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.

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.

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.

Platelet-activating factor and progressive brain damage following focal brain injury

1990 ◽  
Vol 73 (2) ◽  
pp. 223-233 ◽  
Author(s):  
Kai U. Frerichs ◽  
Perttu J. Lindsberg ◽  
John M. Hallenbeck ◽  
Giora Z. Feuerstein
Keyword(s):  
Brain Injury ◽  
Brain Damage ◽  
Neuronal Death ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Platelet Activating Factor ◽  
Secondary Brain Damage ◽  
Content Type ◽  
Focal Brain Injury ◽  
Fine Print

✓ The effects of a platelet-activating factor (PAF) antagonist on brain edema, cortical microcirculation, blood-brain barrier (BBB) disruption, and neuronal death following focal brain injury are reported. A neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was used to induce highly reproducible focal cortical lesions in anesthetized rats. Secondary brain damage in this model was characterized by progressive cortical hypoperfusion, edema, and BBB disruption in the vicinity of the hemispheroid lesion occurring acutely after injury. The histopathological evolution was followed for up to 4 days. Neuronal damage in the cortex and the hippocampus (CA-1) was assessed quantitatively, revealing secondary and progressive loss of neuronal tissue within the first 24 hours following injury. Pretreatment with the PAF antagonist BN 50739 ameliorated the severe hypoperfusion in 12 rats (increasing local cerebral blood flow from a mean ± standard error of the mean of 40.5% ± 8.3% to 80.2% ± 7.8%, p < 0.01) and reduced edema by 70% in 10 rats (p < 0.05) acutely after injury. The PAF antagonist also reduced the progression of neuronal damage in the cortex and the CA-1 hippocampal neurons (decrease of neuronal death from 88.0% ± 3.9% to 49.8% ± 4.2% at 24 hours in the cortex and from 40.2 ± 5.0% to 13.2% ± 2.1% in the hippocampus in 30 rats; p < 0.05). This study provides evidence to support progressive brain damage following focal brain injury, associated with secondary loss of neuronal cells. In this latter process, PAF antagonists may provide significant therapeutic protection in arresting secondary brain damage following cerebral ischemia and neurological trauma.

scholarly journals A Novel Role of Fungal Type I Myosin in Regulating Membrane Properties and Its Association with D-Amino Acid Utilization in Cryptococcus gattii

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Ami Khanal Lamichhane ◽  
H. Martin Garraffo ◽  
Hongyi Cai ◽  
Peter J. Walter ◽  
Kyung J. Kwon-Chung ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Membrane Permeability ◽  
Cryptococcus Gattii ◽  
Membrane Properties ◽  
Type I ◽  
Content Type ◽  
Myosin I ◽  
Amino Acid Utilization

ABSTRACT We found a novel role of Myo5, a type I myosin (myosin-I), and its fortuitous association with d-amino acid utilization in Cryptococcus gattii. Myo5 colocalized with actin cortical patches and was required for endocytosis. Interestingly, the myo5Δ mutant accumulated high levels of d-proline and d-alanine which caused toxicity in C. gattii cells. The myo5Δ mutant also accumulated a large set of substrates, such as membrane-permeant as well as non-membrane-permeant dyes, l-proline, l-alanine, and flucytosine intracellularly. Furthermore, the efflux rate of fluorescein was significantly increased in the myo5Δ mutant. Importantly, the endocytic defect of the myo5Δ mutant did not affect the localization of the proline permease and flucytosine transporter. These data indicate that the substrate accumulation phenotype is not solely due to a defect in endocytosis, but the membrane properties may have been altered in the myo5Δ mutant. Consistent with this, the sterol staining pattern of the myo5Δ mutant was different from that of the wild type, and the mutant was hypersensitive to amphotericin B. It appears that the changes in sterol distribution may have caused altered membrane permeability in the myo5Δ mutant, allowing increased accumulation of substrate. Moreover, myosin-I mutants generated in several other yeast species displayed a similar substrate accumulation phenotype. Thus, fungal type I myosin appears to play an important role in regulating membrane permeability. Although the substrate accumulation phenotype was detected in strains with mutations in the genes involved in actin nucleation, the phenotype was not shared in all endocytic mutants, indicating a complicated relationship between substrate accumulation and endocytosis. IMPORTANCE Cryptococcus gattii, one of the etiological agents of cryptococcosis, can be distinguished from its sister species Cryptococcus neoformans by growth on d-amino acids. C. gattii MYO5 affected the growth of C. gattii on d-amino acids. The myo5Δ cells accumulated high levels of various substrates from outside the cells, and excessively accumulated d-amino acids appeared to have caused toxicity in the myo5Δ cells. We provide evidence on the alteration of membrane properties in the myo5Δ mutants. Additionally, alteration in the myo5Δ membrane permeability causing higher substrate accumulation is associated with the changes in the sterol distribution. Furthermore, myosin-I in three other yeasts also manifested a similar role in substrate accumulation. Thus, while fungal myosin-I may function as a classical myosin-I, it has hitherto unknown additional roles in regulating membrane permeability. Since deletion of fungal myosin-I causes significantly elevated susceptibility to multiple antifungal drugs, it could serve as an effective target for augmentation of fungal therapy.

Loss of forebrain cholinergic neurons following fluid-percussion injury: implications for cognitive impairment in closed head injury

1995 ◽  
Vol 83 (3) ◽  
pp. 496-502 ◽  
Author(s):  
Richard H. Schmidt ◽  
M. Sean Grady
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Cholinergic Neurons ◽  
Nucleus Basalis ◽  
Neuron Loss ◽  
Content Type ◽  
Fluid Percussion ◽  
Concussive Injury ◽  
Fine Print

✓ Disturbances in memory, concentration, and problem solving are common after even mild to moderate traumatic brain injury. Because these functions are mediated in part by forebrain cholinergic and catecholaminergic innervation, in this study the authors sought to determine if experimental concussive injury produces detectable morphological damage to these systems. Fluid-percussion head injury, sufficient to cause a 13- to 14-minute loss of righting reflex, was produced in rats that had been anesthetized with halothane. Injury was delivered either at midline or 2 mm off midline and compared with appropriate sham-injured controls. After 11 to 15 days, the rat brains were stained in serial sections for choline acetyltransferase, tyrosine hydroxylase, dopamine β-hydroxylase, acetylcholinesterase, and nicotinamide adenine dinucleotide phosphate diaphorase. Cell counts were determined for the entire population of ventrobasal forebrain cholinergic cells. Midline injury produced a bilateral loss of cholinergic neurons averaging 36% in area Ch1 (medial septal nucleus), 45% in Ch2 (nucleus of the diagonal band of Broca), and 41% in Ch4 (nucleus basalis of Meynart), (p ≤ 0.05). Lateralized injury resulted in cholinergic neuron loss of similar magnitude ipsilaterally (p ≤ 0.05), but a smaller contralateral loss of between 11% and 28%. No loss of neurons was detected in the pontomesencephalic cholinergic groups Ch5 and Ch6. There was no visible effect of head injury on forebrain dopamine or noradrenergic innervation. A significant and apparently selective loss of ventrobasal forebrain cholinergic neurons following brief concussive injury in rats is demonstrated in this study. This type of injury is known to produce significant disturbance in cognitive tasks linked to neocortical and hippocampal cholinergic function. It remains to be determined how this neuron loss occurs, whether it can be prevented with neuroprotective agents, how it affects innervation in target tissues, and whether it occurs in human victims of traumatic brain injury.

Posttraumatic narcolepsy: the complete syndrome with tissue typing

1989 ◽  
Vol 71 (5) ◽  
pp. 765-767 ◽  
Author(s):  
Janine L. Good ◽  
Elizabeth Barry ◽  
Paul S. Fishman
Keyword(s):  
Brain Injury ◽  
Head Injury ◽  
Human Lymphocyte ◽  
Genetic Predisposition ◽  
Sleep Disturbances ◽  
Content Type ◽  
Lymphocyte Antigen ◽  
Tissue Typing ◽  
The Brain ◽  
Fine Print

✓ Although sleep disturbances following head injury are common, well-documented posttraumatic narcolepsy has rarely been reported. A patient with all four major features of narcolepsy following significant head injury is presented. Tissue typing revealed the presence of the human lymphocyte antigen DR2, which is strongly associated with idiopathic narcolepsy. Interaction between the brain injury and a genetic predisposition appears to be involved in the development of posttraumatic narcolepsy.

Impaired cerebral mitochondrial function after traumatic brain injury in humans

2000 ◽  
Vol 93 (5) ◽  
pp. 815-820 ◽  
Author(s):  
Bon H. Verweij ◽  
J. Paul Muizelaar ◽  
Federico C. Vinas ◽  
Patti L. Peterson ◽  
Ye Xiong ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Oxygen Content ◽  
Mitochondrial Function ◽  
Oxygen Delivery ◽  
Neuronal Cell ◽  
Content Type ◽  
Atp Production ◽  
Fine Print

Object. Oxygen supply to the brain is often insufficient after traumatic brain injury (TBI), and this results in decreased energy production (adenosine triphosphate [ATP]) with consequent neuronal cell death. It is obviously important to restore oxygen delivery after TBI; however, increasing oxygen delivery alone may not improve ATP production if the patient's mitochondria (the source of ATP) are impaired. Traumatic brain injury has been shown to impair mitochondrial function in animals; however, no human studies have been previously reported.Methods. Using tissue fractionation procedures, living mitochondria derived from therapeutically removed brain tissue were analyzed in 16 patients with head injury (Glasgow Coma Scale Scores 3–14) and two patients without head injury. Results revealed that in head-injured patients mitochondrial function was impaired, with subsequent decreased ATP production.Conclusions. Decreased oxygen metabolism due to mitochondrial dysfunction must be taken into account when clinically defining ischemia and interpreting oxygen measurements such as jugular venous oxygen saturation, arteriovenous difference in oxygen content, direct tissue oxygen tension, and cerebral blood oxygen content determined using near-infrared spectroscopy. Restoring mitochondrial function might be as important as maintaining oxygen delivery.

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.

Head injury caused by underwater explosion of a firecracker

1972 ◽  
Vol 37 (1) ◽  
pp. 95-99 ◽  
Author(s):  
Arthur E. Hirsch ◽  
Ayub K. Ommaya
Keyword(s):  
Brain Injury ◽  
Head Injury ◽  
Severe Head Injury ◽  
Skull Fracture ◽  
Underwater Explosion ◽  
Content Type ◽  
Base Of The Skull ◽  
Impact Energies ◽  
Fine Print

✓ A firecracker exploded in contact with the skin and within 6 inches of the base of the skull of a young man while he was swimming underwater. The resultant severe head injury and death appeared to be directly related to the underwater explosion. Reconstruction of the mechanics of this injury indicates that when the head is subjected to impact energies between 440 to 1800 in.-lb and impact impulses between 1.8 to 3.5 lb/sec, both skull fracture and brain injury can occur.

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