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Developmental differences in antagonism of NMDA toxicity by the polyamine site antagonist ifenprodil
1Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, Piscataway 08854.
Abstract:
Antagonists of 4 distinct regulatory sites on the N-methyl-D-aspartate (NMDA) receptor were tested for their ability to attenuate NMDA-mediated acute excitotoxicity in isolated chick retina of various embryonic ages between days 11 and 19 in ovo. Acute excitotoxicity was monitored by histology and by release of endogenous gamma-aminobutyric acid (GABA) into the medium during 30 min of incubation with 50 microM NMDA. The uncompetitive PCP channel site antagonist, MK-801, the competitive antagonist, CGS 19755, and the strychnine-insensitive glycine site antagonist, 7-chlorokynurenate, completely blocked NMDA-induced cell swelling and increased GABA release at all ages tested. Potencies versus NMDA were MK-801 greater than CGS 19755 greater than 7-chlorokynurenate with IC50S of 0.02, 0.62, and 15 microM, respectively. NMDA antagonism by the polyamine site antagonist, ifenprodil, differed from other classes of antagonists in several respects. At the earlier embryonic ages tested (E12-13) ifenprodil provided differential protection; completely blocking somal and neuritic swelling in most but not all inner nuclear layer neurons and inner plexiform processes. In dose-response studies, ifenprodil attenuated the NMDA-induced increase in medium GABA at all ages tested with an Imax of 10 microM. Ifenprodil, however, showed a decreased ability to completely protect some NMDA-sensitive neurons. This was reflected both histologically and by GABA release. Maximal attenuation of NMDA evoked GABA release was 83, 80, 62 and 50% at days E12, 13, 15 and 19, respectively. Histologically, differential protection was seen at E12 and 13, in limited areas at E15, and was no longer present at E19.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
NMDA receptor antagonists like MK-801, CGS 19755, and 7-chlorokynurenate fully protected chick retinas from excitotoxicity. Ifenprodil offered partial protection, varying with embryonic age.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- The N-methyl-D-aspartate (NMDA) receptor is crucial for synaptic plasticity and development.
- NMDA receptor overactivation leads to excitotoxicity, a significant factor in neurological damage.
- Understanding NMDA receptor antagonists is vital for neuroprotection strategies.
Purpose of the Study:
- To investigate the efficacy of NMDA receptor antagonists at distinct regulatory sites.
- To assess the neuroprotective potential against NMDA-mediated excitotoxicity in developing chick retinas.
- To evaluate age-dependent differences in antagonist effectiveness.
Main Methods:
- Isolated chick retinas from embryonic days 11-19 were used.
- NMDA-induced excitotoxicity was induced with 50 microM NMDA.
- Histology and gamma-aminobutyric acid (GABA) release were used to monitor excitotoxicity.
- Antagonists MK-801 (PCP site), CGS 19755 (competitive), 7-chlorokynurenate (glycine site), and ifenprodil (polyamine site) were tested.
Main Results:
- MK-801, CGS 19755, and 7-chlorokynurenate completely prevented NMDA-induced cell swelling and GABA release across all tested ages.
- Ifenprodil demonstrated differential protection, particularly at earlier embryonic ages (E12-13), with maximal attenuation of GABA release decreasing with age.
- Histological analysis confirmed ifenprodil's age-dependent protective effects, which diminished by embryonic day 19.
Conclusions:
- Competitive, uncompetitive, and glycine site antagonists offer robust neuroprotection against NMDA excitotoxicity in developing retinas.
- The polyamine site antagonist ifenprodil exhibits age-dependent efficacy, suggesting developmental variations in NMDA receptor pharmacology.
- These findings highlight the potential for targeted NMDA receptor modulation in treating excitotoxic injuries during development.