In addition to the therapeutic benefits derived from reductions in extracellular Glu, the neuroprotection resulting from GCP II inhibition can also arise from NAAG acting at several different excitatory amino acid receptors. NAAG has been shown to function as a partial agonist/antagonist at NMDA receptors.9-13 As a partial agonist (with reduced efficacy), NAAG would act as an NMDA receptor antagonist under conditions where synaptic concentrations of Glu are at or near saturation. On the other hand, Losi et al.14 reported a lack of antagonism of NAAG at synaptic or extrasynaptic NMDA receptors in cultured cerebellar granule cells. Very recently however, Bergeron et al.15 demonstrated that NAAG reduces NMDA receptor current in CA1 pyramidal neurons in slices from rat hippocampus and in dissociated neurons. The antagonism of NAAG at the NMDAR was shown to be overcome by glycine, suggesting that NAAG and glycine might compete at the glycine site on the NMDAR. Furthermore, it was suggested that elevated glycine levels in the culture media might account for the absence of NAAG antagonism at the NMDAR in some reports of in vitro studies.

NAAG has also been demonstrated to act as an agonist at group II metabotropic Glu receptors, with greatest selectivity being seen for group II mGluR3 receptors, which are found on both neuronal and glial cells.15,16,76 Group II metabotropic Glu receptors have been proposed to elicit neuroprotective actions through inactivation of voltage-sensitive calcium channels,77 inhibition of cAMP formation,78 and presynaptic reduction of Glu release.79 In addition, the importance of glial mGluR3 receptors to the neuroprotective effect of NAAG and 2-PMPA in certain experimental situations has recently been recognized and has been shown to involve the synthesis and release of TGF-p.47,49,52

In summary, inhibition of GCP II can be expected to reduce levels of Glu and to increase NAAG levels. Possibly, following inhibition of GCP II, NAAG could be neuroprotective via a variety of actions (e.g. via NMDAR, mGluR3 and/or TGF-P mediated mechanisms), and different pathways might predominate in a particular model system. Collectively, this expanding body of data points to potential actions of NAAG contributing to the neuroprotective effects of 2-PMPA.

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