Multimodal assessment of neuroprotection applied to the use of MK-801 in the endothelin-1 model of transient focal brain ischemia.
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.
Moyanova
Slavianka Georgieva
SG
Department of Neurobiology of Adaptation, Laboratory of Integrative Neuropharmacology, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria. slav@bio.bas.bg
Kortenska
Lidia Vasileva
LV
Mitreva
Rumiana Gesheva
RG
Pashova
Vyara Dincova
VD
Ngomba
Richard Teke
RT
Nicoletti
Ferdinando
F
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
D019332:Endothelin-1; D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; D016291:Dizocilpine Maleate; C009591:triphenyltetrazolium