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.

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.

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.

Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine

1987 ◽  
Vol 58 (2) ◽  
pp. 251-266 ◽  
Author(s):  
J. F. MacDonald ◽  
Z. Miljkovic ◽  
P. Pennefather
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Aspartic Acid ◽  
Excitatory Amino Acids ◽  
Hippocampal Neurons ◽  
Excitatory Amino Acid ◽  
Outward Current ◽  
Bathing Solution ◽  
Wide Range ◽  
Repeated Applications

1. Mouse hippocampal neurons grown in dissociated cell culture were patch clamped using a whole cell voltage clamp (discontinuous switching clamp) technique. The currents generated by pressure applications of excitatory amino acids were studied over a wide range of holding potentials, and current-voltage curves were plotted. Excitatory amino acids that activated the N-methyl-D-aspartic acid (NMDA) receptor demonstrated some degree of desensitization with repeated applications, whereas the currents observed in response to kainic acid (KAI) did not. Desensitization could be minimized by keeping the frequency of application sufficiently low (i.e., less than 0.1 Hz). 2. The short-acting dissociative anaesthetic, ketamine (2–50 microM), selectively blocked L-aspartic acid (L-Asp), NMDA, and L-glutamic acid (L-Glu) currents while sparing those in response to KAI. Therefore, ketamine is a relatively selective blocker of the NMDA response versus that (those) activated by KAI. 3. The block by ketamine of excitatory amino acid currents is highly voltage dependent. Concentrations of ketamine that had little effect on outward current responses at depolarized potentials were quite effective at blocking inward current responses at hyperpolarized potentials. In contrast, DL-2-amino-5-phosphonovaleric acid (APV) was equally effective at blocking both inward and outward currents (voltage independent). The voltage dependence of ketamine (a positively charged molecule) could be accounted for if ketamine blocked the NMDA response by binding to a site that experienced 55% of the membrane field. 4. In the presence of ketamine, peak inward currents evoked by repeated applications of NMDA, L-Asp, or L-Glu progressively declined to a steady-state level of block (use-dependent block). This decrement occurred at frequencies much lower than those that were employed to demonstrate desensitization (in the absence of ketamine). Moving the membrane potential to depolarized values did not, in itself, relieve the ketamine block. However, if the appropriate excitatory amino acid (L-Asp, NMDA, L-Glu) was applied during the period of depolarization, a relief of the block could be demonstrated. No recovery from the blockade occurred with periods of rest (no amino acid application) as long as 5 min. Furthermore, no recovery was observed even when ketamine was washed out of the bathing solution until the appropriate agonist was applied. Thus recovery from blockade, like development of blockade, was use dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationship between apoE4 allele and excitatory amino acid levels after traumatic brain injury

2003 ◽  
Vol 31 (9) ◽  
pp. 2371-2379 ◽  
Author(s):  
Mary E. Kerr ◽  
M. Ilyas Kamboh ◽  
Kim Yookyung ◽  
Marilyn F. Kraus ◽  
Ava M. Puccio ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Amino Acid ◽  
Brain Injury ◽  
Excitatory Amino Acid ◽  
Apoe4 Allele ◽  
Amino Acid Levels

The role of excitatory amino acids and NMDA receptors in traumatic brain injury

Science ◽  
1989 ◽  
Vol 244 (4906) ◽  
pp. 798-800 ◽  
Author(s):  
A. Faden ◽  
P Demediuk ◽  
S. Panter ◽  
R Vink
Keyword(s):  
Amino Acids ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Nmda Receptors ◽  
Excitatory Amino Acids
Sign in / Sign up

Export Citation Format

Share Document