Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine.
OBJECTIVE
It is well known that acute exposure to high concentrations of glutamate is toxic to central mammalian neurons. However, the effect of a chronic, minor elevation over endogenous glutamate levels has not been explored. The authors have suggested that such chronic exposure may play a role in glaucomatous neuronal loss. In the current study, they sought to explore whether a chronic, low-dose elevation in vitreal glutamate was toxic to retinal ganglion cells and whether this toxicity could be prevented with memantine, a glutamate antagonist.


METHODS
Rats were injected serially and intravitreally with glutamate to induce chronic elevations in glutamate concentration. A second group of rats was treated with intraperitoneal memantine and glutamate. Control groups received vehicle injection with or without concurrent memantine therapy. After 3 months, the animals were killed, and ganglion cell survival was evaluated.


RESULTS
Intravitreal injections raised the intravitreal glutamate levels from an endogenous range of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate elevation killed 42% of the retinal ganglion cells after 3 months. Memantine treatment alone had no effect on ganglion cell survival. However, when memantine was given concurrently with low-dose glutamate, memantine was partially protective against glutamate toxicity.


CONCLUSIONS
These data suggest that minor elevations in glutamate concentration can be toxic to ganglion cells if this elevation is maintained for 3 months. Furthermore, memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity.
Vorwerk
C K
CK
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
Lipton
S A
SA
Zurakowski
D
D
Hyman
B T
BT
Sabel
B A
BA
Dreyer
E B
EB
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D002452:Cell Count; D002470:Cell Survival; D015259:Dopamine Agents / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000008:administration & dosage / Q000187:drug effects / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008559:Memantine / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology; D014822:Vitreous Body
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D008559:Memantine