Abstract
The mechanisms underlying the neuroprotective effects of the group II metabotropic glutamate receptor (mGluR) agonist LY379268 were investigated in a gerbil model of global ischemia. LY379268 (10 mg/kg i.p.) 30 or 60 min after 5-min bilateral carotid artery occlusion (BCAO) attenuated the ischemia-induced hyperactivity and provided protection in the CA1 hippocampal cells. This neuroprotective effect was maintained (P < .001) when histological analysis was performed 14 and 28 days after BCAO. Furthermore, 24- or 48-h pretreatment with LY379268, 10 mg/kg i.p., before 5-min BCAO markedly reduced (P < .001 andP < .05, respectively) the damage to CA1 hippocampal neurons. This result is consistent with the induction of neuroprotective factors or a very long brain half-life. To study the possible induction of neuroprotective factors as contributing to this action of LY379268, brains were examined for expression of neurotrophic factors. Results indicated that LY379268 (10 mg/kg i.p.) failed to alter the expression of transforming growth factor-β, brain-derived neurotrophic factor, nerve growth factor, and basic fibroblast growth factor in the hippocampal regions of brains taken from gerbils sacrificed at 6, 24, 72, and 120 h postinjection. The new group II mGlu antagonist, LY341495, administered 1 h before 5-min BCAO, attenuated the neuroprotective effect of LY379268 administered 24 h before 5-min BCAO. Complementary pharmacokinetic studies showed that a significant receptor-active concentration persisted in the brain 24 h after LY379268 10 mg/kg i.p. We conclude that group II mGluR occupancy, rather than induction of neuroprotective factors, explains the long-lasting neuroprotective effect of LY379268 in the gerbil model of global ischemia.
Footnotes
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Send reprint requests to: Dr. Michael J. O'Neill, Eli Lilly & Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. E-mail: ONEILL_MICHAEL_J{at}Lilly.com
- Abbreviations:
- iGlu
- ionotropic glutamate
- mGlu
- metabotropic glutamate
- mGluR
- mGlu receptor
- BCAO
- bilateral carotid artery occlusion
- TGF-β1
- transforming growth factor-β1
- TGF-β2
- transforming growth factor-β2
- BDNF
- brain-derived neurotrophic factor
- NGF
- nerve growth factor
- bFGF
- basic fibroblast growth factor
- NMDA
- N-methyl-d-aspartate
- AMPA
- α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid
- DCG-IV
- (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine
- 4C3HPG
- (S)-4-carboxy-3-hydroxyphenylglycine
- L-CCG-1
- (2S,1S,2S)-2(carboxycyclopropyl) glycine
- LY354740
- (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
- LY379268
- (1R,4R,5S,6R)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate
- LY341495
- 2S-2-amino-2-(1S,2S-2-caroxycyclopropy-1-yl)-30(xanth-9-yl)propionic acid
- NBQX
- 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline
- MK-801
- (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine
- ACEA1021
- 5-nitro-6,7-dichloro-2,3-quinoxalinedione
- GV150526A
- [(E)-3[(phenylcarbamoyl) ethenyl]-4,6-dichloroindole-2-carboxylic acid
- GYKI52466
- 1-(aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
- LY300164
- (+)-3-N-acetyl-1(aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
- Received February 17, 2000.
- Accepted April 27, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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