Glutamate receptors as therapeutic targets for Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor and bradykinesia. The primary pathophysiology underlying PD is the degeneration of dopaminergic neurons of the substantia nigra pars compacta. Loss of these neurons causes pathological changes in neurotransmission in the basal ganglia motor circuit. The ability of ionotropic and metabotropic glutamate receptors to modulate neurotransmission throughout the basal ganglia suggests that these receptors may be targets for reversing the effects of altered neurotransmission in PD. Studies in animal models suggest that modulating the activity of these receptors may alleviate the primary motor symptoms of PD as well as side effects induced by dopamine replacement therapy. Moreover, glutamate receptor ligands may slow disease progression by delaying progressive dopamine neuron degeneration. Antagonists of NMDA receptors have shown promise in reversing motor symptoms, levodopa-induced dyskinesias, and neurodegeneration in preclinical PD models. The effects of drugs targeting AMPA receptors are more complex; while antagonists of these receptors exhibit utility in the treatment of levodopa-induced dyskinesias, AMPA receptor potentiators show promise for neuroprotection. Pharmacological modulation of metabotropic glutamate receptors (mGluRs) may hold even more promise for PD treatment due to the ability of mGluRs to fine-tune neurotransmission. Antagonists of mGluR5, as well as activators of group II mGluRs and mGluR4, have shown promise in several animal models of PD. These drugs reverse motor deficits in addition to providing protection against neurodegeneration. Glutamate receptors therefore represent exciting targets for the development of novel pharmacological therapies for PD.
Johnson
Kari A
KA
Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Conn
P Jeffrey
PJ
Niswender
Colleen M
CM
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*
D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate
Ann Neurol. 1998 Sep;44(3 Suppl 1):S175-88
9749591
Neurology. 2000 Apr 25;54(8):1583-8
10762497
Drugs Aging. 2003;20(5):377-97
12696997
Neuroscience. 2003;122(3):747-56
14622918
J Neurochem. 1993 Oct;61(4):1191-206
8376979
J Neurosci. 2004 Jan 28;24(4):828-35
14749427
Eur J Neurosci. 2005 Oct;22(7):1799-806
16197521
J Neurosci. 1997 Jun 1;17(11):4415-25
9151758
Neurotox Res. 2007 Apr;11(3-4):151-67
17449457
Ann Neurol. 2001 Apr;49(4):525-9
11310632
Eur Arch Psychiatry Clin Neurosci. 2008 Nov;258 Suppl 5:55-9
18985296
J Neurophysiol. 1994 Aug;72(2):507-20
7983515
Neuroscience. 1998 Dec;87(4):881-91
9759976
Neuron. 2006 Oct 5;52(1):197-204
17015236
Eur J Pharmacol. 1993 Jun 11;237(1):1-7
8359205
J Neurochem. 2001 Jan;76(2):351-60
11208898
Exp Neurol. 2004 May;187(1):86-93
15081591
J Neural Transm Gen Sect. 1994;95(2):123-36
7865167
Naunyn Schmiedebergs Arch Pharmacol. 1998 Oct;358(4):500-2
9826074
Adv Exp Med Biol. 2002;513:197-223
12575822
J Med Chem. 2000 May 4;43(9):1892-7
10794706
J Neurosci. 2003 Sep 10;23(23):8302-9
12967992
Br J Pharmacol. 1997 Mar;120(6):1007-14
9134210
J Neural Transm Gen Sect. 1994;97(3):175-85
7873128
J Pharmacol Exp Ther. 2003 Aug;306(2):752-62
12730350
Pharmacotherapy. 2007 Dec;27(12 Pt 2):161S-173S
18041936
Eur J Neurosci. 2000 Jan;12(1):337-44
10651888
Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:2749-2755
16278972
Neurosci Lett. 1992 Aug 17;142(2):179-82
1280793
J Neurosci. 2007 Jun 20;27(25):6701-11
17581957
Curr Med Chem. 2008;15(7):671-84
18336281
Neurosci Lett. 1997 Dec 12;239(1):49-53
9547169
Parkinsonism Relat Disord. 2001 Jul;7(3):193-198
11331186
Ann Neurol. 1991 Nov;30(5):717-23
1662477
Neuropharmacology. 2008 Sep;55(4):483-90
18625257
Eur J Pharmacol. 1996 Apr 22;301(1-3):67-73
8773448
Annu Rev Pharmacol Toxicol. 1997;37:205-37
9131252
Neurosci Biobehav Rev. 1997 Jul;21(4):381-92
9195596
Mol Cells. 1997 Dec 31;7(6):749-54
9509416
Neuroscientist. 2005 Feb;11(1):37-49
15632277
Pharmacol Biochem Behav. 2002 Sep;73(2):455-66
12117601
Clin Neurophysiol. 2002 Nov;113(11):1667-72
12417218
Cell Tissue Res. 2004 Oct;318(1):215-24
15503155
Lancet Neurol. 2004 Dec;3(12):719-28
15556804
Ann Neurol. 1990 Oct;28(4):539-46
2252365
Neurobiol Aging. 1993 Jul-Aug;14(4):295-301
8103573
Eur J Pharmacol. 1997 Aug 6;332(2):153-60
9286616
Pharmacol Rev. 1999 Mar;51(1):7-61
10049997
J Neurochem. 1992 Aug;59(2):733-9
1629743
Br J Pharmacol. 1998 Feb;123(4):667-74
9517386
Exp Neurol. 2000 Sep;165(1):136-42
10964492
Eur J Neurosci. 2006 Jan;23(1):151-60
16420425
Exp Neurol. 2002 Jun;175(2):303-17
12061862
Eur J Pharmacol. 1995 Jan 16;272(2-3):123-9
7713155
Neurobiol Aging. 2008 Jul;29(7):1040-51
17353071
Eur J Pharmacol. 2008 Feb 2;580(1-2):95-9
18035348
Neuropharmacology. 1999 Jan;38(1):109-19
10193902
Neurobiol Dis. 2003 Dec;14(3):404-16
14678757
J Pharmacol Exp Ther. 2009 Jul;330(1):227-35
19357321
Mov Disord. 2007 Sep;22 Suppl 17:S335-42
18175394
Neuroscience. 1998 Sep;86(2):353-87
9881853
Naunyn Schmiedebergs Arch Pharmacol. 1997 Jun;355(6):767-73
9205962
Proc Natl Acad Sci U S A. 1985 Apr;82(7):2173-7
3872460
Neurol Sci. 2001 Feb;22(1):49-50
11487196
J Neural Transm Suppl. 1992;38:55-64
1491248
J Neurosci. 2006 Jul 5;26(27):7222-9
16822979
Naunyn Schmiedebergs Arch Pharmacol. 1993 Dec;348(6):586-92
7907775
Life Sci. 1990;47(18):PL91-7
2250573
J Neural Transm Suppl. 2006;(70):17-20
17017503
Exp Neurol. 2001 Oct;171(2):405-17
11573992
J Neurosci. 2003 Aug 6;23(18):7218-26
12904482
J Neurochem. 2001 Aug;78(3):435-45
11483646
Naunyn Schmiedebergs Arch Pharmacol. 1994 Jan;349(1):61-5
7908126
Eur J Pharmacol. 2000 Oct 20;406(3):403-10
11040347
Exp Neurol. 2005 Dec;196(2):422-9
16203001
CNS Drug Rev. 2005 Spring;11(1):77-96
15867954
J Neurosci. 2000 May 1;20(9):3085-94
10777772
Eur J Pharmacol. 2004 Feb 20;486(2):163-74
14975705
J Neurosci. 2000 Sep 1;20(17):6413-20
10964947
Exp Neurol. 1999 Jan;155(1):42-8
9918703
J Neurophysiol. 2001 May;85(5):1960-8
11353013
Neurosci Biobehav Rev. 1997 Jul;21(4):469-75
9195604
Eur J Pharmacol. 1993 Mar 2;232(2-3):247-53
8385618
J Neurosci. 2005 Nov 9;25(45):10414-9
16280580
J Neurosci. 2000 Nov 1;20(21):7871-9
11050106
Neuroreport. 2008 Jan 8;19(1):111-5
18281903
Brain Res. 2001 Apr 27;899(1-2):142-7
11311875
J Neurochem. 2003 Feb;84(4):792-802
12562523
Eur J Pharmacol. 1995 Jul 4;280(2):159-66
7589181
Neuroscience. 2003;122(3):727-37
14622916
Psychopharmacology (Berl). 2004 Sep;175(2):179-88
15007533
Neurobiol Dis. 2008 Jan;29(1):161-8
17933546
Mov Disord. 2002;17 Suppl 3:S15-21
11948751
Neurosci Biobehav Rev. 1997 Jul;21(4):455-68
9195603
Eur J Pharmacol. 1996 Oct 31;314(3):307-11
8957251
Neurology. 2001 Feb 27;56(4):455-62
11222787
J Neurosci. 2007 Aug 1;27(31):8297-308
17670976
Mov Disord. 2003 Jul;18(7):729-37
12815651
J Neural Transm Park Dis Dement Sect. 1994;8(1-2):39-71
7534462
Brain. 2002 Dec;125(Pt 12):2635-45
12429591
J Neural Transm Park Dis Dement Sect. 1991;3(3):203-13
1835581
Pharmacol Biochem Behav. 1989 Mar;32(3):621-3
2544900
J Neurophysiol. 1995 Mar;73(3):1076-83
7608756
N Engl J Med. 1998 Oct 8;339(15):1044-53
9761807
J Neurosci Res. 2005 Dec 15;82(6):778-87
16273546
Neurology. 1998 May;50(5):1323-6
9595981
J Neurol Neurosurg Psychiatry. 2008 Apr;79(4):368-76
18344392
J Pharmacol Exp Ther. 1999 Jun;289(3):1678-87
10336568
Br J Pharmacol. 2004 Jan;141(1):15-22
14597605
Mol Pharmacol. 2008 Nov;74(5):1345-58
18664603
Neuropharmacology. 2003 Aug;45(2):155-66
12842121
Mov Disord. 2005 Aug;20(8):919-31
16007614
Exp Neurol. 2008 Mar;210(1):109-17
18035355
Pharmacol Rev. 1966 Jun;18(2):925-64
5328389
J Neural Transm (Vienna). 1996;103(5):581-90
8811503
Ann Neurol. 1994 Jun;35(6):655-61
8210221
Suppl Clin Neurophysiol. 2004;57:733-6
16106676
J Neurosci. 2002 Jul 1;22(13):5669-78
12097518
Mov Disord. 2006 Sep;21(9):1375-9
16705684
Brain Res. 1996 Oct 14;736(1-2):202-5
8930325
Neuropharmacology. 1995 Jul;34(7):713-21
8532138
J Med Chem. 2007 Jul 26;50(15):3585-95
17602546
J Neurochem. 2007 Apr;101(2):483-97
17359492
J Neurosci. 1997 Mar 15;17(6):1891-7
9045718
Neuroepidemiology. 1993;12(4):195-208
8272179
Pol J Pharmacol. 1995 Nov-Dec;47(6):501-7
8868372
J Neurosci. 2002 Mar 15;22(6):2135-41
11896153
Mov Disord. 2005 Apr;20(4):403-9
15593312
Neuroscience. 2002;113(4):857-69
12182892
Clin Neuropharmacol. 2001 May-Jun;24(3):133-8
11391123
Ann N Y Acad Sci. 1999 Apr 30;868:531-4
10414330
Psychopharmacology (Berl). 1999 Apr;143(3):235-43
10353425
J Neural Transm. 1989;77(1):65-71
2545813
Exp Neurol. 2000 May;163(1):239-43
10785463
J Neural Transm (Vienna). 1996;103(8-9):987-1041
9013391
Psychopharmacology (Berl). 2005 Apr;179(1):154-63
15672275
J Pharmacol Exp Ther. 1993 Dec;267(3):1515-20
8263813
Eur J Neurosci. 1995 May 1;7(5):972-80
7613632
Psychopharmacology (Berl). 2005 Apr;179(1):117-27
15726332
Neuroreport. 1994 Dec 20;5(18):2586-8
7696610
Neuropharmacology. 2002 Mar;42(3):289-96
11897107
Curr Drug Targets CNS Neurol Disord. 2002 Jun;1(3):297-317
12769621
Neurobiol Dis. 2006 Apr;22(1):1-9
16289868
Pharmacol Ther. 2007 Jul;115(1):116-47
17582504
J Pharmacol Exp Ther. 2005 Jun;313(3):1296-304
15761115
Neurology. 2000 Apr 25;54(8):1589-95
10762498
Clin Exp Pharmacol Physiol. 2008 Nov;35(11):1388-94
18785982
J Comp Neurol. 2000 Apr 17;419(4):407-21
10742712
Nature. 1991 Jan 31;349(6308):414-8
1846943
CNS Neurol Disord Drug Targets. 2007 Apr;6(2):87-100
17430147
Neuropharmacology. 1995 Jan;34(1):1-26
7623957
Exp Neurol. 2005 Feb;191 Suppl 1:S17-27
15629758
CNS Drugs. 2007;21(8):677-92
17630819
Arch Neurol. 1991 Sep;48(9):977-81
1835370
Pharmacol Ther. 2000 Dec;88(3):427-35
11337032
J Med Chem. 1997 Sep 12;40(19):3119-29
9301676
Eur J Neurosci. 2002 Jan;15(1):120-32
11860512
J Neural Transm Park Dis Dement Sect. 1995;10(1):27-39
8619907
J Pharmacol Exp Ther. 2007 Jan;320(1):397-409
17012606
J Neural Transm Gen Sect. 1994;98(1):57-67
7710739
Synapse. 1997 Aug;26(4):381-91
9215597
J Pharmacol Exp Ther. 1997 Jan;280(1):439-46
8996226
Neuropharmacology. 2003 Dec;45(7):895-906
14573382
Arch Neurol. 2001 Oct;58(10):1660-8
11594926
Trends Neurosci. 2000 Oct;23(10 Suppl):S28-33
11052217
Bioorg Med Chem Lett. 1999 Oct 4;9(19):2815-8
10522697
Neuropsychopharmacology. 2004 Aug;29(8):1451-61
15039773
Neuropharmacology. 2001 Sep;41(4):413-20
11543761
J Pharmacol Exp Ther. 1999 Sep;290(3):1034-40
10454475
J Neurosci. 2002 Jul 15;22(14):6176-85
12122076
J Neurol Neurosurg Psychiatry. 1992 Jul;55(7):630-1
1386383
Br J Pharmacol. 2000 Feb;129(3):541-6
10711353
J Neurochem. 1992 May;58(5):1979-982
1560247
J Comp Neurol. 1998 Jan 5;390(1):63-74
9456176
Neuroepidemiology. 1994;13(4):175-8
8090259
Brain Res Bull. 2006 Apr 14;69(3):318-26
16564428
Nat Rev Neurosci. 2005 Oct;6(10):787-98
16276355
Eur J Neurosci. 2005 Dec;22(11):2765-74
16324110
Curr Opin Neurobiol. 1996 Dec;6(6):751-8
9000030
Arch Neurol. 2007 Jan;64(1):20-4
17210805
J Neural Transm. 1989;75(3):221-6
2538557
J Neurochem. 2007 Nov;103(3):1075-91
17714448
Bioessays. 2002 Apr;24(4):308-18
11948617
J Neural Transm Park Dis Dement Sect. 1994;7(2):143-52
7710666
J Cell Physiol. 2002 May;191(2):125-37
12064455
Eur J Neurosci. 2006 Aug;24(4):1201-8
16930445
Neuropharmacology. 2005 Sep;49(4):447-55
15919101
Neuropsychopharmacology. 2009 Feb;34(3):729-38
18704096
Neuropharmacology. 2003 Jul;45(1):45-56
12814658
J Neurosci. 2006 Mar 29;26(13):3567-83
16571765
J Neurosci. 1997 Jan 1;17(1):204-15
8987749
Neuropharmacology. 2002 Aug;43(2):147-59
12213269
Mov Disord. 2002;17 Suppl 4:S13-22
12211136
J Neural Transm Gen Sect. 1992;87(1):23-35
1346965
Synapse. 2001 Oct;42(1):40-7
11668589
Neuroscience. 2007 Mar 16;145(2):611-20
17224239
FEBS J. 2008 Apr;275(7):1384-1391
18279376
Brain Res. 2005 Feb 8;1033(2):216-20
15694927
J Neurosci. 2002 Jul 1;22(13):5403-11
12097492
Prog Neuropsychopharmacol Biol Psychiatry. 2002 Apr;26(3):487-95
11999899
J Neurosci. 2001 Sep 15;21(18):7001-12
11549710
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13668-73
14593202
Synapse. 2001 May;40(2):145-53
11252026
Curr Opin Pharmacol. 2007 Feb;7(1):39-47
17088105
J Comp Neurol. 1999 Apr 28;407(1):33-46
10213186
Acta Neurol Scand. 2007 Dec;116(6):374-9
17986095
Prog Neurobiol. 2000 Sep;62(1):63-88
10821982
Clin Neuropharmacol. 2008 Jan-Feb;31(1):51-6
18303491
Neuroreport. 2008 Mar 5;19(4):475-8
18287950
Parkinsonism Relat Disord. 2005 Jun;11 Suppl 1:S3-7
15885625
Life Sci. 1990;46(1):37-42
2153885
Mov Disord. 2008 Oct 15;23(13):1860-6
18759356
J Neurosci. 1998 Dec 1;18(23):9594-600
9822720