title: Riluzole elevates GLT-1 activity and levels in striatal astrocytes.
abstract: Drugs which upregulate astrocyte glutamate transport may be useful neuroprotective compounds by preventing excitotoxicity. We set up a new system to identify potential neuroprotective drugs which act through GLT-1. Primary mouse striatal astrocytes grown in the presence of the growth-factor supplement G5 express high levels of the functional glutamate transporter, GLT-1 (also known as EAAT2) as assessed by Western blotting and ³H-glutamate uptake assay, and levels decline following growth factor withdrawal. The GLT-1 transcriptional enhancer dexamethasone (0.1 or 1 μM) was able to prevent loss of GLT-1 levels and activity following growth factor withdrawal. In contrast, ceftriaxone, a compound previously reported to enhance GLT-1 expression, failed to regulate GLT-1 in this system. The neuroprotective compound riluzole (100 μM) upregulated GLT-1 levels and activity, through a mechanism that was not dependent on blockade of voltage-sensitive ion channels, since zonasimide (1 mM) did not regulate GLT-1. Finally, CDP-choline (10 μM-1 mM), a compound which promotes association of GLT-1/EAAT2 with lipid rafts was unable to prevent GLT-1 loss under these conditions. This observation extends the known pharmacological actions of riluzole, and suggests that this compound may exert its neuroprotective effects through an astrocyte-dependent mechanism.
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK.
authors.forename: Marica
authors.initials: M
authors.lastname: Carbone
authors.forename: Susan
authors.initials: S
authors.lastname: Duty
authors.forename: Marcus
authors.initials: M
authors.lastname: Rattray
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002443:Ceftriaxone / Q000494:pharmacology; D002478:Cells, Cultured; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D017072:Neostriatum / Q000166:cytology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019782:Riluzole / Q000494:pharmacology*; D015854:Up-Regulation; D000078305:Zonisamide
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D007555:Isoxazoles; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D000078305:Zonisamide; D002443:Ceftriaxone; D019782:Riluzole
references.citation: Neurodegeneration. 1996 Jun;5(2):121-8
references.pmid: 8819132
references.citation: Neurosci Lett. 1992 Jun 22;140(2):225-30
references.pmid: 1501783
references.citation: Brain Res. 2000 Jul 21;871(2):175-80
references.pmid: 10899284
references.citation: CNS Neurosci Ther. 2011 Feb;17(1):4-31
references.pmid: 20236142
references.citation: Brain. 1993 Apr;116 ( Pt 2):433-52
references.pmid: 8096420
references.citation: Neurochem Int. 1998 Jul;33(1):11-22
references.pmid: 9694037
references.citation: Neurobiol Dis. 2000 Aug;7(4):375-83
references.pmid: 10964608
references.citation: J Neurochem. 1997 Dec;69(6):2612-5
references.pmid: 9375696
references.citation: Prog Neurobiol. 2001 Sep;65(1):1-105
references.pmid: 11369436
references.citation: Glia. 1996 Sep;18(1):73-7
references.pmid: 8891694
references.citation: J Neurosci. 2003 Mar 1;23(5):1688-96
references.pmid: 12629173
references.citation: J Biol Chem. 2011 Jan 28;286(4):2785-94
references.pmid: 21098017
references.citation: Neurosci Lett. 1990 Jul 31;115(2-3):248-52
references.pmid: 1978265
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16400-6
references.pmid: 12200548
references.citation: Exp Neurol. 2006 Sep;201(1):15-23
references.pmid: 16806177
references.citation: Exp Neurol. 2008 Sep;213(1):229-37
references.pmid: 18625223
references.citation: Neurochem Int. 2005 Jan;46(2):137-47
references.pmid: 15627514
references.citation: J Biol Chem. 2008 May 9;283(19):13116-23
references.pmid: 18326497
references.citation: Brain Res Mol Brain Res. 2003 Aug 19;116(1-2):1-6
references.pmid: 12941455
references.citation: J Neurochem. 2004 Jan;88(2):481-93
references.pmid: 14690536
references.citation: Neurobiol Dis. 2005 Mar;18(2):336-45
references.pmid: 15686962
references.citation: Eur J Pharmacol. 1993 Dec 21;250(3):473-6
references.pmid: 8112408
references.citation: Chem Biol. 2010 Nov 24;17(11):1177-82
references.pmid: 21095567
references.citation: Exp Neurol. 2005 Feb;191(2):276-84
references.pmid: 15649482
references.citation: Neurosci Lett. 1997 Jun 13;228(3):207-11
references.pmid: 9218644
references.citation: Eur J Neurosci. 1995 Oct 1;7(10):2036-41
references.pmid: 8542061
references.citation: Seizure. 2004 Dec;13 Suppl 1:S5-9; discussion S10
references.pmid: 15511691
references.citation: Neurosci Lett. 2001 Sep 14;310(2-3):117-20
references.pmid: 11585581
references.citation: Eur J Pharmacol. 2008 Jan 14;578(2-3):171-6
references.pmid: 18036519
references.citation: Mol Pharmacol. 2009 May;75(5):1062-73
references.pmid: 19201818
references.citation: PLoS One. 2008 Aug 06;3(8):e2864
references.pmid: 18682744
references.citation: Br J Pharmacol. 2007 Jan;150(1):5-17
references.pmid: 17088867
references.citation: Ann Neurol. 2010 Feb;67(2):239-49
references.pmid: 20225289
references.citation: J Med Chem. 2010 Jan 28;53(2):734-44
references.pmid: 19950903
references.citation: Neuropharmacology. 2011 Jun;60(7-8):1168-75
references.pmid: 21034752
references.citation: J Neurochem. 2008 Sep;106(5):2194-204
references.pmid: 18624917
references.citation: J Neurochem. 2009 Oct;111(2):332-43
references.pmid: 19694903
references.citation: Neuroscience. 2008 Apr 22;153(1):329-37
references.pmid: 18353560
references.citation: Neurosci Lett. 2009 Apr 24;454(2):161-4
references.pmid: 19429076
references.citation: Neuroscience. 2010 Sep 15;169(4):1888-900
references.pmid: 20547213
references.citation: Brain Res. 2011 Apr 12;1384:1-8
references.pmid: 21295555
references.citation: Glia. 2005 Mar;49(4):520-41
references.pmid: 15578656
references.citation: Nature. 2005 Jan 6;433(7021):73-7
references.pmid: 15635412
references.citation: N Engl J Med. 1994 Mar 3;330(9):585-91
references.pmid: 8302340
references.citation: Neurobiol Dis. 2008 Jan;29(1):123-31
references.pmid: 17884513
references.citation: J Neurochem. 2003 Feb;84(3):522-32
references.pmid: 12558972
references.citation: J Neurosci. 1995 Mar;15(3 Pt 1):1835-53
references.pmid: 7891138
references.citation: Exp Neurol. 2003 Sep;183(1):124-35
references.pmid: 12957496
references.citation: Cell Mol Neurobiol. 2004 Feb;24(1):123-8
references.pmid: 15049516
references.citation: J Biomol Screen. 2010 Jul;15(6):653-62
references.pmid: 20508255
references.citation: J Neurochem. 2006 Apr;97(1):128-39
references.pmid: 16524382
references.citation: Eur J Neurosci. 2002 Sep;16(5):836-42
references.pmid: 12372019
references.citation: Neurobiol Dis. 2006 Mar;21(3):556-67
references.pmid: 16274998
references.citation: Trends Neurosci. 1990 Feb;13(2):43-6
references.pmid: 1690928
references.citation: J Biol Chem. 2005 Oct 14;280(41):34924-32
references.pmid: 16079146
references.citation: Eur J Pharmacol. 2010 Jul 25;638(1-3):65-71
references.pmid: 20423712