The low success of NMDA or AMPA receptor antagonists in clinical trials has switched the interest (owards metabotropic glutamate (mGlu) receptors as targets for neuroprotective drugs. The mGlu receptors form a family of eight subtypes (mGlul to -8) subdivided into three groups based on their sequence homology and transduction mechanisms. The first group includes mGlul and -5 receptors, which are coupled to polyphosphoinositide hydrolysis, whereas members of the second (mGlu2 and -3) and third (mGlu4, -6, -7 and -8) groups are coupled to a Gi protein. Novel potent and selective mGlu1 and -5 antagonists (CPCCOEt and MPEP, respectively) are neuroprotective in in vitro and in vivo models of excitotoxic death, suggesting that endogenous activation of rnGlu1 and -5 receptors facilitates neurodegeneration at least under particular circumstances. However, only the action of CPCCOEt and other selective mGlu1 receptor antagonists but not the action of MPEP - is abolished in the presence of GABAA and GABAB receceptor antagonists. The mGlu1 antagonists are able to enhance GABA release in microdialysis studies, suggesting that the main function of mGlul receptors is to inhibit GABAergic transmission. The mGlul antagonists might therefore be particularly useful under conditions in which neurodegeneration results from the loss of synaptic inhibition. The mGlu2/3 receptor agonists are also neuroprotective, but through an entirely different mechanism. These drugs, typified by the compound LY379268, stimulate glial mGlu3 receptors, thereby promoting the de novo synthesis of TGF-β1. This effect is mediated by the activation of the MAP kinase and phosphatidylinositol-3-kinase pathways. Specific inhibitors of these two pathways (i.e., the compounds PD98059 and LY294002) prevent both the increase in TGF-β1 and neuroprotection. TGF-β1 is endowed with neuroprotective activity against a variety of insults, including excitotoxins, β-amyloid peptide, oxygen-glucose deprivation, and the HIV coat protein, gp120. Hence, mGlu2/3 agonists might have a broad therapeutic application in acute and chronic CNS disorders.
Metabotropic glutamate receptors as targets for neuroprotective drugs
Copani A.;Catania M. V.;D'Onofrio M.;
2000-01-01
Abstract
The low success of NMDA or AMPA receptor antagonists in clinical trials has switched the interest (owards metabotropic glutamate (mGlu) receptors as targets for neuroprotective drugs. The mGlu receptors form a family of eight subtypes (mGlul to -8) subdivided into three groups based on their sequence homology and transduction mechanisms. The first group includes mGlul and -5 receptors, which are coupled to polyphosphoinositide hydrolysis, whereas members of the second (mGlu2 and -3) and third (mGlu4, -6, -7 and -8) groups are coupled to a Gi protein. Novel potent and selective mGlu1 and -5 antagonists (CPCCOEt and MPEP, respectively) are neuroprotective in in vitro and in vivo models of excitotoxic death, suggesting that endogenous activation of rnGlu1 and -5 receptors facilitates neurodegeneration at least under particular circumstances. However, only the action of CPCCOEt and other selective mGlu1 receptor antagonists but not the action of MPEP - is abolished in the presence of GABAA and GABAB receceptor antagonists. The mGlu1 antagonists are able to enhance GABA release in microdialysis studies, suggesting that the main function of mGlul receptors is to inhibit GABAergic transmission. The mGlul antagonists might therefore be particularly useful under conditions in which neurodegeneration results from the loss of synaptic inhibition. The mGlu2/3 receptor agonists are also neuroprotective, but through an entirely different mechanism. These drugs, typified by the compound LY379268, stimulate glial mGlu3 receptors, thereby promoting the de novo synthesis of TGF-β1. This effect is mediated by the activation of the MAP kinase and phosphatidylinositol-3-kinase pathways. Specific inhibitors of these two pathways (i.e., the compounds PD98059 and LY294002) prevent both the increase in TGF-β1 and neuroprotection. TGF-β1 is endowed with neuroprotective activity against a variety of insults, including excitotoxins, β-amyloid peptide, oxygen-glucose deprivation, and the HIV coat protein, gp120. Hence, mGlu2/3 agonists might have a broad therapeutic application in acute and chronic CNS disorders.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
