Retinal ischemia, a major cause of visual loss, is believed to result
from overexcitation of glutamate receptors. However, under euglycemic
and normoxic conditions, exogenously applied glutamate is not
neurotoxic in the retina. Under such conditions, exogenous glutamate
typically causes glia swelling and requires very high concentrations to
produce neurotoxicity. To determine whether ischemic conditions enhance
the neurotoxicity of endogenous and exogenous glutamate, we examined
the effects of simulated ischemia (deprivation of both glucose and
oxygen) on retinal morphology and lactate dehydrogenase (LDH) release.
In an ex vivo rat retinal preparation, glutamate was
administered during simulated ischemia in the presence of riluzole, an
inhibitor of glutamate release. Deprivation of both glucose and oxygen
for 60 min at 30°C produced severe acute neurodegeneration. This
neurodegeneration, characterized by bull's eye formation in the
inner nuclear layer and spongy appearance in the inner plexiform layer,
was prevented by the combination of MK-801 and DNQX, antagonists of
N-methyl-D-aspartate (NMDA) and non-NMDA receptors, indicating that the
damage results from activation of both glutamate receptors. We also
found that administration of glutamate pyruvate transaminase (alanine
aminotransaminase) with pyruvate diminished the neurodegeneration
during simulated ischemia. Furthermore, riluzole, an inhibitor of
glutamate release, attenuated the neurodegeneration, suggesting the
importance of endogenous glutamate in ischemic damage. In the presence
of riluzole and simulated ischemia, exogenously applied glutamate
failed to cause Müller cell swelling but was extremely neurotoxic.
These results suggest that simulated ischemia enhances
glutamate-mediated neurotoxicity in part by depressing glutamate
uptake. When glutamate transport is impaired, sub-millimolar glutamate
concentrations become profoundly neurotoxic.
Ginkgo Extract EGb761 Confers Neuroprotection by Reduction of Glutamate Release in Ischemic Brain
