CORRELATION OF CGS-19755 NEUROPROTECTION AGAINST IN-VITRO EXCITOTOXICITY AND FOCAL CEREBRAL-ISCHEMIA

Citation
Ma. Perezpinzon et al., CORRELATION OF CGS-19755 NEUROPROTECTION AGAINST IN-VITRO EXCITOTOXICITY AND FOCAL CEREBRAL-ISCHEMIA, Journal of cerebral blood flow and metabolism, 15(5), 1995, pp. 865-876
Citations number
62
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences,"Endocrynology & Metabolism",Hematology
ISSN journal
0271-678X
Volume
15
Issue
5
Year of publication
1995
Pages
865 - 876
Database
ISI
SICI code
0271-678X(1995)15:5<865:COCNAI>2.0.ZU;2-C
Abstract
The in vivo neuroprotective effect and brain levels of cis-4-phosphono methyl-2-piperidine carboxylic acid (CGS 19755), a competitive N-methy l-D-aspartate (NMDA) antagonist, were compared with its in vitro neuro protective effects. The dose-response for in vitro neuroprotection aga inst both NMDA toxicity and combined oxygen-glucose deprivation (OGD) was determined in murine neocortical cultures. Primary cultures of neo cortical cells from fetal mice were injured by exposure to 500 mu M NM DA for 10 min or to OGD for 45 min. The effect of CGS 19755 in both in jury paradigms was assessed morphologically and quantitated by determi nation of lactate dehydrogenase release. Near complete neuroprotection was found at high doses of CGS 19755. The ED(50) for protection again st NMDA toxicity was 25.4 mu mM, and against OGD the ED(50) was 15.2 m u M. For the in vivo paradigm rabbits underwent 2 h of left internal c arotid, anterior cerebral, and middle cerebral artery occlusion follow ed by 4 h reperfusion; ischemic injury was assessed by magnetic resona nce imaging and histopathology. The rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after arterial occlusion. CSF and bra in levels of CGS 19755 were 12 mu M and 5 mu M, respectively, at 1 h, 6 mu M and 5 mu M at 2 h, and 13 mu M and 7 mu M at 4 h. These levels were neuroprotective in this model, reducing cortical ischemic edema b y 48% and ischemic neuronal damage by 76%. These results suggest that a single i.v. dose penetrates the blood-brain barrier, attaining susta ined neuroprotective levels that are in the range for in vitro neuropr otection.