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Neuroprotective effects of the N-methyl-D-aspartate receptor antagonists ifenprodil and SL-82,0715 on hippocampal cells in culture.
J Pharmacol Exp Ther. 1992 Feb; 260(2):925-32.JP

Abstract

The N-methyl-D-aspartate (NMDA) antagonists ifenprodil and SL-82,0715 were examined for neuroprotective efficacy against glutamate toxicity of hippocampal neurons in culture. Hippocampal cells were grown on 96-well culture plates for 2 to 3 weeks and then exposed for a 15-min period to glutamate or NMDA. Neurodegeneration was quantified 24 hr after the excitotoxin exposure, by measuring the activity of lactate dehydrogenase leaked into the culture medium by the damaged cells. Glutamate induced a concentration-dependent increase in lactate dehydrogenase that reached 3-fold the activity of control cultures. The NMDA antagonists MK-801 and AP-7 blocked this neurotoxicity when added either during or after the glutamate exposure. Ifenprodil and SL-82,0715 blocked the neurotoxicity only when added during the excitotoxin exposure. Ifenprodil was 3 times more potent than SL-82,0715 in blocking glutamate or NMDA-induced neurotoxicity. Glycine did not reverse the neuroprotective effects of these antagonists. The neuroprotective effect of ifenprodil or SL-82,0715 did not appear to result from actions at alpha-1 adrenergic or sigma receptor sites because the alpha-1 adrenergic antagonist prazosin and the sigma ligands haloperidol, 3-(3-hydroxyphenyl)-N-propylpiperidine) and 1,3-di-o-tolylguanidine) showed no neuroprotective activity. We conclude that ifenprodil and SL-82,0715 protect cultured hippocampal neurons from excitotoxic damage by antagonizing NMDA receptors.

Authors+Show Affiliations

Shalaby IA
Department of Neuroscience, Pfizer Inc., Groton, Connecticut.
Chenard BL
No affiliation info available
Prochniak MA
No affiliation info available
Butler TW
No affiliation info available

MeSH

AnimalsCells, CulturedCulture MediaDizocilpine MaleateDrug AntagonismGlutamatesGlutamic AcidHippocampusL-Lactate DehydrogenaseN-MethylaspartatePiperidinesRatsReceptors, N-Methyl-D-AspartateReceptors, Neurotransmitter

Pub Type(s)

Journal Article

Language

eng

PubMed ID

1346650

Citation

Shalaby, I A., et al. "Neuroprotective Effects of the N-methyl-D-aspartate Receptor Antagonists Ifenprodil and SL-82,0715 On Hippocampal Cells in Culture." The Journal of Pharmacology and Experimental Therapeutics, vol. 260, no. 2, 1992, pp. 925-32.
Shalaby IA, Chenard BL, Prochniak MA, et al. Neuroprotective effects of the N-methyl-D-aspartate receptor antagonists ifenprodil and SL-82,0715 on hippocampal cells in culture. J Pharmacol Exp Ther. 1992;260(2):925-32.
Shalaby, I. A., Chenard, B. L., Prochniak, M. A., & Butler, T. W. (1992). Neuroprotective effects of the N-methyl-D-aspartate receptor antagonists ifenprodil and SL-82,0715 on hippocampal cells in culture. The Journal of Pharmacology and Experimental Therapeutics, 260(2), 925-32.
Shalaby IA, et al. Neuroprotective Effects of the N-methyl-D-aspartate Receptor Antagonists Ifenprodil and SL-82,0715 On Hippocampal Cells in Culture. J Pharmacol Exp Ther. 1992;260(2):925-32. PubMed PMID: 1346650.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotective effects of the N-methyl-D-aspartate receptor antagonists ifenprodil and SL-82,0715 on hippocampal cells in culture. AU - Shalaby,I A, AU - Chenard,B L, AU - Prochniak,M A, AU - Butler,T W, PY - 1992/2/1/pubmed PY - 1992/2/1/medline PY - 1992/2/1/entrez SP - 925 EP - 32 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 260 IS - 2 N2 - The N-methyl-D-aspartate (NMDA) antagonists ifenprodil and SL-82,0715 were examined for neuroprotective efficacy against glutamate toxicity of hippocampal neurons in culture. Hippocampal cells were grown on 96-well culture plates for 2 to 3 weeks and then exposed for a 15-min period to glutamate or NMDA. Neurodegeneration was quantified 24 hr after the excitotoxin exposure, by measuring the activity of lactate dehydrogenase leaked into the culture medium by the damaged cells. Glutamate induced a concentration-dependent increase in lactate dehydrogenase that reached 3-fold the activity of control cultures. The NMDA antagonists MK-801 and AP-7 blocked this neurotoxicity when added either during or after the glutamate exposure. Ifenprodil and SL-82,0715 blocked the neurotoxicity only when added during the excitotoxin exposure. Ifenprodil was 3 times more potent than SL-82,0715 in blocking glutamate or NMDA-induced neurotoxicity. Glycine did not reverse the neuroprotective effects of these antagonists. The neuroprotective effect of ifenprodil or SL-82,0715 did not appear to result from actions at alpha-1 adrenergic or sigma receptor sites because the alpha-1 adrenergic antagonist prazosin and the sigma ligands haloperidol, 3-(3-hydroxyphenyl)-N-propylpiperidine) and 1,3-di-o-tolylguanidine) showed no neuroprotective activity. We conclude that ifenprodil and SL-82,0715 protect cultured hippocampal neurons from excitotoxic damage by antagonizing NMDA receptors. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/1346650/Neuroprotective_effects_of_the_N_methyl_D_aspartate_receptor_antagonists_ifenprodil_and_SL_820715_on_hippocampal_cells_in_culture_ DB - PRIME DP - Unbound Medicine ER -