|Autori||Di Prisco S, Merega E, Bonfiglio T, Olivero G, Cervetto C, Grilli M, Usai C, Marchi M, Pittaluga A|
|Abstract||Background and PurposePresynaptic, release-regulating metabotropic glutamate 2 and 3 (mGlu(2/3)) autoreceptors exist in the CNS. They represent suitable targets for therapeutic approaches to central diseases that are typified by hyperglutamatergicity. The availability of specific ligands able to differentiate between mGlu(2) and mGlu(3) subunits allows us to further characterize these autoreceptors. In this study we investigated the pharmacological profile of mGlu(2/3) receptors in selected CNS regions and evaluated their functions in mice with experimental autoimmune encephalomyelitis (EAE). |
Experimental ApproachThe comparative analysis of presynaptic mGlu(2/3) autoreceptors was performed by determining the effect of selective mGlu(2/3) receptor agonist(s) and antagonist(s) on the release of [H-3]-d-aspartate from cortical and spinal cord synaptosomes in superfusion. In EAE mice, mGlu(2/3) autoreceptor-mediated release functions were investigated and effects of in vivo LY379268 administration on impaired glutamate release examined ex vivo.
Key ResultsWestern blot analysis and confocal microscopy confirmed the presence of presynaptic mGlu(2/3) receptor proteins. Cortical synaptosomes possessed LY541850-sensitive, NAAG-insensitive autoreceptors having low affinity for LY379268, while LY541850-insensitive, NAAG-sensitive autoreceptors with high affinity for LY379268 existed in spinal cord terminals. In EAE mice, mGlu(2/3) autoreceptors completely lost their inhibitory activity in cortical, but not in spinal cord synaptosomes. In vivo LY379268 administration restored the glutamate exocytosis capability in spinal cord but not in cortical terminals in EAE mice.
Conclusions and ImplicationsWe propose the existence of mGlu(2)-preferring and mGlu(3)-preferring autoreceptors in mouse cortex and spinal cord respectively. The mGlu(3)-preferring autoreceptors could represent a target for new pharmacological approaches for treating demyelinating diseases
|Rivista||British Journal Of Pharmacology|
|Autori IBF||Cesare USAI|
|Linee di Ricerca IBF||MD.P01.001.001|