Ischemic neuronal damage after acute subdural hematoma in the rat: effects of pretreatment with a glutamate antagonist

Abstract

The ability of a competitive N-methyl-D-aspartate (NMDA) receptor antagonist (D-CPP-ene) to reduce irreversible brain damage has been examined in a rodent model of acute subdural hematoma. Acute subdural hematoma was produced by the slow injection of 400 microliters homologous blood into the subdural space overlying the parietal cortex in halothane-anesthetized rats. Brain damage was assessed histologically in sections at multiple coronal planes in animals sacrificed 4 hours after induction of the subdural hematoma. Pretreatment with D-CPP-ene (15 mg/kg) significantly reduced the volume of ischemic brain damage produced by the subdural hematoma from 62 +/- 8 cu mm (mean +/- standard error of the mean) in vehicle-treated control rats to 29 +/- 7 cu mm in drug-treated animals. These data demonstrate the anti-ischemic efficacy of NMDA antagonists in an animal model of intracranial hemorrhage in which intracranial pressure is elevated, and suggest that excitotoxic mechanisms (which are susceptible to antagonism by D-CPP-ene) may play a role in the ischemic brain damage which is observed in patients who die after acute subdural hematoma.

Factors affecting excitatory amino acid release following severe human head injury

“…Studies conducted by Katayama, et al, [28] Faden, et al, [17] and our own previous studies have shown brief, transient elevations of EAAs to two to seven times higher than basal levels, persisting only 10 to 30 minutes after impact, in both fluid percussion injury and subdural hematoma in the rat. [6,8,12] Animal studies have only assessed events over a few hours before and after impact. In contrast, these human studies have only captured data for the postimpact period, ranging from 3 hours to 6 days after impact.…”

“…[3,6,11,22,23,43,49] In these models, a variety of drugs that block the effects of glutamate both presynaptically and at postsynaptic receptor sites have reduced both ischemic brain damage and glutamate release. [5,7,12,20,21,24,25,29,32,33,36,40,53,55,56] There are now several Phase II and Phase III trials in progress to evaluate the efficacy of glutamate antagonist drugs in both neurotrauma and stroke. However, the pattern of glutamate release after neurotrauma has hitherto only been documented in the cerebrospinal fluid and in small numbers of patients by using the microdialysis technique.…”

“…[2,3,8,9,15,28] At least four glutamate receptor subtypes exist on different parts of mammalian neurons, and now extensive studies have characterized the responses of these receptors to glutamate and its coagonists (including aspartate and glycine). [3,12,17,20,23,26,29,35,46,53,54] Many of the normal physiological processes of the cortex and the hippocampus, in particular, are thought to depend on this neurotransmitter function of glutamate. [15,30,31,46] However, when glutamate is present in excessive quantities, it may overactivate specific ion channels, especially the N-methyl-D-aspartate channel.…”

Development of a Model of Hemispheric Hypodensity (“Big Black Brain”)

“…[16][17][18] Although the exact etiological mechanisms that cause injury in children with AHT remain controversial, repetitive motions attempting to model aspects of shaking have been employed in some animal models to investigate injury, but none has resulted in the extensive SDH nor the widespread hypoxic-ischemic type damage observed after the more severe forms of AHT in children. [19][20][21] Here we present a unique, immature, large-animal model designed to replicate the constellation of injuries and insults typical in AHT-associated patterns of predominantly unilateral hypodensity with patterns of tissue damage seen in children.…”

Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?

“…Summarization studies in animal models have provided a large body of evidence that glutamate accumulation in the synaptical fissure is a main cause of cell death. Reduction of glutamate levels or neurotransmission via different pharmacological agents can ameliorate such effects (43,(46)(47)(48).…”