title: Multimodal assessment of neuroprotection applied to the use of MK-801 in the endothelin-1 model of transient focal brain ischemia.
abstract: Transient focal ischemia produced by local infusion of endothelin-1 (ET1) in the territory of the middle cerebral artery has been proposed as a potentially useful model for the screening of drugs developed for the treatment of thrombo-embolic stroke. However, most of the data rely exclusively on the assessment of the infarct volume, which is only a partial predictor of the neurological outcome of stroke. Here, we have validated the model using a multimodal approach for the assessment of neuroprotection, which includes (i) determination of the infarct volume by 2,3,5-triphenyltetrazolium chloride staining; (ii) an in-depth behavioral analysis of the neurological deficit; and (iii) an EEG analysis of electrophysiological abnormalities in the peri-infarct somatosensory forelimb cortical area, S1FL. The non-competitive NMDA receptor antagonist, MK-801 (3 mg/kg, injected i.p. 20 min after ET1 infusion in conscious rats) could reduce the infarct volume, reverse the EEG changes occurring at early times post-ET1, and markedly improve the neurological deficit in ischemic animals. The latter effect, however, was visible at day 3 post-ET1, because the drug itself produced substantial behavioral abnormalities at earlier times. We conclude that a multimodal approach can be applied to the ET1 model of focal ischemia, and that MK-801 can be used as a reference compound to which the activity of safer neuroprotective drugs should be compared.
authors.affiliation: Department of Neurobiology of Adaptation, Laboratory of Integrative Neuropharmacology, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria. slav@bio.bas.bg
authors.forename: Slavianka Georgieva
authors.initials: SG
authors.lastname: Moyanova
authors.forename: Lidia Vasileva
authors.initials: LV
authors.lastname: Kortenska
authors.forename: Rumiana Gesheva
authors.initials: RG
authors.lastname: Mitreva
authors.forename: Vyara Dincova
authors.initials: VD
authors.lastname: Pashova
authors.forename: Richard Teke
authors.initials: RT
authors.lastname: Ngomba
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004569:Electroencephalography / Q000187:drug effects; D019332:Endothelin-1; D007839:Functional Laterality; D002546:Ischemic Attack, Transient / Q000139:chemically induced* / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013003:Somatosensory Cortex / Q000187:drug effects / Q000503:physiopathology; D013778:Tetrazolium Salts
chemical_list: D019332:Endothelin-1; D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; D016291:Dizocilpine Maleate; C009591:triphenyltetrazolium