The neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia.

N-Acetylaspartylglutamate (NAAG) is the most abundant and widely distributed peptide transmitter in the mammalian nervous system. NAAG activates the metabotropic glutamate mGlu(3) receptor at presynaptic sites, inhibiting the release of neurotransmitters, including glutamate, and activates mGlu(3) receptors on glial cells, stimulating the release of neuroprotective growth factors from these cells. Elevated levels of glutamate released from neurons are associated with the pathology of stroke, traumatic nervous system injury, amyotrophic lateral sclerosis, inflammatory and neuropathic pain, diabetic neuropathy and the schizophrenia-like symptoms elicited by phencyclidine. NAAG is inactivated by specific peptidases following its synaptic release. Novel compounds that inhibit these enzymes prolong the activity of synaptically released NAAG and have significant therapeutic efficacy in animal models of these diverse clinical conditions. In this review, we summarize recent studies in these animal models and discuss the mechanisms by which NAAG peptidase inhibitors achieve these effects.

Biosynthesis of NAAG by an enzyme-mediated process in rat central nervous system neurons and glia.

The peptide transmitter N-acetylaspartylglutamate (NAAG) is present in millimolar concentrations in mammalian spinal cord. Data from the rat peripheral nervous system suggest that this peptide is synthesized enzymatically, a process that would be unique for mammalian neuropeptides. To test this hypothesis in the mammalian CNS, rat spinal cords were acutely isolated and used to study the incorporation of radiolabeled amino acids into NAAG. Consistent with the action of a NAAG synthetase, inhibition of protein synthesis did not affect radiolabel incorporation into NAAG. Depolarization of spinal cords stimulated incorporation of radiolabel. Biosynthesis of NAAG by cortical astrocytes in cell culture was demonstrated by tracing incorporation of [3H]-glutamate by astrocytes. In the first test of the hypothesis that NAA is an immediate precursor in NAAG biosynthesis, [3H]-NAA was incorporated into NAAG by isolated spinal cords and by cell cultures of cortical astrocytes. Data from cerebellar neurons and glia in primary culture confirmed the predominance of neuronal synthesis and glial uptake of NAA, leading to the hypothesis that while neurons synthesize NAA for NAAG biosynthesis, glia may take it up from the extracellular space. However, cortical astrocytes in serum-free low-density cell culture incorporated [3H]-aspartate into NAAG, a result indicating that under some conditions these cells may also synthesize NAA. Pre-incubation of isolated spinal cords and cultures of rat cortical astrocytes with unlabeled NAA increased [3H]-glutamate incorporation into NAAG. In contrast, [3H]-glutamine incorporation in spinal cord was not stimulated by unlabeled NAA. These results are consistent with the glutamate-glutamine cycle greatly favoring uptake of glutamine into neurons and glutamate by glia and suggest that NAA availability may be rate-limiting in the synthesis of NAAG by glia under some conditions.