Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death
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Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death. / Vorwerk, C K; Naskar, R; Schuettauf, F; Quinto, K; Zurakowski, D; Gochenauer, G; Robinson, M B; Mackler, S A; Dreyer, E B.
in: INVEST OPHTH VIS SCI, Jahrgang 41, Nr. 11, 10.2000, S. 3615-21.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Depression of retinal glutamate transporter function leads to elevated intravitreal glutamate levels and ganglion cell death
AU - Vorwerk, C K
AU - Naskar, R
AU - Schuettauf, F
AU - Quinto, K
AU - Zurakowski, D
AU - Gochenauer, G
AU - Robinson, M B
AU - Mackler, S A
AU - Dreyer, E B
PY - 2000/10
Y1 - 2000/10
N2 - PURPOSE: Elevated levels of extracellular glutamate have been implicated in the pathophysiology of neuronal loss in both central nervous system and ophthalmic disorders, including glaucoma. This increase in glutamate may result from a failure of glutamate transporters (molecules that ordinarily regulate extracellular glutamate; E:xcitatory A:mino A:cid T:ransporter; EAAT). Elevated glutamate levels can also lead to alterations in glutamate receptor expression. It was hypothesized that selective blockade of glutamate transporters would be toxic to retinal ganglion cells.METHODS: Glutamate transporters were blocked either pharmacologically or with subtype-specific antisense oligonucleotides against EAAT1. Glutamate levels, transporter levels and ganglion cell survival were assayed.RESULTS: Pharmacological inhibition of glutamate transporters with either an EAAT2 specific inhibitor or a nonspecific inhibitor of all the subtypes of transporters was toxic to ganglion cells. Treatment with oligonucleotides against the glutamate transporter EAAT1 decreased the levels of expression of the transporter, increased vitreal glutamate, and was toxic to ganglion cells.CONCLUSIONS: These results demonstrate that normal function of EAAT1 and EAAT2 is necessary for retinal ganglion cell survival and plays an important role in retinal excitotoxicity. Manipulation of retinal glutamate transporter expression may become a useful tool in understanding retinal neuronal loss.
AB - PURPOSE: Elevated levels of extracellular glutamate have been implicated in the pathophysiology of neuronal loss in both central nervous system and ophthalmic disorders, including glaucoma. This increase in glutamate may result from a failure of glutamate transporters (molecules that ordinarily regulate extracellular glutamate; E:xcitatory A:mino A:cid T:ransporter; EAAT). Elevated glutamate levels can also lead to alterations in glutamate receptor expression. It was hypothesized that selective blockade of glutamate transporters would be toxic to retinal ganglion cells.METHODS: Glutamate transporters were blocked either pharmacologically or with subtype-specific antisense oligonucleotides against EAAT1. Glutamate levels, transporter levels and ganglion cell survival were assayed.RESULTS: Pharmacological inhibition of glutamate transporters with either an EAAT2 specific inhibitor or a nonspecific inhibitor of all the subtypes of transporters was toxic to ganglion cells. Treatment with oligonucleotides against the glutamate transporter EAAT1 decreased the levels of expression of the transporter, increased vitreal glutamate, and was toxic to ganglion cells.CONCLUSIONS: These results demonstrate that normal function of EAAT1 and EAAT2 is necessary for retinal ganglion cell survival and plays an important role in retinal excitotoxicity. Manipulation of retinal glutamate transporter expression may become a useful tool in understanding retinal neuronal loss.
KW - ATP-Binding Cassette Transporters/antagonists & inhibitors
KW - Amino Acid Transport System X-AG
KW - Animals
KW - Blotting, Western
KW - Cell Death
KW - Chromatography, High Pressure Liquid
KW - DNA Primers/chemistry
KW - Dicarboxylic Acids/pharmacology
KW - Excitatory Amino Acid Transporter 2
KW - Glutamic Acid/metabolism
KW - Kainic Acid/analogs & derivatives
KW - Neurotransmitter Uptake Inhibitors/pharmacology
KW - Oligonucleotides, Antisense/pharmacology
KW - Pyrrolidines/pharmacology
KW - Rats
KW - Rats, Long-Evans
KW - Receptors, Neurotransmitter/antagonists & inhibitors
KW - Retinal Ganglion Cells/pathology
KW - Vitreous Body/metabolism
M3 - SCORING: Journal article
C2 - 11006260
VL - 41
SP - 3615
EP - 3621
JO - INVEST OPHTH VIS SCI
JF - INVEST OPHTH VIS SCI
SN - 0146-0404
IS - 11
ER -