Neuroprotective effects of LY379268, a selective mGlu2/3 receptor agonist: investigations into possible mechanism of action in vivo.
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 and P <.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-beta, 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.
Bond
A
A
Eli Lilly & Co. Ltd., Lilly Research Centre, Windlesham, Surrey, United Kingdom.
Jones
N M
NM
Hicks
C A
CA
Whiffin
G M
GM
Ward
M A
MA
O'Neill
M F
MF
Kingston
A E
AE
Monn
J A
JA
Ornstein
P L
PL
Schoepp
D D
DD
Lodge
D
D
O'Neill
M J
MJ
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002340:Carotid Artery Diseases / Q000150:complications; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000596:Amino Acids; D019208:Brain-Derived Neurotrophic Factor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D016212:Transforming Growth Factor beta; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D020932:Nerve Growth Factor