Abstract
The effect of selective group I metabotropic glutamate receptor subtype 5 (mGluR5) antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB-1893) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. Treatment with MPEP and SIB-1893 showed significant neuroprotective effects in rat cortical neuronal cultures subjected to mechanical injury. Application of the antagonists also attenuated glutamate- andN-methyl-d-aspartate (NMDA)-induced neuronal cell death in vitro. Intracerebroventricular administration of MPEP to rats markedly improved motor recovery and reduced deficits of spatial learning after lateral fluid percussion-induced traumatic brain injury. Lesion volumes as assessed by magnetic resonance imaging were also substantially reduced by MPEP treatment. Although we show that MPEP acts as a potent mGluR5 antagonist in our culture system, where it completely blocks agonist-induced phosphoinositide hydrolysis, electrophysiological and pharmacological studies indicate that MPEP and SIB-1893 also inhibit NMDA receptor activity at higher concentrations that are neuroprotective. Taken together, these data suggest that MPEP and SIB-1893 may have therapeutic potential in brain injury, although the mechanisms of neuroprotective action for these drugs may reflect their ability to modulate NMDA receptor activity.
Footnotes
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Send reprint requests to: Alan I. Faden, M.D., Georgetown Institute for Cognitive and Computational Sciences, Department of Neuroscience, Georgetown University Medical Center, 3900 Reservoir Rd. N.W., Research Bldg., Rm. EP12, Washington, DC 20007. E-mail:fadena{at}giccs.georgetown.edu
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This study was supported by grants from the National Institutes of Health (RO1NS37313) and the Department of Defense (DAMD-17-93-V-3018).
- Abbreviations:
- mGluR
- metabotropic glutamate receptor
- IP
- inositol phosphate(s)
- MPEP
- 2-methyl-6-(phenylethynyl)-pyridine
- SIB-1893
- (E)-2-methyl-6-(2-phenylethenyl)-pyridine
- TBI
- traumatic brain injury
- NMDA
- N-methyl-d-aspartate
- DIV
- day in vitro
- CHPG
- (R,S)-2-chloro-5-hydroxyphenylglycine
- LDH
- lactate dehydrogenase
- MRI
- magnetic resonance imaging
- PI
- phosphoinositide
- MK801
- (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
- TR/TE
- repetition time/echo time
- RARE
- rapid acquisition with relaxation enhancement
- Received June 13, 2000.
- Accepted September 14, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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