Activation of mGlu1 but not mGlu5 metabotropic glutamate receptors contributes to postischemic neuronal injury in vitro and in vivo.
In order to investigate the involvement of mGlu1 and mGlu5 metabotropic glutamate receptors in the development of postischemic neuronal death, we examined the effects of selective agonists and antagonists in models of cerebral ischemia in vitro and in vivo. In murine cortical cell cultures and rat organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD), the mGlu1 antagonists 1-aminoindan-1,5-dicarboxylic acid (AIDA; 300 microM), (S)-(+)-2-(3'-carboxybicyclo[1.1.1]pentyl)-glycine (CBPG; 300 microM), 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt; 10-30 microM) and (+)-2-methyl-4-carboxyphenylglycine (LY367385; 30-100 microM) reduced neuronal loss when added to the medium during OGD and the subsequent 24-h recovery period. On the contrary, the potent and selective mGlu5 antagonist methyl-6-(phenylethynyl)-pyridine (MPEP; 0.1-1 microM) did not exhibit neuroprotection in any of these in vitro models. Incubation with the nonselective mGlu1 and mGlu5 agonist 3,5-dihydroxyphenylglycine (3,5-DHPG; 300 microM) but not with the mGlu5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 1 mM) enhanced the severity of OGD-induced neuronal damage. In gerbils subjected to global ischemia, intracerebroventricular administration of AIDA (100 nmol two times) or CBPG (300 nmol, two times) afforded consistent protection against CA1 pyramidal cell death, whereas MPEP (10 pmol i.c.v two times and 10 mg/kg i.p two times) failed to reduce postischemic hippocampal damage. Our results suggest that activation of mGlu1 but not mGlu5 receptor contributes to postischemic neuronal injury.
Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Viale G. Pieraccini 6, Firenze, Italy.
Elena
E
Meli
Roberta
R
Picca
Sabina
S
Attucci
Andrea
A
Cozzi
Fiamma
F
Peruginelli
Flavio
F
Moroni
Domenico E
DE
Pellegrini-Giampietro
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005849:Gerbillinae; D005947:Glucose / Q000172:deficiency / Q000502:physiology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D010101:Oxygen Consumption / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors; D010738:Type C Phospholipases / Q000378:metabolism
C095756:1-aminoindan-1,5-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D018696:Neuroprotective Agents; D010716:Phosphatidylinositols; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C100726:UPF 596; C104077:metabotropic glutamate receptor type 1; D010738:Type C Phospholipases; D005947:Glucose; D005998:Glycine