After our studies on ganglion cell degeneration in the glaucomatous retina, the current work further confirmed the reduction of amacrine cells in the retina after the onset of glaucoma. Present study also tried to understand the possible mechanisms underlying neuronal degeneration in the glaucomatous retina. Changes of expressions in immediate early genes (IEGs), glutamate receptors (GluRs), calcium-binding proteins (CaBPs), 8-hydroxy-deoxyguanosine (8-OH-dG) and nitric oxide synthase (NOS), as well as apoptotic-related factors including caspase 3, bax, and bcl-2 were examined. IEGs such as c-fos and c-jun were induced in the retina of the glaucomatous rat as early as 2 hr after the onset of glaucoma and lasted up to 2 weeks. Expressions of GluRs and CaBPs (i.e., parvalbumin and calbindin D-28k) were observed to be increased in the retinal ganglion cell layer (GCL) and inner nuclear layer (INL) at 3 days and 1 week after the onset of glaucoma. The increase occurred well before and during the phase where significant neuronal death was observed in the GCL and INL of the glaucomatous retinae. Induction of 8-OH-dG was present in both the GCL and INL of the glaucomatous retina at 3 days after the onset of glaucoma before significant neuronal death was observed. Furthermore, confocal microscopy study showed the complete colocalization of immunohistochemical expression of caspase 3 with glial fibrillary acidic protein (GFAP), but not with neuronal nuclei (NeuN). It indicates that astrocytes and Müller cells are involved in the pathological processes of neuronal death. The relationship between the linked factors and neuronal degeneration is also discussed.