Concurrent downregulation of a glutamate transporter and receptor in glaucoma.
OBJECTIVE
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, which are molecules that ordinarily regulate extracellular glutamate. Elevated glutamate levels can also lead to a perturbation in glutamate receptors. The hypothesis for the current study was that glutamate transporters and/or receptors are altered in human glaucoma.


METHODS
Immunohistochemical analyses of human eyes with glaucoma and control eyes were performed to evaluate glutamate receptors and transporters. These molecules were also assayed in rat eyes injected with glial-derived neurotrophic factor (GDNF).


RESULTS
Glaucomatous eyes had decreased levels of both the glutamate transporter, excitatory amino acid transporter (EAAT)-1, and the glutamate receptor subunit N-methyl-D-aspartate (NMDA)-R1. Eyes treated with GDNF had elevated levels of both EAAT1 and NMDAR1.


CONCLUSIONS
The loss of EAAT1 in glaucoma may account for the elevated level of glutamate found in glaucomatous vitreous and lead to a compensatory downregulation of NMDAR1. Inasmuch as GDNF can increase levels of both EAAT1 and NMDAR1, it may be a useful therapeutic approach to restore homeostatic levels of these in glaucoma.
Naskar
R
R
Scheie Eye Institute, Department of Ophthalmology, Veterans Administration, Philadelphia, USA.
Vorwerk
C K
CK
Dreyer
E B
EB
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D027322:Amino Acid Transport System X-AG; D000818:Animals; D015536:Down-Regulation; D015812:Glaucoma, Angle-Closure / Q000378:metabolism*; D005902:Glaucoma, Open-Angle / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018698:Glutamic Acid; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C495039:GDNF protein, human; C495041:Gdnf protein, rat