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
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.