist therapy. Cerebrospinal fluid was sampled fresh from ventricular drains every 12 hours and analyzed using high-performance liquid chromatography for the excitatory amino acids. The peak concentrations of glutamate in the CSF of the 12 brain-injured patients ranged from 14 to 474 µM and were significantly higher than those in the three control patients, 4.9 to 17 µM (Mann-Whitney U-test, p < 0.02). Glutamate concentrations in five of the eight patients who were still being sampled on Day 3 were beyond the control group range. The implication of this study is that severely head-injured patients are exposed to high concentrations of a neurotoxic amino acid for days following injury and thus may benefit from antagonist intervention.

Hepatic glutamine transporter activation in burn injury: role of amino acids and phosphatidylinositol-3-kinase

2000 ◽  
Vol 278 (4) ◽  
pp. G532-G541 ◽  
Author(s):  
Timothy M. Pawlik ◽  
Rüdiger Lohmann ◽  
Wiley W. Souba ◽  
Barrie P. Bode
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Burn Injury ◽  
Cell Swelling ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Inhibitors ◽  
Glutamine Transporter ◽  
Hypermetabolic State ◽  
Phosphatidylinositol 3

Burn injury elicits a marked, sustained hypermetabolic state in patients characterized by accelerated hepatic amino acid metabolism and negative nitrogen balance. The transport of glutamine, a key substrate in gluconeogenesis and ureagenesis, was examined in hepatocytes isolated from the livers of rats after a 20% total burn surface area full-thickness scald injury. A latent and profound two- to threefold increase in glutamine transporter system N activity was first observed after 48 h in hepatocytes from injured rats compared with controls, persisted for 9 days, and waned toward control values after 18 days, corresponding with convalescence. Further studies showed that the profound increase was fully attributable to rapid posttranslational transporter activation by amino acid-induced cell swelling and that this form of regulation may be elicited in part by glucagon. The phosphatidylinositol-3-kinase (PI3K) inhibitors wortmannin and LY-294002 each significantly attenuated transporter stimulation by amino acids. The data suggest that PI3K-dependent system N activation by amino acids may play an important role in fueling accelerated hepatic nitrogen metabolism after burn injury.

Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury

1990 ◽  
Vol 73 (6) ◽  
pp. 889-900 ◽  
Author(s):  
Yoichi Katayama ◽  
Donald P. Becker ◽  
Toru Tamura ◽  
David A. Hovda
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Brain Injury ◽  
Excitatory Amino Acids ◽  
Kynurenic Acid ◽  
Excitatory Amino Acid ◽  
Maximum Effect ◽  
Receptor Subtypes ◽  
Severity Of Injury

✓ An increase in extracellular K+ concentration ([K+]e) of the rat hippocampus following fluid-percussion concussive brain injury was demonstrated with microdialysis. The role of neuronal discharge was examined with in situ administration of 0.1 mM tetrodotoxin, a potent depressant of neuronal discharges, and of 0.5 to 20 mM cobalt, a blocker of Ca++ channels. While a small short-lasting [K+]e increase (1.40- to 2.15-fold) was observed after a mild insult, a more pronounced longer-lasting increase (4.28- to 5.90-fold) was induced without overt morphological damage as the severity of injury rose above a certain threshold (unconscious for 200 to 250 seconds). The small short-lasting increase was reduced with prior administration of tetrodotoxin but not with cobalt, indicating that neuronal discharges are the source of this increase. In contrast, the larger longer-lasting increase was resistant to tetrodotoxin and partially dependent on Ca++, suggesting that neurotransmitter release is involved. In order to test the hypothesis that the release of the excitatory amino acid neurotransmitter glutamate mediates this increase in [K+]e, the extracellular concentration of glutamate ([Glu]e) was measured along with [K+]e. The results indicate that a relatively specific increase in [Glu]e (as compared with other amino acids) was induced concomitantly with the increase in [K+]e. Furthermore, the in situ administration of 1 to 25 mM kynurenic acid, an excitatory amino acid antagonist, effectively attenuated the increase in [K+]e. A dose-response curve suggested that a maximum effect of kynurenic acid is obtained at a concentration that substantially blocks all receptor subtypes of excitatory amino acids. These data suggest that concussive brain injury causes a massive K+ flux which is likely to be related to an indiscriminate release of excitatory amino acids occurring immediately after brain injury.

scholarly journals NOC/oFQ contributes to age-dependent impairment of NMDA-induced cerebrovasodilation after brain injury

2000 ◽  
Vol 279 (5) ◽  
pp. H2188-H2195 ◽  
Author(s):  
William M. Armstead
Keyword(s):  
Cerebrospinal Fluid ◽  
Amino Acid ◽  
Brain Injury ◽  
Excitatory Amino Acid ◽  
Age Groups ◽  
Orphanin Fq ◽  
Pial Artery ◽  
Age Related ◽  
Age Dependent

This study characterized the effects of fluid percussion brain injury (FPI) on N-methyl-d-aspartate (NMDA)-induced vasodilation and determined the role of nociceptin/orphanin FQ (NOC/oFQ) in such changes as a function of age and time postinsult. FPI elevated cerebrospinal fluid (CSF) NOC/oFQ from 70 ± 3 to 444 ± 56 pg/ml (≈10−10 M) within 1 h and to 1,931 ± 112 pg/ml within 8 h, whereas values returned to control levels within 168 h in the newborn pig. In contrast, FPI elevated CSF NOC/oFQ from 77 ± 4 to 202 ± 16 pg/ml within 1 h and values returned to control levels within 8 h in the juvenile pig. Topical NOC/oFQ (10−10 M) had no effect on pial artery diameter but attenuated NMDA (10−8, 10−6M)-induced dilation (9 ± 1 and 16 ± 1 vs. 5 ± 1 and 10 ± 1%) in both age groups. In the newborn, NMDA-induced pial artery dilation was reversed to vasoconstriction within 1 h post-FPI and responses remained impaired for 72 h, but such vasoconstriction was attenuated by pretreatment with [F/G]NOC/oFQ(1–13)-NH2 (10−6 M, 1 mg/kg iv), an NOC/oFQ antagonist (9 ± 1 and 16 ± 1 vs. −7 ± 1 and −12 ± 1 vs −2 ± 1 and −3 ± 1% for control, FPI, and FPI pretreated with the NOC/oFQ antagonist). In contrast, in the juvenile, NMDA-induced vasodilation was only attenuated within 1 h post-FPI and returned to control within 8 h. Such dilation was also partially restored by the NOC/oFQ antagonist. These data indicate that NOC/oFQ contributes to impaired NMDA pial artery dilation after FPI. These data suggest that the greater NOC/oFQ release in the newborn versus the juvenile may contribute to age-related differences in FPI effects on excitatory amino acid-induced pial dilation.

Role of Excitatory Amino Acid-Mediated Ionic Fluxes in Traumatic Brain Injury

1995 ◽  
Vol 5 (4) ◽  
pp. 427-435 ◽  
Author(s):  
Yoichi Katayama ◽  
Takeshi Maeda ◽  
Morimichi Koshinaga ◽  
Tatsuro Kawamata ◽  
Takashi Tsubokawa
Keyword(s):  
Traumatic Brain Injury ◽  
Amino Acid ◽  
Brain Injury ◽  
Excitatory Amino Acid ◽  
Ionic Fluxes
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