Lack of effect of L-687,414 ((+)-cis-4-methyl-HA-966), an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology.
1. N-methyl-D-aspartate (NMDA) receptor ion channel antagonists have been reported to cause pronounced increases in cerebral glucose metabolism (CMRglc) and transient reversible vacuolation within pyramidal cortical neurones. The present studies examined in rats the effects of the NMDA receptor antagonist, L-687,414 (R-(+)-cis-4-methyl-3-amino-l-hydroxypyrolid-2-one (+)-cis-4-methyl-HA-966) on regional CMRglc and cortical neuronal morphology. 2. L-687,414 was given as a steady state intravenous infusion for 4 h in a neuroprotective dose regime of 17.5 mg free base kg-1 bolus followed by 225 micrograms kg-1 min-1 (n = 8) or at the higher dose rate of 35 mg kg-1 bolus followed by 440 micrograms kg-1 min-1 (n = 10). Data were compared to a parallel series of experiments in rats given the NMDA receptor ion channel antagonist, dizocilpine for 4 h in the optimum intravenous neuroprotective dose-regime of 0.12 mg kg-1 bolus followed by 1.8 micrograms kg-1 min-1 (n = 8) or at the higher dose rate of 0.4 mg kg-1 bolus followed by 6 micrograms kg-1 min-1 (n = 4; morphology only studied). A saline-infused group of rats (n = 8) were used as controls. 3. CMRglc was studied by use of [14C]-2-deoxyglucose and autoradiography (n = 4 each group) whilst plasma drug levels were in a steady state during the final 45 min of the 4 h drug infusion. Effects on cortical neuronal morphology were assessed at the end of the 4 h infusion period using light microscopic techniques (n = 4-6 each group).4. The results showed a selective activation of limbic CMRglc by dizocilpine at optimal neuroprotective dose levels and showed that this dose was at the threshold for the neuronal vacuolation response as I of 4 rats showed morphological changes in the pyramidal neurones in the posterior cingulate and retrosplenial cortices. At the higher dose rate of dizocilpine, all 4 animals showed extensive morphological changes in these cortical neurones. In contrast, L-687,414 did not increase limbic CMRglc, nor evoke vacuolation when given in the neuroprotective dose-regime or at the higher dosage rate.5. The findings of the present study suggest that neuroprotection mediated through the NMDA receptor complex can be achieved without changes in CMRglc or cortical neuronal morphology by antagonism at the glycine modulatory site.
Hargreaves
R J
RJ
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, Harlow, Essex.
Rigby
M
M
Smith
D
D
Hill
R G
RG
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D005998:Glycine / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D011760:Pyrrolidinones / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D001786:Blood Glucose; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; C084173:L 687414; D016291:Dizocilpine Maleate; D003847:Deoxyglucose; D005947:Glucose; D005998:Glycine