Glutamate (Glu) is the most abundant excitatory transmitter in the central nervous system. However, excessive glutamatergic transmission can damage or kill neurons, and has therefore been implicated in a variety of neurological disorders.
N-Acetyl-L-aspartyl-L-glutamate (NAAG), one of the three most prevalent neurotransmitters, acts as an agonist at group II metabotropic glutamate receptors with preference for metabotropic glutamate (mGlu3) receptors on neurons and glia. Two extracellular enzymes, glutamate carboxypeptidase II and III (GCPII and III), hydrolyse NAAG to N-acetylaspartate (NAA) and glutamate following its release into the synaptic cleft.
Inhibition of these NAAG peptidases (NPs) is thought to provide neuroprotection by increasing the intrasynaptic concentration of NAAG. NAAG decreases the release of glutamate by activation of presynaptic group II mGlu receptors and stimulates release of trophic factors from glia. Those actions of NAAG may provide neuroprotection in clinical conditions in which glutamate mediates and mGlu3 receptor activation reduces pathology.
Importantly, NP inhibitors do not seem to affect normal glutamate function. NP inhibition enhances a natural ongoing regulatory process rather than chronically activating or inhibiting receptors in a manner that is unrelated to ongoing chemical neurotransmission. NP represents an intriguing target for drug discovery aimed at unmet medical needs.
Additionally, human GCPII has also been identified as prostate-specific membrane antigen (PSMA), a cell surface protein expressed in elevated levels by prostate cancer. Its X-ray crystal structure was recently reported.
Studies using small-molecule-based NP inhibitors have confirmed their beneficial effects in animal models relevant to neurodegenerative diseases as well as cancer.
NP inhibitors therefore have significant potential for use as both diagnostic and therapeutic agents. Specific applications include neuropathic and inflammatory pain, traumatic brain injury, ischemic stroke, schizophrenia, diabetic neuropathy, amyotrophic lateral sclerosis, drug addiction, as well as prostate cancer.
Modulation of N-acetyl-L-aspartyl-L-glutamate peptidase activity with small-molecule inhibitors holds promise for a wide variety of diseases that involve glutamatergic transmission, and has implications for the diagnosis and therapy of cancer. This new class of compounds, of which at least one has entered clinical trials and proven to be well tolerated, has demonstrated efficacy in experimental models of pain, schizophrenia, amyotrophic lateral sclerosis, traumatic brain injury and, when appropriately functionalized, can image prostate cancer. Further investigation of these promising drug candidates will be needed to bring them to the marketplace. The recent publication of the X-ray crystal structure for the enzymatic target of these compounds should facilitate the development of other new agents with enhanced activity that could improve both the diagnosis and treatment of neurological disorders.
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Research and Markets. Neuroprotection — Drugs, Markets and Companies [online], <http://www.researchandmarkets.com/reportinfo.asp?cat_id=0&report_id=39073&q=neuroprotection&p=1> (2005).
Conn, P. J. Physiological roles and therapeutic potential of metabotropic glutamate receptors. Ann. NY Acad. Sci. 1003, 12–21 (2003).
Whelan, J. NAALADase inhibitors: a novel approach to glutamate regulation. Drug Discov. Today 5, 171–172 (2000).
Neale, J. H., Bzdega, T. & Wroblewska, B. N-Acetylaspartylglutamate: the most abundant peptide neurotransmitter in the mammalian central nervous system. J. Neurochem. 75, 443–452 (2000). An excellent review that extensively describes the roles of NAAG.
Coyle, J. T. The nagging question of the function of N-acetylaspartylglutamate. Neurobiol. Dis. 4, 231–238 (1997).
Wroblewska, B., Wroblewski, J. T., Pshenichkin, S., Surin, A., Sullivan, S. E. & Neale, J. H. N-Acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J. Neurochem. 69, 174–182 (1997).
Wroblewska, B., Santi, M. R. & Neale, J. H. N-Acetylaspartylglutamate activates cyclic-AMP coupled metabotropic glutamate receptors in cerebellar astrocytes. Glia 24, 172–180 (1998).
Wroblewska, B., Wroblewski, J. T., Saab, O. & Neale, J. H. N-Acetylaspartylglutamate inhibits forskolin-stimulated cyclic AMP levels via a metabotropic glutamate receptor in cultured cerebellar granule cells. J. Neurochem. 61, 943–948 (1993).
Wroblewska, B., Wegorzewska, I. N., Bzdega, T., Olszewski, R. T. & Neale, J. H. Differential negative coupling of type 3 metabotropic glutamate receptor to cGMP levels in neurons and astrocytes. J. Neurochem. (in the press).
Cartmell, J. & Schoepp, D. D. Regulation of neurotransmitter release by metabotropic glutamate receptors. J. Neurochem. 75, 889–907 (2000). Outstanding review that addresses the neurochemical evidence for mGluR-mediated regulation of neurotransmitters.
Varney, M. A. & Gereau, R. W. Metabotropic glutamate receptor involvement in models of acute and persistent pain: Prospects for the development of novel analgesics. Curr. Drug Targets CNS Neurol. Disord. 1, 283–296 (2002).
Riveros, N. & Orrego, F. A study of possible excitatory effects of N-acetylaspartylglutamate in different in vivo and in vitro brain preparations. Brain Res. 299, 393–395 (1984).
Robinson, M. B., Blakely, R. D., Couto, R. & Coyle, J. T. Hydrolysis of the brain dipeptide N-acetyl-L-aspartyl-L-glutamate. J. Biol. Chem. 262, 14498–14506 (1987).
Carter, R. E., Feldman, A. R. & Coyle, J. T. Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic characteristics of a neuropeptidase. Proc. Natl Acad. Sci. USA 93, 749–753 (1996).
Bzdega, T. et al. Molecular cloning of a peptidase against N-acetylaspartylglutamate (NAAG) from a rat hippocampal cDNA library. J. Neurochem. 69, 2270–2277 (1997).
Bzdega, T. et al. The cloning and characterization of a second brain enzyme with NAAG peptidase activity. J. Neurochem. 89, 627–635 (2004).
O'Keefe, D. S. et al. Mapping, genomic organization and promoter analysis of the human prostate-specific membrane antigen gene. Biochim. Biophys. Acta 1443, 113–127 (1998).
Bacich, D. J., Pinto, J. T., Tong, W. P. & Heston, W. D. Cloning, expression, genomic localization, and enzymatic activities of the mouse homolog of prostate-specific membrane antigen/NAALADase/folate hydrolase. Mamm. Genome 12, 117–123 (2001).
Zhao, J. et al. NAAG inhibits [3H]-GABA release from cortical neurons via the type 3 metabotropic glutamate receptor. Eur. J. Neurosci. 13, 340–346 (2001).
Sanabria, E. R., Wozniak, K. M., Slusher, B. S. & Keller, A. GCP II (NAALADase) Inhibition suppresses mossy fiber-CA3 synaptic neurotransmission by a presynaptic mechanism. J. Neurophysiol. 91, 182–193 (2004).
Bruno, V., Wroblewska, B., Wroblewski, J. T., Fiore & L. & Nicoletti, F. Neuroprotective activity of N-acetylaspartylglutamate in cultured cortical cells. Neurosci. 85, 751–757 (1998).
Slusher, B. S. et al. Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nature Med. 5, 1396–1402 (1999).
Thomas, A. G. et al. Neuroprotection mediated by glutamate carboxypeptidase II (NAALADase) inhibition requires TGF-β. Eur. J. Pharmacol. 430, 33–40 (2001).
Jackson, P. F. et al. Design, synthesis, and biological activity of a potent inhibitor of neuropeptidase N-acetylated-α-linked acidic dipeptidase. J. Med. Chem. 39, 619–622 (1996).
Yourick, D. L., Koenig, M. L., Durden,. & Long, J. B. N-acetylaspartylglutamate and β-NAAG protect against injury induced by NMDA and hypoxia in primary spinal cord cultures. Brain Res. 991, 56–64 (2003).
Parsons, C. G., Danysz, W. & Quack, G. Glutamate in CNS disorders as a target for drug development: an update. Drug News Perspect. 11, 523–569 (1998). Excellent review that describes the role of glutamate in CNS disorders.
van der Post, J. P. et al. The central nervous system effects, pharmacokinetics and safety of the NAALADase-inhibitor GPI 5693. Br. J. Clin. Pharmacol. 60, 128–136 (2005).
Speno, H. S. et al. Site-directed mutagenesis of predicted active site residues in glutamate carboxypeptidase II. Mol. Pharmacol. 55, 179–185 (1999). An important paper describing the enzyme structure and function of GCPII.
Tsai, G. et al. Early embryonic death of glutamate carboxypeptidase II (NAALADase) homozygous mutants. Synapse 50, 285–292 (2003).
Maras, B. et al. Aminopeptidase from Streptomyces griseus: primary structure and comparison with other zinc containing aminopeptidases. Eur. J. Biochem. 236, 843–846 (1996).
van Heeke, G., Denslow, S., Watkins, J., Wilson, K. & Wagner, F. Cloning and nucleotide sequence of the Vibrio proteolyticus aminopeptidase gene. Biochim. Biophys. Acta 1131, 337–340 (1992).
Heston, W. D. Significance of prostate-specific membrane antigen (PSMA). A neurocarboxypeptidase and membrane folate hydrolase. Urologe A. 35, 400–407 (1996).
Rawlings, N. D. & Barrett, A. J. Structure of membrane glutamate carboxypeptidase. Biochim. Biophys. Acta 1339, 247–252 (1997).
Mahadevan, D. & Saldanha, J. W. The extracellular regions of PSMA and the transferring receptor contain an aminopeptidase domain: implications for drug design. Protein Sci. 8, 2546–2549 (1999).
Rong, S. B. et al. Molecular modeling of the interactions of glutamate carboxypeptidase II with its potent NAAG-based inhibitors. J. Med. Chem. 45, 4140–4152 (2002). An outstanding paper describing the molecular modelling of NAAG peptidase inhibitors.
Davis, M. I., Bennett, M. J., Thomas, L. M. & Bjorkman, P. J. Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proc. Natl Acad. Sci. USA 102, 5981–5986 (2005). An outstanding paper that describes the crystal structure of PSMA (GCPII) peptidase.
Subasinghe, N. et al. Synthesis of acyclic and dehydroaspartic acid analogues of Ac-Asp-Glu-OH and their inhibition of rat brain N-acetylated-linked acidic dipeptidase (NAALA dipeptidase). J. Med. Chem. 33, 2734–2744 (1990).
Serval, V., Galli, T., Cheramy, A., Glowinski, J. & Lavielle, S. In vitro and in vivo inhibition of N-acetyl-L-aspartyl-L-glutamate catabolism by N-acylated-L-glutamate analogs. J. Pharmacol. Exp. Ther. 260, 1093–1100 (1992).
Jackson, P. F. & Slusher, B. S. Design of NAALADase inhibitors: a novel neuroprotective strategy. Curr. Med. Chem. 8, 949–957 (2001). An important and early review describing NAAG peptidase inhibitors of phosphinic acid derivatives.
Bennett, B. & Holz, R. C. Inhibition of the aminopeptidase from Aeromonas Proteolytica by L-leucinephosphonic acid, a transition state analogue of peptide hydrolysis. J. Am. Chem. Soc. 120, 12139–12140 (1998).
Jackson, P. F. et al. Design and pharmacological activity of phosphinic acid based NAALADase inhibitors. J. Med. Chem. 44, 4170–4175 (2001).
Tsukamoto, T. et al. Phosphonate and phosphinate analogues of N-acylated-glutamylglutamate: Potent inhibitors of glutamate carboxypeptidase II. Bioorg. Med. Chem. Lett. 12, 2189–2192 (2002).
Tang, H. et al. Prostate targeting ligands based on N-acetylated α-linked acidic dipeptidase. Biochem. Biophys. Res. Commun. 307, 8–14 (2003).
Oliver, A. J., Wiest, O., Helquist, P., Miller, M. J. & Tenniswood, M. Conformational and SAR analysis of NAALADase and PSMA inhibitors. Bioorg. Med. Chem. 11, 4455–4461 (2003).
Maung, J. et al. Probing for a hydrophobic a binding register in prostate-speci. c membrane antigen with phenylalkylphosphonamidates. Bioorg. Med. Chem. 12, 4969–4979 (2004).
Tsukamoto, T. et al. Enantiospecificity of glutamate carboxypeptidase II inhibition. J. Med. Chem. 48, 2319–2324 (2005).
Vitharana, D. et al. Synthesis and biological evaluation of (R)- and (S)-2-(phosphonomethyl)pentanedioic acids as inhibitors of glutamate carboxypeptidase II. Tetrahedron: Asymm. 13, 1609–1614 (2002).
Majer, P. et al. Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: Discovery of an orally active GCP II inhibitor. J. Med. Chem. 46, 1989–1996 (2003).
Tsukamoto, T., Grella, B. & Majer, P. Indoles as NAALADase inhibitors. US patent 2005/0080128A1. April 14, 2005.
Stoermer, D. et al. Synthesis and biological evaluation of hydroxamate-based Inhibitors of glutamate Carboxypeptidase II. Bioorg. Med. Chem. Lett. 13, 2097–2100 (2003).
Ding, P. et al. Syntheses of conformationally constricted molecules as potential NAALADase/PSMA inhibitors. Org. Lett. 6, 1805–1808 (2004).
Maison, W., Grohs, D. C. & Prenzel, A. H. G. P. Efficient synthesis of structurally diverse diazabicycloalkanes: scaffolds for modular dipeptide mimetics with tunable backbone conformations. Eur. J. Org. Chem. 17, 1527–1543 (2004).
Grohs, D. C. & Maison, W. Synthesis of modular dipeptide mimetics on the basis of diazabicycloalkanes and derivatives thereof with sulphur containing side chains. Amino Acids 29, 131–138 (2005).
Nan, F. et al. Dual function glutamate-related ligands: Discovery of a novel, potent inhibitor of glutamate carboxypeptidase II possessing mGluR3 agonist activity. J. Med. Chem. 43, 772–774 (2000).
Kozikowski, A. P. et al. Design of remarkably simple, yet potent urea-based inhibitors of glutamate carboxypeptidase II (NAALADase). J. Med. Chem. 44, 298–301 (2001).
Kozikowski, A. P. et al. Synthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II: efficacy as analgesic agents. J. Med. Chem. 47, 1729–1738 (2004).
Yamamoto, T., Nozaki-Taguchi, N. & Sakashita, T. Spinal N-acetylated-α-linked acidic dipeptidase (NAALADase) inhibition attenuates mechanical allodynia induced by paw carrageenan injection in the rat. Brain Res. 909, 138–144 (2001).
Yamamoto, T., Nozaki-Taguchi, N., Sakashita, Y. & Inagaki, T. Inhibition of spinal N-acetylated-α-linked acidic dipeptidase produces an antinociceptive effect in the rat formalin test. Neurosci. 102, 473–479 (2001).
Chen, S. R., Wozniak, K. M., Slusher, B. S. & Pan, H. L. Effect of 2-(phosphonomethyl)-pentanedioic acid on allodynia and afferent ectopic discharges in a rat model of neuropathic pain. J. Pharmacol. Exp. Ther. 300, 662–667 (2002).
Carpenter, K. J. et al. Effects of GCP-II inhibition on responses of dorsal horn neurones after inflammation and neuropathy: an electrophysiological study in the rat. Neuropeptides 37, 298–306 (2003).
Yamamoto, T. et al. Antinociceptive effects of N-acetylaspartylglutamate (NAAG) peptidase inhibitors ZJ 11, ZJ 17 and ZJ 43 in the rat formalin test and in the rat neuropathic pain model. Eur. J. Neurosci. 20, 483–494 (2004).
Losi, G., Vicini, S. & Neale, J. NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons. Neuropharmacology 46, 490–496 (2004).
Bergeron, R., Coyle, J. T., Tsai, G. & Greene, R. W. NAAG reduces NMDA receptor current in CA1 hippocampal pyramidal neurons of acute slices and dissociated neurons. Neuropsychopharmacology 30, 7–16 (2005).
Narayan, R. K. &, Michael, M. E. The clinical trials in head injury study group. Clinical trials in head injury. J. Neurotrauma 19, 503–557 (2002).
Murray, C. J. L. & Lopez, A. D. Global mortality, disability and the contribution of the risk factors: global burden of disease study. Lancet 349, 1436–1442 (1997).
Tolias, C. M. & Bullock, M. R. Critical appraisal of neuroprotection trials in head injury: what have we learned? J. Am. Soc. Exp. NeuroTherapeutics 1, 71–79 (2004). An outstanding review that describes the recent development of drug discovery in head injury.
Faden, A. I., Demediuk, P., Panter, S. S. & Vink, R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244, 798–800 (1989).
Katayama, Y., Becker, D. P., Tamura, T. & Hovda, D. A. Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J. Neurosurg. 73, 889–900 (1990).
Globus, M. Y., Alonso, O., Dietrich, W. D., Busto, R. & Ginsberg, M. D. Glutamate release and free radical production following brain injury. J. Neurochem. 65, 1704–1711 (1995).
Bullock, R., Lyeth, B. G. & Muizelaar, J. P. Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. Neurosurgery 45, 207–217 (1999).
Zhong, C. et al. NAAG peptidase inhibitor reduces acute neuronal degeneration and astrocyte damage following lateral fluid percussion TBI in rats. J. Neurotrauma 22, 266–276 (2005).
Xiong, Z. et al. Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels. Cell 118, 687–698 (2004).
Martin, L. et al. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res. Bull. 46, 281–309 (1998).
Muir, K. & Grosset, D. Neuroprotection for acute stroke: making clinical trials work. Stroke 30, 180–182 (1999).
Williams, A. J., Lu, X. M., Slusher, B. & Tortella, F. C. Electroencephalogram analysis and neuroprotective profile of the N-acetylated-α-linked acidic dipeptidase inhibitor, GPI5232, in normal and brain-injured rats. J. Pharmacol. Exp. Ther. 299, 48–57 (2001).
Cai, Z., Lin, S. & Rhodes, P. G. Neuroprotective effects of N-acetylaspartylglutamate in a neonatal rat model of hypoxia-ischemia. Eur. J. Pharmacol. 437, 139–45 (2002).
Carlsson, A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1, 179–186 (1988).
Tsai, G. et al. Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch. Gen. Psychiatry 52, 829–836 (1995).
Flores, C. & Coyle, J. T. Regulation of glutamate carboxypeptidase II function in corticolimbic regions of rat brain by phencyclidine, haloperidol, and clozapine. Neuropsychopharmacology 28, 1227–1234 (2003).
Tsai, G. & Coyle, J. T. Glutamatergic mechanisms in schizophrenia. Annu. Rev. Pharmacol. Toxicol. 42, 165–179 (2002).
Marek, G. J. Glutamate and schizophrenia: pathophysiology and therapeutics. Curr. Med. Chem.-Central Nervous System Agents 2, 29–44 (2002). Excellent review that describes the involvement of glutamatergic neurotransmission in schizophrenia as well as the relevant therapeutics.
McCarley, R. W. et al. Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects. Eur. Arch. Psychiatry Clin. Neurosci. 249, (Suppl. 4), 69–82 (1999).
Johnstone, M., Evans, V., Baigel, S. Sernyl (Cl-395) in clinical anaesthesia. J. Anaesth. 31, 433–439 (1959).
Luby, E. D., Cohen, B. D., Rosenbaum, F., Gottlieb, J. & Kelley, R. Study of a new schizophrenomimetic drug, Sernyl. Arch. Neurol. Psychiatry 81, 363–369 (1959).
Javitt, D. C. & Zukin, S. R. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry 148, 1301–1308 (1991).
Krystal, J. H. et al. NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harv. Rev. Psychiatry 7, 125–143 (1999).
Moghaddam, B. & Adams, B. W. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352 (1998).
Cartmell, J., Monn, J. A. & Schoepp, D. D. The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J. Pharmacol. Exp. Ther. 291, 161–170 (1999).
Olszewski, R. T. et al. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J. Neurochem. 89, 876–885 (2004).
Sima, A. A. F. Diabetic neuropathy: pathogenetic background, current and future therapies. Expert Rev. Neurotherapeutics 1, 225–238 (2001).
Berent-Spillson, A. et al. Protection against glucose-induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3. J. Neurochem. 89, 90–99 (2004).
Rosson, G. D., Dellon, A. L. Vascular risk factors and diabetic neuropathy. N. Engl. J. Med. 352, 1925–1927 (2005).
Cameron, N. E. & Cotter, M. A. in Chronic Complications in Diabetes. Oxidative Stress and Abnormal Lipid Metabolism in Diabetic Complication. Frontiers in Animal Diabetes Research vol. 1 (ed. Sima, A. A. F.) 97–130 (Harwood, Amsterdam, 2000).
Coppey, L. J., Davidson, E. P., Dunlap, J. A., Lund, D. D. & Yorek, M. A. Slowing of motor nerve conduction velocity in streptozotocin-induced diabetic rats is preceded by impaired vasodilatation in arterioles that overlie the sciatic nerve. Int. J. Exp. Diabetes Res. 1, 131–143 (2000).
Srinivasan, S., Stevens, M. & Wiley, J. W. Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. Diabetes 49, 1932–1938 (2000).
Tomiyama, M. et al. Upregulation of mRNAs coding for AMPA and NMDA receptor subunits and metabotropic glutamate receptors in the dorsal horn of the spinal cord in a rat model of diabetes mellitus. Brain Res. Mol. Brain Res. 136, 275–281 (2005).
Zhang, W. et al. GCPII (NAALADase) inhibition prevents long-term diabetic neuropathy in type 1 diabetic BB/Wor rats. J. Neurological Sci. 194, 21–28 (2002).
National Institute of Neurological Disorders and Stroke. Neuroscience news [online] <http://www.ninds.nih.gov/index.htm> (2005).
Cleveland, D. W. & Rothstein, J. D. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nature Rev. Neurosci. 2, 806–819 (2001).
Cluskey, S. & Ramsden, D. B. Mechanisms of neurodegeneration in amyotrophic lateral sclerosis. Mol. Pathol. 54, 386–392 (2001).
Bruneteau, G., Demeret, S. & Meininger, V. Physiopathology of ALS: therapeutic approach. Rev. Neurol. (Paris) 160, 235–241 (2004).
McGeer, E. G., & McGeer, P. L. Pharmacologic approaches to the treatment of amyotrophic lateral sclerosis. BioDrugs 19, 31–37 (2005).
Kwak, S. & Kawahara, Y. Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J. Mol. Med. 83, 110–120 (2005).
Rembach, A. et al. Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS. J. Neurosci. Res. 77, 573–582 (2004).
Vanoni, C. et al. Increased internalisation and degradation of GLT-1 glial glutamate transporter in a cell model for familial amyotrophic lateral sclerosis (ALS). J. Cell Sci. 117, 5417–5426 (2004).
Iwasaki, Y., Ikeda, K. & Kinoshita, M. Molecular and cellular mechanism of glutamate receptors in relation to amyotrophic lateral sclerosis. Curr. Drug Targets 1, 511–518 (2002).
Ghadge, G. D. et al. Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models. Proc. Natl Acad. Sci. USA 100, 9554–9559 (2003).
Zhou, J. et al. Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: Synthesis and evaluation of their uptake inhibition at monoamine transporter sites. J. Med. Chem. 46, 1997–2007 (2003).
Kalivas, P. W. Glutamate systems in cocaine addiction. Curr. Opin. Pharmacol. 4, 23–29 (2004).
Kalivas, P. W. et al. Glutamate transmission and addiction to cocaine. Ann. N. Y. Acad. Sci. 1003, 169–175 (2003).
Baker, D. A. et al. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nature Neurosci. 6, 743–749 (2003).
Sutton, M. A. et al. Extinction-induced upregulation in AMPA receptors reduces cocaine seeking behaviour. Nature 421, 70–75 (2003).
Robbe, D., Bockaert, J. & Manzoni, O. J. Metabotropic glutamate receptor 2/3-dependent long-term depression in the nucleus accumbens is blocked in morphine withdrawn mice. Eur. J. Neurosci. 16, 2231–2235 (2002).
Vekovischeva, O. Y. et al. Morphine-induced dependence and sensitization are altered in mice deficient in AMPA-type glutamate receptor-A subunits. J. Neurosci. 21, 4451–4459 (2001).
Watkins, S. S., Koob, G. F. & Markou, A. Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine Tob. Res. 2, 19–37 (2000).
De Witte, P. Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol. Addict. Behav. 29, 1325–1339 (2004).
Spanagel, R. The role of the glutamatergic system in alcohol addiction. Fortschr. Neurol. Psychiatr. 71, (Suppl 1), S33–S35 (2003).
Tessari, M., Pilla, M., Andreoli, M., Hutcheson, D. M. & Heidbreder, C. A. Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. Eur. J. Pharmacol. 499, 121–133 (2004).
Kenny, P. J. & Markou, A. The ups and downs of addiction: role of metabotropic glutamate receptors. Trends Pharmacol. Sci. 25, 265–272 (2004).
Lovinger, D. M., Partridge, J. G. & Tang, K. C. Plastic control of striatal glutamatergic transmission by ensemble actions of several neurotransmitters and targets for drugs of abuse. Ann. N. Y. Acad. Sci. 1003, 226–240 (2003).
Tzschentke, T. M. & Schmidt, W. J. Glutamatergic mechanisms in addiction. Mol. Psychiatr. 8, 373–382 (2003).
Heidbreder, C. Recent advances in the pharmacotherapeutic management of drug dependence and addiction. Curr. Psychiatry Rev. 1, 45–67 (2005). Outstanding review that summarizes the most promising therapeutic strategies in the field of drug abuse.
Slusher, B. S., Thomas, A., Paul, M., Schad, C. A. & Ashby, Jr., C. R. Expression and acquisition of the conditioned place preference response to cocaine in rats is blocked by selective inhibitors of the enzyme N-acetylated-α-linked-acidic dipeptidase (NAALADase). Synapse 41, 22–28 (2001).
Witkin, J. M. et al. NAALADase (GCP II) inhibition prevents cocaine-kindled seizures. Neuropharmacology 43, 348–356 (2002).
Popik, P., Kozela, E., Wrobel, M., Wozniak, K. M. & Slusher, B. S. Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selective glutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA. Neuropsychopharmacology 28, 457–467 (2003).
Mckinzie, D. L., Li, T. -K., Mcbride, W. J. & Slusher, B. S. NAALADase inhibition reduces alcohol consumption in the alcohol-preferring (P) line of rats. Addict. Biol. 5, 411–416 (2000).
Senkowska, A. & Ossowska, K. Role of metabotropic glutamate receptors in animal models of Parkinson's disease. Pol. J. Pharmacol. 55, 935–950 (2003).
Kieburtz, K. Antiglutamate therapies in Huntington's disease. J. Neural Transm. Suppl. 55, 97–102 (1999).
Hynd, M. R., Scott, H. L. & Dodd, P. R. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochem. Int. 45, 583–595 (2004).
Lee Q. et al. Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer's disease. Acta. Neuropathol. (Berl). 107, 365–371 (2004).
Jaarsma, D., Veenma-van der Duin, L. & Korf, J. N-Acetylaspartate and N-acetylaspartylglutamate levels in Alzheimer's disease post-mortem brain tissue. J. Neurol. Sci. 127, 230–233 (1994).
Passani, L. A., Vonsattel, J. P. & Coyle, J. T. Distribution of N-acetylaspartylglutamate immunoreactivity in human brain and its alteration in neurodegenerative disease. Brain Res. 772, 9–22 (1997).
Passani, L. A., Vonsattel, J. P., Carter, R. E. & Coyle, J. T. N-Acetylaspartylglutamate, N-acetylaspartate, and N-acetylated α-linked acidic dipeptidase in human brain and their alterations in Huntington and Alzheimer's diseases. Mol. Chem. Neuropathol. 31, 97–118 (1997).
Jemal, A., Thomas, A., Murray, T. & Thun, M. Cancer statistics. CA Cancer J. Clin. 52, 23–47 (2002).
Leach, F. Targeting prostate-specific membrane antigen in cancer therapy: can molecular medicine be brought to the surface? Cancer Biol. Ther. 3, 559–560 (2004).
Chang, S. S. et al. Prostate-specific membrane antigen is produced in tumor-associated neovasculature. Clin. Cancer Res. 5, 2674–2681 (1999).
Chang, S. S. et al. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res. 59, 3192–3198 (1999).
Chang, S. S. Monoclonal antibodies and prostate specific membrane antigen. Curr. Opin. Investig. Drugs 5, 611–615 (2004).
Ghosh, A. & Heston, W. D. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J. Cell Biochem. 91, 528–539 (2004).
Gong, M. C. et al. Overview of evolving strategies incorporating prostate-specific membrane antigen as target for therapy. Mol. Urol. 4, 217–222 (2000).
Chang, S. S. & Heston, W. D. The clinical role of prostate-specific membrane antigen (PSMA). Urol. Oncol. 7, 7–12 (2002).
She, Y. et al. 2-MPPA, a selective inhibitor of PSMA, delays prostate cancer growth and attenuates taxol-induced neuropathy in mice. Am. Soc. Clin. Oncol. Annu. Mtg Alexandria, Virginia May 13–17 (2005).
Milowsky, M. I. et al. Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer. J. Clin. Oncol. 22, 2522–2531 (2004).
Nargund, V. et al. Imaging with radiolabelled monoclonal antibody (MUJ591) to prostate-specific membrane antigen in staging of clinically localized prostatic carcinoma: comparison with clinical, surgical and histological staging. BJU Int. 95, 1232–1236 (2005).
Pomper, M. G. et al. 11C-MCG: Synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase). Mol. Imaging 1, 96–101 (2002).
Foss, C. A. et al. Radiolabeled small-molecule ligands for prostate-specific membrane antigen: In vivo imaging in experimental models of prostate cancer. Clin. Cancer Res. 11, 4022–4028 (2005). A key paper that describes NAAG peptidase inhibitors as promising PET/SPECT imaging ligands for prostate cancer.
Tasch, J., Gong, M., Sadelain, M. & Heston, W. D. A unique folate hydrolase, prostate-specific membrane antigen (PSMA): a target for immunotherapy? Crit. Rev. Immunol. 21, 249–261 (2001).
The authors thank W. Tueckmantel of Acenta Discovery, Inc. for helpful discussions. This work was supported by the National Institutes of Health (NIH), including a National Institute of Mental Health grant, National Institute of Neurological Disorders and Stroke grants and a National Cancer Institute grant.
The authors declare no competing financial interests.
An agent that reduces nerve cell death, particularly that resulting from excess glutamate release.
Loss of blood flow to a tissue; in this review we primarily consider loss of blood flow to the nervous system.
Receptors that are also ion channels.
Receptors that are not ion channels but rather are coupled to second-messenger cascades.
Neurons using glutamate as one of their neurotransmitters.
An increase in pain perception above the normal response to a stimulus.
An agent that induces a psychotic-like state.
An extension of a nerve cell that is used to communicate information back to the body of the cell.
- SUPEROXIDE DISMUTASE
An enzyme that mediates the conversion of toxic superoxide radicals to peroxide and then to oxygen and water.
A monoclonal antibody to the prostate-specific membrane antigen labeled with indium-111 for the detection of prostate cancer.
- POSITRON-EMISSION TOMOGRAPHY
A noninvasive, molecular imaging technique of high sensitivity that detects species labelled with positron-emitting radionuclides in vivo.
The suitability of a lead candidate that has the requisite physico-chemical/absorption, distribution, metabolism and excretion properties for development as a drug candidate.
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Zhou, J., Neale, J., Pomper, M. et al. NAAG peptidase inhibitors and their potential for diagnosis and therapy. Nat Rev Drug Discov 4, 1015–1026 (2005). https://doi.org/10.1038/nrd1903
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