Self-protective mechanism awakened by glutamate in retinal ganglion cells

The progression of degeneration in chronic optic neuropathies or in animal models of optic nerve injury is thought to be caused, at least in part, by an increase in glutamate to abnormally high concentrations. We show here th at glutamate, when injected in subtoxic amounts into the vitreal body of th e rat eye, transduces a self-protecting signal that renders the retinal gan glion cells resistant to further toxicity, whether glutamate-derived or not . This neuroprotective effect is attained within 24 h and lasts at least 4 days. Western blot analysis of rat retinas revealed increased amounts of bc I-2 four days after injection of glutamate in either subtoxic or toxic (120 nmol) amounts, but not after saline injection. The effects of intravitreal glutamate or saline injection on the secretion of neurotrophins by retinal ganglion cells was evaluated in rat aqueous humor 6 h, 1 day, and 4 days a fter injection. Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 showed similar kinetic patterns in all of the eyes; that is , they increased to a peak 1 day after the injection and returned to normal by day 4. However, increased amounts the neurotrophin receptor TrkA within the retinal ganglion cell layer and nerve fiber layer were detected 1 day after injection of glutamate in either toxic or subtoxic amounts, but not a fter saline injection. This finding points to the possible involvement of n eurotrophin receptors in regulation of the cellular responses to glutamate challenge. Identification of the intracellular signals that trigger the glu tamate-induced self-protective mechanism would shed light on the genetic ba lance needed for survival, and guide the development of drugs for the up-re gulation of desired genes and their products.