Neuroprotective and symptomatic effects of targeting group III mGlu receptors in neurodegenerative disease

Journal of Neurochemistry

Volumn 129, Issue 1, 2014, Pages 4-20

  Williams, Claire J ^a   Dexter, David T ^a  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

Alzheimer's disease; glutamate; group III mGlu receptor; neuroinflammation; neuroprotection; Parkinson's disease

Indexed keywords

CENTRAL NERVOUS SYSTEM AGENTS; GLUTAMIC ACID; METABOTROPIC RECEPTOR 1 ANTAGONIST; METABOTROPIC RECEPTOR 3; METABOTROPIC RECEPTOR 3 AGONIST; METABOTROPIC RECEPTOR 4 AGONIST; METABOTROPIC RECEPTOR AGONIST; METABOTROPIC RECEPTOR ANTAGONIST; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; POSITIVE AND NEGATIVE ALLOSTERIC MODULATOR; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; AMINO ACID TRANSPORT; ASTROCYTE; CENTRAL NERVOUS SYSTEM DISEASE; DEGENERATIVE DISEASE; DISEASE COURSE; DRUG MECHANISM; DRUG POTENTIATION; DRUG RESEARCH; DRUG TARGETING; EXCITOTOXICITY; GLIA; HUMAN; NERVE STIMULATION; NERVOUS SYSTEM INFLAMMATION; NEUROMODULATION; NEUROPROTECTION; NEUROTRANSMITTER RELEASE; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; REVIEW; SIGNAL TRANSDUCTION; SYMPTOM;

ALZHEIMER'S DISEASE; GLUTAMATE; GROUP III MGLU RECEPTOR; NEUROINFLAMMATION; NEUROPROTECTION; PARKINSON'S DISEASE;

ANIMALS; DRUG DELIVERY SYSTEMS; EXCITATORY AMINO ACID AGONISTS; HUMANS; NEURODEGENERATIVE DISEASES; NEUROPROTECTIVE AGENTS; RECEPTORS, METABOTROPIC GLUTAMATE; TREATMENT OUTCOME;

EID: 84897111080     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/jnc.12608     Document Type: Review

References (201)

1. Albin R. L., and, Greenamyre J. T., (1992) Alternative excitotoxic hypotheses. Neurology 42, 733-738.
2. Albin R. L., Young A. B., and, Penney J. B., (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366-375.
3. Amalric M., Lopez S., Goudet C., Fisone G., Battaglia G., Nicoletti F., Pin J. P., and, Acher F. C., (2013) Group III and subtype 4 metabotropic glutamate receptor agonists: discovery and pathophysiological applications in Parkinson's disease. Neuropharmacology 66, 53-64.
4. Andersen J. K., (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat. Rev. Neurosci. 5, S18-S25.
5. Anderson C. M., and, Swanson R. A., (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32, 1-14.
6. Annoura H., Fukunaga A., Uesugi M., Tatsuoka T., and, Horikawa Y., (1996) A novel class of antagonists for metabotropic glutamate receptors, 7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylates. Bioorg. Med. Chem. Lett. 6, 763-766.
7. Aronica E., Gorter J. A., Ijlst-Keizers H., Rozemuller A. J., Yankaya B., Leenstra S., and, Troost D., (2003) Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur. J. Neurosci. 17, 2106-2118.
8. Austin P. J., Betts M. J., Broadstock M., O'Neill M. J., Mitchell S. N., and, Duty S., (2010) Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease. Br. J. Pharmacol. 160, 1741-1753.
9. Barger S. W., and, Basile A. S., (2001) Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J. Neurochem. 76, 846-854.
10. Barger S. W., Goodwin M. E., Porter M. M., and, Beggs M. L., (2007) Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. J. Neurochem. 101, 1205-1213.
11. Barnham K. J., Masters C. L., and, Bush A. I., (2004) Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug. Discov. 3, 205-214.
12. Battaglia G., Busceti C. L., Molinaro G., Biagioni F., Traficante A., Nicoletti F., and, Bruno V., (2006) Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. J. Neurosci. 26, 7222-7229.
13. Beal M. F., (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann. Neurol. 31, 119-130.
14. Beller J. A., Gurkoff G. G., Berman R. F., and, Lyeth B. G., (2011) Pharmacological enhancement of glutamate transport reduces excitotoxicity in vitro. Restor. Neurol. Neurosci. 29, 331-346.
15. Benarroch E. E., (2008) Metabotropic glutamate receptors. Neurology 70, 964-968.
16. Bennouar K.-E., Uberti M. A., Melon C., Bacolod M. D., Jimenez H. N., Cajina M., Kerkerian-Le Goff L., Doller D., and, Gubellini P., (2013) Synergy between l-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia. Neuropharmacology 66, 158-169.
17. Benoit M., Desnues B., and, Mege J.-L., (2008) Macrophage polarization in bacterial infections. J. Immunol. 181, 3733-3739.
18. Besong G., Battaglia G., D'Onofrio M., et al,. (2002) Activation of group III metabotropic glutamate receptors inhibits the production of RANTES in glial cell cultures. J. Neurosci. 22, 5403-5411.
19. Betts M. J., O'Neill M. J., and, Duty S., (2012) Allosteric modulation of the group III mGlu receptor 4 provides functional neuroprotection in the 6-OHDA rat model of Parkinson's disease. Br. J. Pharmacol. 166, 2317-2330.
20. Beurrier C., Lopez S., Révy D., et al,. (2009) Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism. FASEB J. 23, 3619-3628.
21. Blandini F., Greenamyre J. T., Fancellu R., and, Nappi G., (2001) Blockade of subthalamic glutamatergic activity corrects changes in neuronal metabolism and motor behavior in rats with nigrostriatal lesions. Neurol. Sci. 22, 49-50.
22. Block M. L., Zecca L., and, Hong J.-S., (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69.
23. Bordji K., Becerril-Ortega J., Nicole O., and, Buisson A., (2010) Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-β production. J. Neurosci. 30, 15927-15942.
24. Bradley S. R., Standaert D. G., Levey A. I., and, Conn P. J., (1999) Distribution of group III mGluRs in rat basal ganglia with subtype-specific antibodies. Ann. N. Y. Acad. Sci. 868, 531-534.
25. Broadstock M., Austin P. J., Betts M. J., and, Duty S., (2012) Antiparkinsonian potential of targeting group III metabotropic glutamate receptor subtypes in the rodent substantia nigra pars reticulata. Br. J. Pharmacol. 165, 1034-1045.
26. Bruno V., Copani A., Bonanno L., Knoepfel T., Kuhn R., Roberts P. J., and, Nicoletti F., (1996) Activation of group III metabotropic glutamate receptors is neuroprotective in cortical cultures. Eur. J. Pharmacol. 310, 61-66.
27. Bruno V., Battaglia G., Ksiazek I., et al,. (2000) Selective activation of mGlu4 metabotropic glutamate receptors Is protective against excitotoxic neuronal death. J. Neurosci. 20, 6413-6420.
28. Carlsson A., Lindqvist M., and, Magnusson T., (1957) 3, 4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180, 1200.
29. Cartmell J., and, Schoepp D. D., (2000) Regulation of neurotransmitter release by metabotropic glutamate receptors. J. Neurochem. 75, 889-907.
30. Célanire S., and, Campo B., (2012) Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders. Expert Opin. Drug Discov. 7, 261-280.
31. Chan H. H. N., (2010) Neuroprotective Effects and Mechanisms of the Activation of GroupIII Metabotropic Glutamate Receptors in Rodent Models of Parkinson's Disease. PhD Thesis.
32. Chao C., Hu S., Molitor T., Shaskan E., and, Peterson P., (1992) Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J. Immunol. 149, 2736-2741.
33. Chen H., Jacobs E., Schwarzschild M. A., McCullough M. L., Calle E. E., Thun M. J., and, Ascherio A., (2005) Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease. Ann. Neurol. 58, 963-967.
34. Chio C.-C., Chang Y.-H., Hsu Y.-W., Chi K.-H., and, Lin W.-W., (2004) PKA-dependent activation of PKC, p38 MAPK and IKK in macrophage: implication in the induction of inducible nitric oxide synthase and interleukin-6 by dibutyryl cAMP. Cell. Signal. 16, 565-575.
35. Choi D. W., (1987) Ionic dependence of glutamate neurotoxicity. J. Neurosci. 7, 369-379.
36. Combs C. K., Johnson D. E., Karlo J. C., Cannady S. B., and, Landreth G. E., (2000) Inflammatory mechanisms in Alzheimer's disease: inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists. J. Neurosci. 20, 558-567.
37. Conn P. J., and, Pin J.-P., (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37, 205-237.
38. Conn P. J., Battaglia G., Marino M. J., and, Nicoletti F., (2005) Metabotropic glutamate receptors in the basal ganglia motor circuit. Nat. Rev. Neurosci. 6, 787-798.
39. Conn P. J., Christopoulos A., and, Lindsley C. W., (2009) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discovery 8, 41-54.
40. Connor B., and, Dragunow M., (1998) The role of neuronal growth factors in neurodegenerative disorders of the human brain. Brain Res. Brain Res. Rev. 27, 1-39.
41. Copani A., Bruno V., Battaglia G., Leanza G., Pellitteri R., Russo A., Stanzani S., and, Nicoletti F., (1995) Activation of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by beta-amyloid peptide. Mol. Pharmacol. 47, 890-897.
42. Cunningham C., (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61, 71-90.
43. Cunningham C., Wilcockson D. C., Campion S., Lunnon K., and, Perry V. H., (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J. Neurosci. 25, 9275-9284.
44. Defagot M., Cristina I. A., Villar M. J., and, Antonelli M. C., (2002) Differential localization of metabotropic glutamate receptors during postnatal development. Dev. Neurosci. 24, 272-282.
45. Dexter D. T., Sian J., Rose S., et al,. (1994) Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann. Neurol. 35, 38-44.
46. DiFiglia M., (1990) Excitotoxic injury of the neostriatum: a model for Huntington's disease. Trends Neurosci. 13, 286-289.
47. Domercq M., Sánchez-Gómez M. V., Sherwin C., Etxebarria E., Fern R., and, Matute C., (2007) System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes. J. Immunol. 178, 6549-6556.
48. Duvoisin R. M., Pfankuch T., Wilson J. M., Grabell J., Chhajlani V., Brown D. G., Johnson E., and, Raber J., (2010) Acute pharmacological modulation of mGluR8 reduces measures of anxiety. Behav. Brain Res. 212, 168-173.
49. Duvoisin R. M., Villasana L., Davis M. J., Winder D. G., and, Raber J., (2011) Opposing roles of mGluR8 in measures of anxiety involving non-social and social challenges. Behav. Brain Res. 221, 50-54.
50. East S. P., Bamford S., Dietz M. G. A., et al,. (2010) An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction. Bioorg. Med. Chem. Lett. 20, 4901-4905.
51. Engers D. W., and, Lindsley C. W., (2012) Allosteric modulation of Class C GPCRs: a novel approach for the treatment of CNS disorders. Drug. Discov. Today Technol. 10, 269-276.
52. Engers D. W., Niswender C. M., Weaver C. D., Jadhav S., Menon U. N., Zamorano R., Conn P. J., Lindsley C. W., and, Hopkins C. R., (2009) Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). J. Med. Chem. 52, 4115-4118.
53. Engers D. W., Gentry P. R., Williams R., et al,. (2010) Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS). Bioorg. Med. Chem. Lett. 20, 5175-5178.
54. Faden A. I., Ivanova S. A., Yakovlev A. G., and, Mukhin A. G., (1997) Neuroprotective effects of group III mGluR in traumatic neuronal injury. J. Neurotrauma 14, 885-895.
55. Fahn S., and, Cohen G., (1992) The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. Ann. Neurol. 32, 804-812.
56. Fallarino F., Volpi C., Fazio F., et al,. (2010) Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation. Nat. Med. 16, 897-902.
57. Fan M. M. Y., and, Raymond L. A., (2007) N-Methyl-d-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease. Prog. Neurobiol. 81, 272-293.
58. Ferraguti F., and, Shigemoto R., (2006) Metabotropic glutamate receptors. Cell Tissue Res. 326, 483-504.
59. Flor P. J., and, Acher F. C., (2012) Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. Biochem. Pharmacol. 84, 414-424.
60. Flor P. J., Battaglia G., Nicoletti F., Gasparini F., and, Bruno V., (2002) Neuroprotective activity of metabotropic glutamate receptor ligands. Adv. Exp. Med. Biol. 513, 197-223.
61. Foran E., and, Trotti D., (2009) Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxid. Redox Signal. 11, 1587-1602.
62. Francis P. T., Parsons C. G., and, Jones R. W., (2012) Rationale for combining glutamatergic and cholinergic approaches in the symptomatic treatment of Alzheimer's disease. Expert Rev. Neurother. 12, 1351-1365.
63. Frizzo M. E., Dall'Onder L. P., Dalcin K. B., and, Souza D. O., (2004) Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell. Mol. Neurobiol. 24, 123-128.
64. Gao H. M., and, Hong J. S., (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol. 29, 357-365.
65. Gao H.-M., Hong J.-S., Zhang W., and, Liu B., (2002a) Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J. Neurosci. 22, 782-790.
66. Gao H.-M., Jiang J., Wilson B., Zhang W., Hong J.-S., and, Liu B., (2002b) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease. J. Neurochem. 81, 1285-1297.
67. Gasparini F., Bruno V., Battaglia G., et al,. (1999) (R, S)-4-phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist, is anticonvulsive and neuroprotective in vivo. J. Pharmacol. Exp. Ther. 289, 1678-1687.
68. Geurts J. J. G., Wolswijk G., Bö L., Redeker S., Ramkema M., Troost D., and, Aronica E., (2005) Expression patterns of Group III metabotropic glutamate receptors mGluR4 and mGluR8 in multiple sclerosis lesions. J. Neuroimmunol. 158, 182-190.
69. Glass C. K., Saijo K., Winner B., Marchetto M. C., and, Gage F. H., (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934.
70. Gomes P., and, Soares-da-Silva P., (2002) Role of cAMP-PKA-PLC signaling cascade on dopamine-induced PKC-mediated inhibition of renal Na+-K + -ATPase activity. Am. J. Physiol.Renal Physiol. 282, F1084-F1096.
71. Goudet C., Vilar B., Courtiol T., et al,. (2012) A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. FASEB J. 26, 1682-1693.
72. Greco B., Lopez S., van der Putten H., Flor P. J., and, Amalric M., (2010) Metabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of PARKINSON'S disease. J. Pharmacol. Exp. Ther. 332, 1064-1071.
73. Guillet B. A., Velly L. J., Canolle B., Masmejean F. M., Nieoullon A. L., and, Pisano P., (2005) Differential regulation by protein kinases of activity and cell surface expression of glutamate transporters in neuron-enriched cultures. Neurochem. Int. 46, 337-346.
74. Hardingham G. E., Fukunaga Y., and, Bading H., (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405-414.
75. Heng M. Y., Detloff P. J., Wang P. L., Tsien J. Z., and, Albin R. L., (2009) In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of Huntington disease. J. Neurosci. 29, 3200-3205.
76. Herrera A. J., Tomás-Camardiel M., Venero J. L., Cano J., and, Machado A., (2005) Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons. J. Neural. Transm. 112, 111-119.
77. Hickman S. E., Allison E. K., and, El Khoury J., (2008) Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 28, 8354-8360.
78. Hirsch E. C., and, Hunot S., (2009) Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol. 8, 382-397.
79. Hovelsø N., Sotty F., Montezinho L., Pinheiro P., Herrik K., and, Mørk A., (2012) Therapeutic potential of metabotropic glutamate receptor modulators. Curr. Neuropharmacol. 10, 12.
80. Hubert G. W., and, Smith Y., (2004) Age-related changes in the expression of axonal and glial group I metabotropic glutamate receptor in the rat substantia nigra pars reticulata. J. Comp. Neurol. 475, 95-106.
81. Hunot S., Boissiere F., Faucheux B., Brugg B., Mouatt-Prigent A., Agid Y., and, Hirsch E., (1996) Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience 72, 355-363.
82. Hynd M. R., Scott H. L., and, Dodd P. R., (2004) Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochem. Int. 45, 583-595.
83. Iacovelli L., Bruno V., Salvatore L., Melchiorri D., Gradini R., Caricasole A., Barletta E., De Blasi A., and, Nicoletti F., (2002) Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways. J. Neurochem. 82, 216-223.
84. Ischiropoulos H., and, Beckman J. S., (2003) Oxidative stress and nitration in neurodegeneration: cause, effect, or association? J. Clin. Investig. 111, 163-169.
85. Janssens N., and, Lesage A. S. J., (2001) Glutamate receptor subunit expression in primary neuronal and secondary glial cultures. J. Neurochem. 77, 1457-1474.
86. Jiang Q., Yan Z., and, Feng J., (2006) Activation of group III metabotropic glutamate receptors attenuates rotenone toxicity on dopaminergic neurons through a microtubule-dependent mechanism. J. Neurosci. 26, 4318-4328.
87. Jimenez S., Baglietto-Vargas D., Caballero C., et al,. (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic. J. Neurosci. 28, 11650-11661.
88. Jimenez H. N., Liu K. G., Hong S.-P., et al,. (2012) 4-(1-Phenyl-1H- pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators. Bioorg. Med. Chem. Lett. 22, 3235-3239.
89. Johnson K. A., Jones C. K., Tantawy M. N., Bubser M., Marvanova M., Ansari M., Baldwin R. M., Conn P. J., and, Niswender C. M., (2013) The metabotropic glutamate receptor 8 agonist (< i> S)-3, 4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson's disease. Neuropharmacology 66, 187-195.
90. Jones C. K., Engers D. W., Thompson A. D., et al,. (2011) Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2, 5-Dioxopyrrolidin-1-yl) phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4) with Oral efficacy in an antiparkinsonian animal model. J. Med. Chem. 54, 7639-7647.
91. Jones C. K., Bubser M., Thompson A. D., et al,. (2012) The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with l-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease. J. Pharmacol. Exp. Ther. 340, 404-421.
92. Kalinichev M., Rouillier M., Girard F., et al,. (2013) ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7. In vitro and in vivo characterization. J. Pharmacol. Exp. Ther. 344, 624-636.
93. Kłak K., Pałucha A., Brański P., Sowa M., and, Pilc A., (2007) Combined administration of PHCCC, a positive allosteric modulator of mGlu4 receptors and ACPT-I, mGlu III receptor agonist evokes antidepressant-like effects in rats. Amino Acids 32, 169-172.
94. Kosinski C. M., Risso Bradley S., Conn P. J., Levey A. I., Landwehrmeyer G. B., Penney J. B., Jr, Young A. B., and, Standaert D. G., (1999) Localization of metabotropic glutamate receptor 7 mRNA and mGluR7a protein in the rat basal ganglia. J. Comp. Neurol. 415, 266-284.
95. Kostic M., Zivkovic N., and, Stojanovic I., (2013) Multiple sclerosis and glutamate excitotoxicity. Rev. Neurosci. 24, 71-88.
96. Kreutzberg G. W., (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312-318.
97. Kutzelnigg A., Lucchinetti C. F., Stadelmann C., Brück W., Rauschka H., Bergmann M., Schmidbauer M., Parisi J. E., and, Lassmann H., (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128, 2705-2712.
98. Lafon-Cazal M., Pietri S., Culcasi M., and, Bockaert J., (1993) NMDA-dependent superoxide production and neurotoxicity. Nature 364, 535-537.
99. Lau A., and, Tymianski M., (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch. 460, 525-542.
100. Le Poul E., Bolea C., Girard F., et al,. (2012) A potent and selective mGluR4 positive allosteric modulator improves movement in rodent models of Parkinson's disease. J. Pharmacol. Exp. Ther. 343, 167-177.
101. Lee H.-G., Zhu X., O Neill M. J., Webber K., Casadesus G., Marlatt M., Raina A. K., Perry G., and, Smith M. A., (2004) The role of metabotropic glutamate receptors in Alzheimer's disease. Acta Neurobiol. Exp. 64, 89-98.
102. Li Y., Maher P., and, Schubert D., (1997) A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 19, 453-463.
103. Liang J., Takeuchi H., Jin S., et al,. (2010) Glutamate induces neurotrophic factor production from microglia via protein kinase C pathway. Brain Res. 1322, 8-23.
104. Lipton S. A., Choi Y.-B., Pan Z.-H., Lei S. Z., Chen H.-S. V., Sucher N. J., Loscalzo J., Singel D. J., and, Stamler J. S., (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626-632.
105. Liu B., and, Hong J.-S., (2003) Role of microglia in inflammation- mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304, 1-7.
106. Lopez S., Turle-Lorenzo N., Acher F., De Leonibus E., Mele A., and, Amalric M., (2007) Targeting group III metabotropic glutamate receptors produces complex behavioral effects in rodent models of Parkinson's disease. J. Neurosci. 27, 6701-6711.
107. Lopez S., Turle-Lorenzo N., Johnston T. H., Brotchie J. M., Schann S., Neuville P., and, Amalric M., (2008) Functional interaction between adenosine A2A and group III metabotropic glutamate receptors to reduce parkinsonian symptoms in rats. Neuropharmacology 55, 483-490.
108. Lopez S., Jouve L., Turle-Lorenzo N., Kerkerian-LeGoff L., Salin P., and, Amalric M., (2012) Antiparkinsonian action of a selective group III mGlu receptor agonist is associated with reversal of subthalamonigral overactivity. Neurobiol. Dis. 46, 69-77.
109. MacInnes N., and, Duty S., (2008) Group III metabotropic glutamate receptors act as hetero-receptors modulating evoked GABA release in the globus pallidus in vivo. Eur. J. Pharmacol. 580, 95-99.
110. MacInnes N., Messenger M. J., and, Duty S., (2004) Activation of group III metabotropic glutamate receptors in selected regions of the basal ganglia alleviates akinesia in the reserpine-treated rat. Br. J. Pharmacol. 141, 15-22.
111. Maiese K., Chong Z. Z., Shang Y. C., and, Hou J., (2008) Therapeutic promise and principles: metabotropic glutamate receptors. Oxid. Med. Cell. Longev. 1, 1-14.
112. Maj M., Bruno V., Dragic Z., et al,. (2003) (a)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology 45, 895-906.
113. Marcus D. L., Thomas C., Rodriguez C., Simberkoff K., Tsai J. S., Strafaci J. A., and, Freedman M. L., (1998) Increased peroxidation and reduced antioxidant enzyme activity in alzheimer's disease. Exp. Neurol. 150, 40-44.
114. Marino M. J., Williams D. L., O'Brien J. A., et al,. (2003) Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Proc. Natl Acad. Sci. 100, 13668-13673.
115. Marinova-Mutafchieva L., Sadeghian M., Broom L., Davis J. B., Medhurst A. D., and, Dexter D. T., (2009) Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson's disease. J. Neurochem. 110, 966-975.
116. Martin G., Nie Z., and, Siggins G. R., (1997) Metabotropic glutamate receptors regulate N-Methyl-d-aspartate-mediated synaptic transmission in nucleus accumbens. J. Neurophysiol. 78, 3028-3038.
117. Matarredona E. R., Santiago M., Venero J. L., Cano J., and, Machado A., (2001) Group II metabotropic glutamate receptor activation protects striatal dopaminergic nerve terminals against MPP+-induced neurotoxicity along with brain-derived neurotrophic factor induction. J. Neurochem. 76, 351-360.
118. Mathiesen J. M., Svendsen N., Bräuner-Osborne H., Thomsen C., and, Ramirez M. T., (2003) Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br. J. Pharmacol. 138, 1026-1030.
119. McGeer P., and, McGeer E., (2002) Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26, 459-470.
120. McMullan S. M., Phanavanh B., Guo Li G., and, Barger S. W., (2012) Metabotropic glutamate receptors inhibit microglial glutamate release. ASN Neuro. 4, e00094.
121. Mennicken F., Maki R., de Souza E. B., and, Quirion R., (1999) Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends Pharmacol. Sci. 20, 73-78.
122. Messenger M. J., Dawson L. G., and, Duty S., (2002) Changes in metabotropic glutamate receptor 1-8 gene expression in the rodent basal ganglia motor loop following lesion of the nigrostriatal tract. Neuropharmacology 43, 261-271.
123. Mitsukawa K., Yamamoto R., Ofner S., et al,. (2005) A selective metabotropic glutamate receptor 7 agonist: activation of receptor signaling via an allosteric site modulates stress parameters in vivo. Proc. Natl Acad. Sci. USA 102, 18712-18717.
124. Moldrich R. X., Beart P. M., Jane D. E., Chapman A. G., and, Meldrum B. S., (2001) Anticonvulsant activity of 3, 4-dicarboxyphenylglycines in DBA/2 mice. Neuropharmacology 40, 732-735.
125. Möller T., (2010) Neuroinflammation in Huntington's disease. J. Neural. Transm. 117, 1001-1008.
126. Montastruc J., Rascol O., Senard J., and, Rascol A., (1992) A pilot study of N-methyl-D-aspartate (NMDA) antagonist in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 55, 630.
127. Muir K. W., (2006) Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Curr. Opin. Pharmacol. 6, 53-60.
128. Nakajima Y., Iwakabe H., Akazawa C., Nawa H., Shigemoto R., Mizuno N., and, Nakanishi S., (1993) Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4-phosphonobutyrate. J. Biol. Chem. 268, 11868-11873.
129. Neher J. J., Neniskyte U., Zhao J.-W., Bal-Price A., Tolkovsky A. M., and, Brown G. C., (2011) Inhibition of microglial phagocytosis Is sufficient to prevent inflammatory neuronal death. J. Immunol. 186, 4973-4983.
130. Neher J. J., Neniskyte U., and, Brown G. C., (2012) Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Front. Pharmacol. 3, 27.
131. Nicoletti F., Bruno V., Copani A., Casabona G., and, Knöpfel T., (1996) Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders? Trends Neurosci. 19, 267-271.
132. Nimmerjahn A., Kirchhoff F., and, Helmchen F., (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318.
133. Niswender C. M., and, Conn P. J., (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 50, 295.
134. Niswender C. M., Johnson K. A., Weaver C. D., et al,. (2008a) Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol. Pharmacol. 74, 1345-1358.
135. Niswender C. M., Lebois E. P., Luo Q., Kim K., Muchalski H., Yin H., Conn P. J., and, Lindsley C. W., (2008b) Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators. Bioorg. Med. Chem. Lett. 18, 5626-5630.
136. Novelli A., Reilly J., Lysko P., and, Henneberry R., (1988) Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res. 451, 205-212.
137. Olney J. W., (1982) The toxic effects of glutamate and related compounds in the retina and the brain. Retina 2, 341-359.
138. Ossowska K., (2004) Potential antipsychotic and extrapyramidal effects of (R, S)-3, 4-dicarboxyphenylglycine [(R, S)-3, 4-DCPG], a mixed AMPA antagonist/mGluR8 agonist. Pharmacol. Reports 56, 295.
139. Palucha A., and, Pilc A., (2007) Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol. Ther. 115, 116.
140. Palucha A., Tatarcznska E., Branski P., Szewczyk B., Wieroska J. M., Klak K., Chojnacka-Wojcik E., Nowak G., and, Pilc A., (2004) Group III mGlu receptor agonists produce anxiolytic- and antidepressant-like effects after central administration in rats. Neuropharmacology 46, 151-159.
141. Palucha-Poniewiera A., Klodzinska A., Stachowicz K., Tokarski K., Hess G., Schann S., Frauli M., Neuville P., and, Pilc A., (2008) Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents. Neuropharmacology 55, 517-524.
142. Pałucha-Poniewiera A., Brański P., Lenda T., and, Pilc A., (2010) The antidepressant-like action of metabotropic glutamate 7 receptor agonist N, N'-Bis(Diphenylmethyl)-1,2-ethanediamine (AMN082) is serotonin-dependent. J. Pharmacol. Exp. Ther. 334, 1066-1074.
143. Parker L. C., Luheshi G. N., Rothwell N. J., and, Pinteaux E., (2002) IL-1β signalling in glial cells in wildtype and IL-1RI deficient mice. Br. J. Pharmacol. 136, 312-320.
144. Pelkey K. A., Lavezzari G., Racca C., Roche K. W., and, McBain C. J., (2005) mGluR7 is a metaplastic switch controlling bidirectional plasticity of feedforward inhibition. Neuron 46, 89-102.
145. Pelkey K. A., Yuan X., Lavezzari G., Roche K. W., and, McBain C. J., (2007) mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082. Neuropharmacology 52, 108-117.
146. Perroy J., Prezeau L., De Waard M., Shigemoto R., Bockaert J., and, Fagni L., (2000) Selective blockade of P/Q-type calcium channels by the metabotropic glutamate receptor type 7 involves a phospholipase C pathway in neurons. J. Neurosci. 20, 7896-7904.
147. Phillips T., Makoff A., Murrison E., Mimmack M., Waldvogel H., Faull R., Rees S., and, Emson P., (1998) Immunohistochemical localisation of mGluR7 protein in the rodent and human cerebellar cortex using subtype specific antibodies. Mol. Brain Res. 57, 132-141.
148. Pin J. P., and, Acher F., (2002) The metabotropic glutamate receptors: structure, activation mechanism and pharmacology. Curr.Drug. Targets CNS Neurol. Disord. 1, 297-317.
149. Pinteaux-Jones F., Sevastou I. G., Fry V. A. H., Heales S., Baker D., and, Pocock J. M., (2008) Myelin-induced microglial neurotoxicity can be controlled by microglial metabotropic glutamate receptors. J. Neurochem. 106, 442-454.
150. Pizzi M., Benarese M., Boroni F., Goffi F., Valerio A., and, Spano P. F., (2000) Neuroprotection by metabotropic glutamate receptor agonists on kainate-induced degeneration of motor neurons in spinal cord slices from adult rat. Neuropharmacology 39, 903-910.
151. Polazzi E., and, Monti B., (2010) Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog. Neurobiol. 92, 293-315.
152. Qin L., Wu X., Block M. L., Liu Y., Breese G. R., Hong J.-S., Knapp D. J., and, Crews F. T., (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55, 453-462.
153. Reiner A., Lafferty D., Wang H., Del Mar N., and, Deng Y., (2012) The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice. Neurobiol. Dis. 47, 75-91.
154. Reynolds I. J., (2011) Novel mGluR4 Positive Allosteric Modulators for Parkinson's Disease. World Pharma Congress-Targeting Parkinson's Disease; Philadelphia.
155. Ritzén A., Mathiesen J. M., and, Thomsen C., (2005) Molecular pharmacology and therapeutic prospects of metabotropic glutamate receptor allosteric modulators. Basic Clin. Pharmacol. Toxicol. 97, 202-213.
156. Rodriguez M. C., Obeso J. A., and, Olanow C. W., (1998) Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection. Ann. Neurol. 44, 175-188.
157. Rodriguez-Oroz M. C., Jahanshahi M., Krack P., Litvan I., Macias R., Bezard E., and, Obeso J. A., (2009) Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms. Lancet Neurol. 8, 1128-1139.
158. Sabelhaus C. F., Schröder U. H., Breder J., Henrich-Noack P., and, Reymann K. G., (2000) Neuroprotection against hypoxic/hypoglycaemic injury after the insult by the group III metabotropic glutamate receptor agonist (R, S)-4-phosphonophenylglycine. Br. J. Pharmacol. 131, 655-658.
159. Schiefer J., Sprünken A., Puls C., Lüesse H.-G., Milkereit A., Milkereit E., Johann V., and, Kosinski C. M., (2004) The metabotropic glutamate receptor 5 antagonist MPEP and the mGluR2 agonist LY379268 modify disease
160. Schoepp D. D., (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299, 12-20.
161. Schoepp D. D., Jane D. E., and, Monn J. A., (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38, 1431-1476.
162. Schulz J. B., Matthews R. T., Klockgether T., Dichgans J., and, Beal M. F., (1997) The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. Mol. Cell. Biochem. 174, 193-197.
163. Sheng J. G., Mrak R. E., and, Griffin W., (1998) Enlarged and phagocytic, but not primed, interleukin-1α-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol. 95, 229-234.
164. Shigemoto R., Kinoshita A., Wada E., et al,. (1997) Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J. Neurosci. 17, 7503-7522.
165. Shimohama S., Tanino H., Kawakami N., et al,. (2000) Activation of NADPH oxidase in Alzheimer's disease brains. Biochem. Biophys. Res. Commun. 273, 5-9.
166. Sofroniew M. V., (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638-647.
167. Solomon J. N., Lewis C.-A. B., Ajami B., Corbel S. Y., Rossi F. M. V., and, Krieger C., (2006) Origin and distribution of bone marrow-derived cells in the central nervous system in a mouse model of amyotrophic lateral sclerosis. Glia 53, 744-753.
168. Spieles-Engemann A. L., Behbehani M. M., Collier T. J., et al,. (2010) Stimulation of the rat subthalamic nucleus is neuroprotective following significant nigral dopamine neuron loss. Neurobiol. Dis. 39, 105-115.
169. Sukoff Rizzo S. J., Leonard S. K., Gilbert A., et al,. (2011) The metabotropic glutamate receptor 7 allosteric modulator AMN082: a monoaminergic agent in disguise? J. Pharmacol. Exp. Ther. 338, 345-352.
170. Suzuki G., Tsukamoto N., Fushiki H., Kawagishi A., Nakamura M., Kurihara H., Mitsuya M., Ohkubo M., and, Ohta H., (2007) In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists. J. Pharmacol. Exp. Ther. 323, 147-156.
171. Szatkowski M., and, Attwell D., (1994) Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends Neurosci. 17, 359-365.
172. Tagliati M., Martin C., and, Alterman R., (2010) Lack of motor symptoms progression in Parkinson's disease patients with long-term bilateral subthalamic deep brain stimulation. Int. J. Neurosci. 120, 717-723.
173. Takeuchi H., Mizuno T., Zhang G., Wang J., Kawanokuchi J., Kuno R., and, Suzumura A., (2005) Neuritic beading induced by activated microglia Is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J. Biol. Chem. 280, 10444-10454.
174. Taylor D. L., Diemel L. T., and, Pocock J. M., (2003) Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity. J. Neurosci. 23, 2150-2160.
175. Taylor D. L., Pirianov G., Holland S., et al,. (2010) Attenuation of proliferation in oligodendrocyte precursor cells by activated microglia. J. Neurosci. Res. 88, 1632-1644.
176. Taylor-Robinson S., Weeks R., Bryant D., Sargentoni J., Marcus C., Harding A., and, Brooks D., (1996) Proton magnetic resonance spectroscopy in Huntington's disease: evidence in favour of the glutamate excitotoxic theory? Mov. Disord. 11, 167-173.
177. Temel Y., Visser-Vandewalle V., Kaplan S., Kozan R., Daemen M. A. R. C., Blokland A., Schmitz C., and, Steinbusch H. W. M., (2006) Protection of nigral cell death by bilateral subthalamic nucleus stimulation. Brain Res. 1120, 100-105.
178. Thomas N. K., Wright R. A., Howson P. A., Kingston A. E., Schoepp D. D., and, Jane D. E., (2001) (S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology 40, 311-318.
179. Tomiyama M., Kimura T., Maeda T., Tanaka H., Furusawa K., Kurahashi K., and, Matsunaga M., (2001) Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis. J. Neurol. Sci. 189, 65-69.
180. Ugolini A., Large C. H., and, Corsi M., (2008) AMN082, an allosteric mGluR7 agonist that inhibits afferent glutamatergic transmission in rat basolateral amygdala. Neuropharmacology 55, 532-536.
181. Valenti O., Marino M. J., Wittmann M., Lis E., DiLella A. G., Kinney G. G., and, Conn P. J., (2003) Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. J. Neurosci. 23, 7218-7226.
182. Valenti O., Mannaioni G., Seabrook G. R., Conn P. J., and, Marino M. J., (2005) Group III metabotropic glutamate-receptor-mediated modulation of excitatory transmission in rodent substantia nigra pars compacta dopamine neurons. J. Pharmacol. Exp. Ther. 313, 1296-1304.
183. Vaughan D. W., and, Peters A., (1974) Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study. J. Neurocytol. 3, 405-429.
184. Vernon A., Palmer S., Datla K., Zbarsky V., Croucher M., and, Dexter D., (2005) Neuroprotective effects of metabotropic glutamate receptor ligands in a 6-hydroxydopamine rodent model of Parkinson's disease. Eur. J. Neurosci. 22, 1799-1806.
185. Vernon A. C., Zbarsky V., Datla K. P., Dexter D. T., and, Croucher M. J., (2007) Selective activation of group III metabotropic glutamate receptors by L-(+)-2-amino-4-phosphonobutryic acid protects the nigrostriatal system against 6-hydroxydopamine toxicity in vivo. J. Pharmacol. Exp. Ther. 320, 397-409.
186. Vernon A. C., Croucher M. J., and, Dexter D. T., (2008) Additive neuroprotection by metabotropic glutamate receptor subtype-selective ligands in a rat Parkinson's model. Neuroreport 19, 475.
187. Vincent A. M., and, Maiese K., (2000) The metabotropic glutamate system promotes neuronal survival through distinct pathways of programmed cell death. Exp. Neurol. 166, 65-82.
188. Vlad S. C., Miller D. R., Kowall N. W., and, Felson D. T., (2008) Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70, 1672-1677.
189. Wang Y., and, Qin Z.-H., (2010) Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis 15, 1382-1402.
190. Wang Z., Li W., Mitchell C. K., and, Carter-Dawson L., (2003) Activation of protein kinase C reduces GLAST in the plasma membrane of rat Müller cells in primary culture. Vis. Neurosci. 20, 611-619.
191. Wang L., Martin B., Brenneman R., Luttrell L. M., and, Maudsley S., (2009) Allosteric modulators of g protein-coupled receptors: future therapeutics for complex physiological disorders. J. Pharmacol. Exp. Ther. 331, 340-348.
192. Wang W. Y., Wang H., Luo Y., Jia L. J., Zhao J. N., Zhang H. H., Ma Z. W., Xue Q. S., and, Yu B. W., (2012) The effects of metabotropic glutamate receptor 7 allosteric agonist N, N'-dibenzhydrylethane-1,2-diamine dihydrochloride on developmental sevoflurane neurotoxicity: role of extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase signaling pathway. Neuroscience 205, 167-177.
193. Werner P., Pitt D., and, Raine C. S., (2001) Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann. Neurol. 50, 169-180.
194. Williams R., Johnson K. A., Gentry P. R., Niswender C. M., Weaver C. D., Conn P. J., Lindsley C. W., and, Hopkins C. R., (2009a) Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4). Bioorg. Med. Chem. Lett. 19, 4967-4970.
195. Williams R., Niswender C. M., Luo Q., Le U., Conn P. J., and, Lindsley C. W., (2009b) Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: challenges in hit-to-lead. Bioorg. Med. Chem. Lett. 19, 962-966.
196. Witte M. E., Geurts J. J., De Vries H. E., van der Valk P., and, van Horssen J., (2010) Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 10, 411-418.
197. Wu D. C., Jackson-Lewis V., Vila M., Tieu K., Teismann P., Vadseth C., Choi D.-K., Ischiropoulos H., and, Przedborski S., (2002) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci. 22, 1763-1771.
198. Wu X.-F., Block M. L., Zhang W., Qin L., Wilson B., Zhang W.-Q., Veronesi B., and, Hong J.-S., (2005) The role of microglia in paraquat-induced dopaminergic neurotoxicity. Antioxid. Redox Signal. 7, 654-661.
199. Yao H.-H., Ding J.-H., Zhou F., Wang F., Hu L.-F., Sun T., and, Hu G., (2005) Enhancement of glutamate uptake mediates the neuroprotection exerted by activating group II or III metabotropic glutamate receptors on astrocytes. J. Neurochem. 92, 948-961.
200. Zeevalk G. D., and, Nicklas W. J., (1992) Evidence that the loss of the voltage-dependent Mg2+ block at the N-Methyl-D-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J. Neurochem. 59, 1211-1220.
201. Zhou F., Yao H.-H., Wu J.-Y., Yang Y.-J., Ding J.-H., Zhang J., and, Hu G., (2006) Activation of Group II/III metabotropic glutamate receptors attenuates LPS-induced astroglial neurotoxicity via promoting glutamate uptake. J. Neurosci. Res. 84, 268-277.