title: A use-dependent sodium channel antagonist, 619C89, in reduction of ischemic brain damage and glutamate release after acute subdural hematoma in the rat.
abstract: Acute subdural hematoma kills or disables more severely head injured patients than any other complication of cranial trauma. The main pathological factor involved is ischemic neuronal damage, which is caused by raised intracranial pressure and local effect. The authors have evaluated the hypothesis that a novel use-dependent sodium channel antagonist, 619C89, could reduce ischemic brain damage in the rat subdural hematoma model. Because previous studies have shown that focal neuronal damage may be mediated by "excitotoxic" mechanisms, and because excitatory amino acid levels have been shown to be markedly elevated after brain trauma in humans, the authors have measured levels of glutamate, aspartate, and threonine within the cortex underneath the hematoma, using in vivo microdialysis before and after induction of hematoma, in both vehicle- and drug-treated rats. Postinjury treatment with 619C89 (30 mg/kg) significantly reduced the volume of hemispheric ischemic damage produced by subdural hematoma, from 99.77 +/- 7.51 mm3 in vehicle-treated control rats to 46.07 +/- 11.06 mm3 (p = 0.0007) in drug-treated animals. In the vehicle-treated animals, induction of subdural hematoma led to a fourfold increase in glutamate in the first 30 minutes after subdural hematoma occurred. The mean extracellular glutamate concentration in these animals remained 2- to 2.6-fold increased over the following 2.5 hours. In the 619C89-treated animals, the release of glutamate from the cortex underneath the hematoma was significantly attenuated. In these rats, induction of subdural hematoma led to a 2.7-fold increase in the first 30-minute sample, but extracellular glutamate concentration returned to near-basal levels thereafter, compared with vehicle-treated animals (p < 0.05). These results show that 619C89 is highly neuroprotective in this model and that its effects may, in part, be mediated by the inhibition of glutamate release from the ischemic cortex underneath the hematoma.
authors.affiliation: Department of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tsuchida
authors.forename: J F
authors.initials: JF
authors.lastname: Harms
authors.forename: J J
authors.initials: JJ
authors.lastname: Woodward
authors.forename: R
authors.initials: R
authors.lastname: Bullock
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy*; D003956:Dialysis; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D006408:Hematoma, Subdural / Q000188:drug therapy*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D013912:Threonine / Q000378:metabolism
chemical_list: D010879:Piperazines; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D013912:Threonine; D001224:Aspartic Acid; D018698:Glutamic Acid; C081980:sipatrigine