Degenerative diseases or injuries to the central nervous system (CNS) are believed to result in elevations of extracellular concentrations of the excitatory amino acid neurotransmitter Glu which, through excessive stimulation of excitatory amino acid receptors, including NMDARs, can evoke a cascade of disruption of intracellular processes inducing cell dysfunction and death.42-44 Although a number of pharmacological agents that selectively antagonize the action of Glu at its receptors have been shown to reduce injury in experimental models of cerebral ischemia and trauma, none have yet been effective in clinical trials, due primarily to unacceptable side effects.45 Consequently, to some extent the focus for development of therapeutic agents has shifted away from NMDA receptor antagonists and has been expanded to include alternative means to interrupt this Glu-mediated excitotoxic cascade.
Because Glu is a product of hydrolysis of NAAG via GCP II activity, NAAG is a potentially important source of synaptic Glu under pathophysiological conditions, and inhibition of GCP II has been considered a promising alternative neuroprotective strategy. Because of its reciprocal influence on the synaptic concentrations of NAAG and Glu, GCP II has recently been identified as a potentially important therapeutic target to pharmacologically counter the Glu-mediated excitotoxic cascade associated with stroke or traumatic injury.46 In particular, in addition to reducing pathophysiological^ deleterious concentrations of extracellular Glu, it has been envisioned that by promoting the extracellular accumulation of NAAG, GCP II inhibitors can elicit neuroprotective mechanisms that are mediated through both neuronal and glial group II metabotropic Glu receptors, since NAAG is a relatively potent and selective agonist at these receptors,15'17'47 which have been shown to mediate neuroprotection through presynaptic inhibition of Glu release and through induction of TGF-P synthesis and release.17,48,49
2-phosphonyl-methyl pentanedioc acid (2-PMPA), a potent inhibitor of GCP II, has been shown to protect against acute neuronal injury caused by middle cerebral artery occlusion (MCAo) in vivo46; and also to protect against injury by metabolic inhibition, hypoxia, or excitatory amino acid exposure in vitro.47,50-52 In the MCAo study, reductions in extracellular Glu and elevations in extracellular NAAG concentrations were reported to occur after administration of 2-PMPA.43
Inhibitors of GCP II have also been shown to be therapeutically effective when administered chronically in a rodent model of hereditary motoneuron disease. Ten percent of patients with ALS suffer from a familial subtype (FALS) of the disease, and of those 20% are caused by mutations of copper/zinc superoxide dismutase type 1 (SOD1). Glu toxicity has been implicated in ALS, including the familial type. Rodents carrying mutant SOD1 have motoneuron degeneration similar to patients with ALS. GCP II inhibitors have been shown to be protective in vitro in cultured neurons transfected with mutant SOD1, as well as in vivo in G93A FALS transgenic mice carrying the SOD1 mutation53. Chronic treatment with 2-MPPA [2-(3-mercaptopropyl)pentanedioc acid], an orally-adminstered analog of 2-PMPA, increased longevity and delayed the onset of 4 out of 5 rated neurological motor symptoms in the G93A FALS transgenic mice. In cultured rat motoneurons transduced to express mutant SOD1, treatment with 2-PMPA was neuroprotective. Interestingly, however, the protective effects of 2-PMPA were not diminished by co-administration of either the group II mGluR antagonist EGLU [(2S)-alpha-ethylglutamic acid] or an antibody against TGF-beta. The authors concluded that in that sytem, the neuroprotective effects of 2-PMPA were mediated neither via TGF-beta nor through the effects of NAAG on mGluR3 receptors.
2-PMPA has been reported to be highly selective for GCP II, and shown not to interact with a range of receptors,46 and discussion continues on the latter point.2,54,55
Repeated administration of 2-PMPA was also shown to be effective in enhancing recovery in an in vivo model of peripheral nerve injury. Four weeks of daily oral administration of a GCP II activity inhibitor was reported to improve nerve morphology, physiology and endurance in a walking test after sciatic nerve crush injury.56 Thus, evidence is accumulating that inhibition of catabolism of NAAG may have significant potential as a therapy for neuronal injury as well as for neurodegenerative disorders.
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