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 that glutamate, when injected in subtoxic amounts into the vitreal body of the rat eye, transduces a self-protecting signal that renders the retinal ganglion 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 bcl-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 after 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 after saline injection. This finding points to the possible involvement of neurotrophin receptors in regulation of the cellular responses to glutamate challenge. Identification of the intracellular signals that trigger the glutamate-induced self-protective mechanism would shed light on the genetic balance needed for survival, and guide the development of drugs for the up-regulation of desired genes and their products.