Role of endogenous excitatory amino acid neurotransmitters in the pathogenesis and evolution of acute brain injury

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.5.h2188 ◽

2000 ◽

Vol 279 (5) ◽

pp. H2188-H2195 ◽

Cited By ~ 8

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.

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