Acute subdural hematoma (SDH) complicates 20% of severe human
head injuries and causes death or severe disability in 60% of these cases, due to
brain swelling and high intracranial pressure. Although the mechanisms for these phenomena are unknown, previous studies have implicated
excitatory amino acid-mediated mechanisms in both humans and animal models. The authors therefore performed in vivo autoradiography using 125I-MK-801, a high-affinity noncompetitive
N-methyl-D-aspartate (
NMDA) receptor antagonist, as a tracer to evaluate
NMDA ion channel activation spatially and temporally as
a factor causing cytotoxic swelling. Acute SDH was induced in 16 anesthetized rats using 0.4 ml autologous venous blood. Fifty microcuries of 125I-MK-801 was injected via an aortic arch
cannula 30 minutes after onset of SDH. The effect of a new putatively
neuroprotective drug,
ACEA-1021, a
glycine-specific binding site
NMDA antagonist, on 125I-MK-801 binding was tested on five animals "Nonspecific" 125I-MK-801 binding in the rat brain was assessed by pretreatment with "cold" (nonradiolabeled)
MK-801 in five more animals. Four hours later the animals were sacrificed and brain sections were apposed to radiation-detecting high-sensitivity photographic film with precalibrated
plastic standards for 4 weeks. A striking and highly significant 1.7- to 4.8-fold increase in 125I-MK-801 binding was seen in the penumbra of viable tissue surrounding the ischemic zone beneath the acute SDH, when compared to contralateral hemisphere binding (p < 0.001). The
MK-801 pretreatment markedly reduced 125I-MK-801 uptake in this penumbral zone (4.73 +/- 0.36 nCi/mg control vs. 2.85 +/- 0.08 nCi/mg cold
MK-801; p < 0.0001), indicating that the increased binding in the penumbra of the lesion was due to
NMDA ion channel activation. Pretreatment with
ACEA-1021 reduced 125I-MK-801 uptake by 28% (3.41 +/- 0.26 nCi/mg vs. 4.73 +/- 0.36 nCi/mg; p < 0.05), indicating that this agent prevents opening of the
NMDA ion channel and, thus, exposure of its receptor for
MK-801 binding. These studies show intense foci of penumbral
NMDA receptor-mediated
ion channel activation after onset of SDH, which is markedly reduced by an
NMDA antagonist. Such agents are thus likely to reduce cell swelling after SDH occurs.