Involvement of endocannabinoid signaling in the neuroprotective effects of subtype 1 metabotropic glutamate receptor antagonists in models of cerebral ischemia.
Experimental evidence indicates that metabotropic glutamate (mGlu) receptors of the mGlu1 and mGlu5 subtypes play a differential role in models of cerebral ischemia and that only mGlu1 receptors are implicated in the pathways leading to postischemic neuronal injury. The localization of mGlu1 receptors in GABA-containing interneurons rather than in hippocampal CA1 pyramidal cells that are vulnerable to ischemia has prompted experimental studies that have demonstrated mGlu1 receptor antagonist agents attenuate postischemic injury by enhancing GABA-mediated neurotransmission, thus providing a new viewpoint on the neuroprotective mechanism of these pharmacological agents. In view of the recent discovery of a functional interaction between group I mGlu receptors and the cannabinoid system in the modulation of synaptic transmission, we propose a novel mechanism that predicts that the neuroprotective effects of mGlu1 receptor antagonists on CA1 pyramidal cells are mediated by a mechanism that overcomes the "synaptic circuit break" operated by endocannabinoids on GABAergic transmission.
Landucci
Elisa
E
Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Firenze 50139, Italy.
Boscia
Francesca
F
Gerace
Elisabetta
E
Scartabelli
Tania
T
Cozzi
Andrea
A
Moroni
Flavio
F
Mannaioni
Guido
G
Pellegrini-Giampietro
Domenico E
DE
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology*; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1