ABSTRACT
Glutamate receptors and excitotoxicity are known to play a pivotal role in the pathogenesis of postischemic neuronal damage. N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists have demonstrated excellent neuroprotection in experimental studies but have failed in clinical trials. Calcium-permeable AMPA receptors and extrasynaptic NMDA receptors containing GluN2B may represent more attractive targets for future drugs. 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. In view of the recent discovery of a functional interaction between group I metabotropic glutamate 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.
