Role of glutamate excitotoxicity and glutamate transporter EAAT2 in epilepsy: Opportunities for novel therapeutics development.

Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE

Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.

Anticonvulsants/*pharmacology ; Epilepsy/*drug therapy ; Epilepsy/*metabolism ; Excitatory Amino Acid Transporter 2/*metabolism ; Glutamic Acid/*metabolism; Animals ; Anticonvulsants/chemistry ; Excitatory Amino Acid Transporter 2/genetics ; Gene Expression Regulation/drug effects ; Humans

Epilepsy is a complex neurological syndrome characterized by seizures resulting from neuronal hyperexcitability and sudden and synchronized bursts of electrical discharges. Impaired astrocyte function that results in glutamate excitotoxicity has been recognized to play a key role in the pathogenesis of epilepsy. While there are 26 drugs marketed as anti-epileptic drugs no current treatments are disease modifying as they only suppress seizures rather than the development and progression of epilepsy. Excitatory amino acid transporters (EAATs) are critical for maintaining low extracellular glutamate concentrations and preventing excitotoxicity. When extracellular glutamate concentrations rise to abnormal levels, glutamate receptor overactivation and the subsequent excessive influx of calcium into the post-synaptic neuron can trigger cell death pathways. In this review we discuss targeting EAAT2, the predominant glutamate transporter in the CNS, as a promising approach for developing therapies for epilepsy. EAAT2 upregulation via transcriptional and translational regulation has proven successful in vivo in reducing spontaneous recurrent seizures and offering neuroprotective effects. Another approach to regulate EAAT2 activity is through positive allosteric modulation (PAM). Novel PAMs of EAAT2 have recently been identified and are under development, representing a promising approach for the advance of novel therapeutics for epilepsy.
(Copyright © 2021 Elsevier Inc. All rights reserved.)

Am J Hum Genet. 2016 Aug 4;99(2):287-98. (PMID: 27476654)
Brain Res Brain Res Rev. 2004 Jul;45(3):250-65. (PMID: 15210307)
Brain Res Mol Brain Res. 1995 Oct;33(1):22-8. (PMID: 8774942)
Acta Neuropathol. 2010 Jan;119(1):7-35. (PMID: 20012068)
J Biochem Mol Toxicol. 2020 Nov;34(11):e22578. (PMID: 32666660)
Ann Neurol. 2004 Apr;55(4):469-77. (PMID: 15048885)
Trends Neurosci. 2013 Mar;36(3):174-84. (PMID: 23298414)
Curr Neurol Neurosci Rep. 2003 Jul;3(4):325-31. (PMID: 12930703)
J Cell Physiol. 2011 Oct;226(10):2484-93. (PMID: 21792905)
Pharmacogn Mag. 2015 Jul-Sep;11(43):579-85. (PMID: 26246735)
J Neurosci. 2021 Mar 10;41(10):2106-2118. (PMID: 33478985)
J Exp Med. 2017 Feb;214(2):547-563. (PMID: 28028152)
Acta Neurol Belg. 2000 Dec;100(4):201-13. (PMID: 11233674)
ASN Neuro. 2012 Mar 22;4(2):. (PMID: 22313347)
Brain Res Bull. 2010 Mar 16;81(4-5):510-6. (PMID: 19853022)
J Neurosci. 2016 Jul 20;36(29):7640-7. (PMID: 27445142)
Neuropathology. 2015 Feb;35(1):1-9. (PMID: 25059512)
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4155-60. (PMID: 9108121)
Neuroscience. 2007 Jun 15;147(1):136-45. (PMID: 17507170)
Neurology. 2021 May 4;96(18):e2261-e2271. (PMID: 33722994)
APMIS. 2009 Apr;117(4):291-301. (PMID: 19338517)
Lancet. 2004 Jan 3;363(9402):28-37. (PMID: 14723991)
Neurosci Lett. 2018 Feb 22;667:84-91. (PMID: 28011391)
Glia. 2006 Jan 15;53(2):212-24. (PMID: 16206168)
CNS Neurosci Ther. 2013 Jun;19(6):411-27. (PMID: 23601960)
Chem Biol Interact. 2013 Mar 25;203(1):154-9. (PMID: 23044489)
J Neurosci. 2015 Apr 1;35(13):5187-201. (PMID: 25834045)
Neurochem Int. 2012 Jan;60(1):31-8. (PMID: 22080156)
J Clin Invest. 2014 Mar;124(3):1255-67. (PMID: 24569372)
Neuropharmacology. 2020 May 15;168:107762. (PMID: 31499048)
Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10955-9. (PMID: 1279699)
Nat Med. 2012 Jul;18(7):1087-94. (PMID: 22683779)
J Neurosci. 1996 Nov 15;16(22):7398-406. (PMID: 8929446)
Neuron. 1996 Mar;16(3):675-86. (PMID: 8785064)
J Neurosci. 2019 Jan 23;39(4):727-742. (PMID: 30504280)
Acta Pharmacol Sin. 2009 Apr;30(4):379-87. (PMID: 19343058)
Br J Pharmacol. 2012 Jan;165(1):20-34. (PMID: 21564084)
Nat Rev Neurol. 2009 Jul;5(7):380-91. (PMID: 19578345)
J Neurotrauma. 2013 Aug 15;30(16):1434-41. (PMID: 23510201)
J Immunol. 1994 Apr 1;152(7):3578-85. (PMID: 8144936)
Neuropsychopharmacology. 2017 Jan;42(1):193-215. (PMID: 27629368)
J Neurol Neurosurg Psychiatry. 2015 Oct;86(10):1150-7. (PMID: 25991402)
Ann Neurol. 2005 Feb;57(2):226-35. (PMID: 15668975)
PLoS One. 2021 Jan 28;16(1):e0246068. (PMID: 33507976)
Epilepsy Behav. 2019 Dec;101(Pt B):106550. (PMID: 31732331)
Neurochem Int. 2007 Nov-Dec;51(6-7):333-55. (PMID: 17517448)
Neuroscience. 2004;125(1):191-201. (PMID: 15051158)
Neuroscientist. 2014 Dec;20(6):610-22. (PMID: 24496610)
Handb Clin Neurol. 2017;145:193-216. (PMID: 28987170)
Nat Med. 2005 Sep;11(9):973-81. (PMID: 16116433)
Neuroscience. 2000;101(3):547-61. (PMID: 11113304)
Cold Spring Harb Perspect Med. 2016 May 02;6(5):. (PMID: 26801895)
J Biol Chem. 2008 May 9;283(19):13116-23. (PMID: 18326497)
J Neurochem. 1995 Aug;65(2):643-51. (PMID: 7616220)
Neurobiol Dis. 2011 Aug;43(2):507-15. (PMID: 21575722)
Epilepsy Behav. 2011 Oct;22(2):158-64. (PMID: 21763206)
Neuroscience. 2021 Sep 15;472:157-166. (PMID: 34400247)
J Neurochem. 1990 Dec;55(6):2091-7. (PMID: 1977889)
Seizure. 2014 Mar;23(3):184-90. (PMID: 24315662)
JAMA Neurol. 2018 Mar 1;75(3):279-286. (PMID: 29279892)
Singapore Med J. 2003 Jan;44(1):31-4. (PMID: 12762561)
Neurobiol Dis. 2007 Feb;25(2):319-30. (PMID: 17112731)
Neuroscience. 2019 Jul 15;411:185-201. (PMID: 31158434)
Nature. 1992 Dec 3;360(6403):467-71. (PMID: 1280334)
CNS Drugs. 2020 Nov;34(11):1089-1103. (PMID: 32926322)
J Nutr. 2000 Apr;130(4S Suppl):1043S-5S. (PMID: 10736378)
Front Neuroanat. 2015 Mar 05;9:23. (PMID: 25798091)
Neurochem Res. 2009 Jul;34(7):1324-31. (PMID: 19169815)
Am J Hum Genet. 2017 Aug 3;101(2):300-310. (PMID: 28777935)
Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14482-7. (PMID: 9826726)
Can J Neurol Sci. 2000 May;27 Suppl 1:S6-10; discussion S20-1. (PMID: 10830320)
Mol Pharmacol. 2007 Nov;72(5):1228-37. (PMID: 17646426)
Neurochem Res. 2017 Jun;42(6):1724-1734. (PMID: 27873132)
Sci STKE. 2006 Oct 10;2006(356):re12. (PMID: 17033045)
J Neurochem. 2006 Aug;98(3):916-25. (PMID: 16771835)
Exp Biol Med (Maywood). 2008 Nov;233(11):1389-94. (PMID: 18703755)
J Neurosci Res. 2016 Sep;94(9):779-80. (PMID: 27316466)
Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6591-5. (PMID: 8393571)
Brain. 2002 Jan;125(Pt 1):32-43. (PMID: 11834591)
Neurosci Lett. 2007 Aug 31;424(1):51-4. (PMID: 17709190)
Brain Commun. 2020 Mar 04;2(1):fcaa022. (PMID: 32954283)
Science. 1989 May 19;244(4906):798-800. (PMID: 2567056)
Neurology. 1990 May;40(5 Suppl 2):13-23. (PMID: 2185436)
Neurochem Res. 2020 Mar;45(3):526-540. (PMID: 32002773)
Neurology. 1999 Feb;52(3):453-72. (PMID: 10025773)
Nat Rev Neurosci. 2019 May;20(5):282-297. (PMID: 30792501)
Neurobiol Dis. 2012 Aug;47(2):145-54. (PMID: 22513140)
Hum Mutat. 2020 Nov;41(11):1892-1905. (PMID: 32741053)
Eur J Pharmacol. 2008 Jan 14;578(2-3):171-6. (PMID: 18036519)
Adv Neurol. 1986;44:857-77. (PMID: 3706027)
Neurochem Int. 2016 Sep;98:56-71. (PMID: 27013346)
J Biol Chem. 1996 Nov 1;271(44):27715-22. (PMID: 8910364)
Exp Brain Res. 2013 Apr;226(2):153-63. (PMID: 23392471)
Int J Biol Sci. 2013 Sep 22;9(9):948-59. (PMID: 24155668)
Brain Res. 2000 Jul 21;871(2):175-80. (PMID: 10899284)
J Cereb Blood Flow Metab. 1990 Sep;10(5):631-7. (PMID: 2384536)
Nature. 2006 Jan 19;439(7074):283-9. (PMID: 16421561)
Neurology. 2006 Jul 11;67(1):20-7. (PMID: 16832072)
Front Neurol. 2020 Sep 08;11:1006. (PMID: 33013665)
J Neurochem. 2015 Sep;134(6):982-1007. (PMID: 26096891)
Oncotarget. 2018 Jun 1;9(42):26954-26976. (PMID: 29928494)
Exp Neurol. 2019 Aug;318:50-60. (PMID: 31022385)
Br J Pharmacol. 2003 Aug;139(7):1297-309. (PMID: 12890709)
J Neurosci. 1994 Sep;14(9):5559-69. (PMID: 7521911)
Neuroscience. 2013 Sep 17;248:602-19. (PMID: 23811393)
J Neurooncol. 2018 May;138(1):49-53. (PMID: 29404978)
NeuroRx. 2004 Jan;1(1):101-10. (PMID: 15717010)
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14488-93. (PMID: 12388773)
Epilepsy Res. 2004 Apr-May;59(2-3):75-82. (PMID: 15246112)
Lancet Neurol. 2011 Feb;10(2):173-86. (PMID: 21256455)
Pharmacol Biochem Behav. 1992 Dec;43(4):1269-72. (PMID: 1475311)
Acta Neurochir (Wien). 2004 Feb;146(2):143-51. (PMID: 14963746)
ACS Chem Neurosci. 2019 Aug 21;10(8):3437-3453. (PMID: 31257852)
J Neurosurg. 1998 Dec;89(6):971-82. (PMID: 9833824)
Glia. 2018 Jun;66(6):1235-1243. (PMID: 29044647)
Glia. 2021 Feb;69(2):296-309. (PMID: 32835451)
Neurobiol Dis. 2010 Mar;37(3):764-71. (PMID: 20045054)
Neurology. 2009 Oct 20;73(16):1323-7. (PMID: 19841385)
Dev Neurosci. 1995;17(4):203-11. (PMID: 8575339)
Epilepsia. 2013 Sep;54 Suppl 6:78-80. (PMID: 24001081)
Nature. 2005 Jan 6;433(7021):73-7. (PMID: 15635412)
Front Neurol. 2018 Oct 29;9:925. (PMID: 30429824)
ACS Chem Neurosci. 2020 Jun 3;11(11):1573-1596. (PMID: 32343555)
Handb Exp Pharmacol. 2018;246:233-250. (PMID: 28939972)
Brain Res Mol Brain Res. 1999 Feb 19;65(1):112-23. (PMID: 10036313)
J Neurochem. 2015 Apr;133(2):199-210. (PMID: 25626691)
Nature. 1995 Jun 15;375(6532):599-603. (PMID: 7791878)
J Neurochem. 2003 Feb;84(3):522-32. (PMID: 12558972)
Lancet. 1993 Jun 26;341(8861):1607-10. (PMID: 8099987)
Expert Rev Neurother. 2010 Jun;10(6):885-91. (PMID: 20518605)
Neuroscience. 1999;88(4):1083-91. (PMID: 10336123)
Nature. 1992 Dec 3;360(6403):464-7. (PMID: 1448170)
Ann Neurol. 2019 Jun;85(6):921-926. (PMID: 30937933)
Exp Neurol. 2016 Sep;283(Pt A):85-96. (PMID: 27155358)
Epilepsy Behav. 2009 May;15(1):10-4. (PMID: 19236943)
Cell Mol Neurobiol. 2004 Feb;24(1):123-8. (PMID: 15049516)
Br J Pharmacol. 1997 Jul;121(6):1171-9. (PMID: 9249254)
J Pharmacol Exp Ther. 2014 Oct;351(1):124-33. (PMID: 25027316)
Exp Neurol. 2019 Oct;320:112959. (PMID: 31108086)
Neuroscience. 1997 May;78(2):351-9. (PMID: 9145792)
Epilepsy Res. 2001 Aug;46(2):101-9. (PMID: 11463511)
J Neurosci. 2007 Oct 3;27(40):10674-84. (PMID: 17913901)
Theranostics. 2020 Jul 9;10(18):8415-8429. (PMID: 32724478)
Brain. 2012 Nov;135(Pt 11):3416-25. (PMID: 23107647)
J Child Neurol. 2004 Aug;19 Suppl 1:S6-14. (PMID: 15526966)
Nat Rev Drug Discov. 2010 Jan;9(1):68-82. (PMID: 20043029)
Epilepsy Curr. 2007 Mar-Apr;7(2):45-50. (PMID: 17505552)
Pol J Pharmacol. 2004 Mar-Apr;56(2):187-93. (PMID: 15156069)
J Neurosci. 2009 Aug 26;29(34):10588-99. (PMID: 19710312)
Glia. 2018 Apr;66(4):777-788. (PMID: 29214672)
Neurosci Lett. 2003 Feb 27;338(2):107-10. (PMID: 12566164)
Arch Neurol. 2009 Jan;66(1):97-101. (PMID: 19139306)
Neurosci Biobehav Rev. 1997 Sep;21(5):559-79. (PMID: 9353792)
J Neurosci. 2002 Nov 1;22(21):9430-44. (PMID: 12417668)
World Neurosurg. 2016 Jun;90:685-690. (PMID: 26709155)
Neurology. 2005 Aug 23;65(4):529-34. (PMID: 16116111)
Exp Physiol. 2021 Aug;106(8):1814-1828. (PMID: 34086374)
Pharmacol Rev. 2020 Jul;72(3):606-638. (PMID: 32540959)
Cold Spring Harb Perspect Med. 2015 Jun 22;5(8):a022863. (PMID: 26101204)
Pharmaceuticals (Basel). 2018 Feb 07;11(1):. (PMID: 29414852)
BMC Genomics. 2010 Apr 08;11:230. (PMID: 20377889)
J Neurosci Res. 2007 Aug 1;85(10):2059-70. (PMID: 17497670)
Epilepsia. 2008 Feb;49(2):226-36. (PMID: 17868051)
Neurobiol Dis. 2013 Jun;54:225-38. (PMID: 23313318)
Mol Psychiatry. 2007 Dec;12(12):1065-78. (PMID: 17684493)
Science. 2000 Aug 11;289(5481):957-60. (PMID: 10938000)
Nature. 2000 Sep 14;407(6801):189-94. (PMID: 11001057)
Brain Pathol. 2004 Apr;14(2):215-22. (PMID: 15193035)
J Neurochem. 1997 Apr;68(4):1564-70. (PMID: 9084427)
Neurosci Res. 1993 Feb;16(2):149-53. (PMID: 8387171)
Glia. 2012 Aug;60(8):1215-26. (PMID: 22592998)
Acta Neurol Scand Suppl. 2013;(197):9-18. (PMID: 23480151)
Future Med Chem. 2012 Sep;4(13):1689-700. (PMID: 22924507)
Neuroreport. 1999 Mar 17;10(4):855-9. (PMID: 10208560)
Neuron. 2001 Aug 2;31(2):247-60. (PMID: 11502256)
IUBMB Life. 2019 Feb;71(2):213-222. (PMID: 30360015)
Naunyn Schmiedebergs Arch Pharmacol. 1998 Aug;358(2):181-90. (PMID: 9750003)
ACS Chem Neurosci. 2018 Mar 21;9(3):522-534. (PMID: 29140675)
Trends Neurosci. 2009 Aug;32(8):421-31. (PMID: 19615761)
Ann Neurol. 2003 Aug;54(2):251-6. (PMID: 12891680)
Adv Neurol. 1983;34:537-41. (PMID: 6829359)
Neuroscience. 2012 Sep 18;220:237-46. (PMID: 22698689)
Epilepsia. 2008;49 Suppl 2:3-12. (PMID: 18226167)
Physiol Rev. 2013 Oct;93(4):1621-57. (PMID: 24137018)
Exp Brain Res. 2007 Aug;181(4):571-7. (PMID: 17486325)
J Exp Med. 2020 Jan 6;217(1):. (PMID: 31699822)
Biochem J. 1971 Jun;123(2):211-8. (PMID: 5164952)
Glia. 2011 Nov;59(11):1635-42. (PMID: 21748805)
Science. 1997 Jun 13;276(5319):1699-702. (PMID: 9180080)
Biomolecules. 2020 Mar 18;10(3):. (PMID: 32197322)
Cell Mol Life Sci. 2015 Sep;72(18):3489-506. (PMID: 26033496)
Epilepsy Behav. 2017 Jun;71(Pt B):124-129. (PMID: 25819950)
J Neurosci Res. 2019 Nov;97(11):1345-1362. (PMID: 30022509)
Prog Neurobiol. 2001 Sep;65(1):1-105. (PMID: 11369436)
Neurochem Res. 2018 Aug;43(8):1671-1682. (PMID: 29936569)
Nature. 2017 Apr 27;544(7651):446-451. (PMID: 28424515)
J Neurosci. 2002 Sep 15;22(18):8028-33. (PMID: 12223556)
Neurochem Int. 2019 Feb;123:22-33. (PMID: 30053506)
J Neurosci. 1998 Nov 1;18(21):8751-7. (PMID: 9786982)
Neurobiol Dis. 2007 Nov;28(2):184-96. (PMID: 17714952)
Neuron. 2008 Apr 24;58(2):168-78. (PMID: 18439402)

R01 NS111767 United States NS NINDS NIH HHS

Keywords: Astrocytes; EAAT2; Epilepsy; Excitotoxicity; Glutamate; Glutamate transporter

0 (Anticonvulsants)
0 (Excitatory Amino Acid Transporter 2)
0 (SLC1A2 protein, human)
3KX376GY7L (Glutamic Acid)

Date Created: 20210927 Date Completed: 20220106 Latest Revision: 20221102

20240829

PMC8605998

10.1016/j.bcp.2021.114786

34571003