Activation of NMDA receptors protects against glutamate neurotoxicity in the retina: evidence for the involvement of neurotrophins

Activation of glutamate receptors has been implicated in excitotoxicity. He re, we have investigated whether subtoxic concentrations of glutamate can m odulate neuronal death in the developing retina. Explants of rat retinas we re pre-incubated with glutamate, N-methyl-D-aspartate (NMDA), kainate, quis qualate or trans-1-amino-1,3-cyclopentanedicarboxyl acid(t-ACPD) for 18 h. Then, glutamate (6 mM) was added to the explants for an additional 6 h. Glu tamate-induced degeneration was restricted to the emerging inner nuclear la yer. Pre-incubation with glutamate, NMDA, or both, reduced glutamate-induce d neuronal death and protected against neuronal death induced by irradiatio n (2 Gy). The NMDA receptor antagonists, 2-amino-5-phosphonovaleric acid (d -APV; 30 mu M) or 5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine h ydrogen maleate (MK-801; 30 mu M), prevented glutamate-induced neuroprotect ion. To investigate whether this neuroprotection was mediated by neurotroph ins, we incubated retinal explants with either brain-derived neurotrophic f actor or neurotrophin-il. Both treatments resulted in partial protection ag ainst glutamate-induced neurotoxicity. Furthermore, NMDA mediated neuroprot ection was totally reversed when a soluble form of the specific tyrosine ki nase receptor B was simultaneously added to the explants. Our results sugge st that activation of NMDA receptors may control neuronal death in the reti na during development. This modulation seems to depend, at least in part, o n the release of neurotrophins within the retina. (C) 1999 Published by Els evier Science B.V. All rights reserved.