Experimental Approaches to Prophylactic Neuroprotective Treatment for Retinal and Optic Nerve Disorders A Review

Neuroprotective treatment is increasingly recommended as a novel intervention for ischemic or degenerative disorders in the retina and optic nerve. To determine prophylactic neuroprotective action and the mechanism of various agents against N-methyl-D-aspartate NMDA- or L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced cell death, in vitro experiments were conducted on retinal neurons and Muller cells. The effects of a calcium channel blocker, diltiazem, and a dopamine precursor, L-dopa, on glutamate agonist exposure were investigated using the TdT-mediated dUTP-biotin nick end labelling (TUNEL) method and comet assay. Prior administration of either one of the above two agents showed that cell death was prevented following exposure to NMDA or AMPA. Isolated administration of L-dopa at a concentration of 10(-4) M facilitates cell death, probably because of nitric oxide (NO) production. L-dopa concentrations of less than 10(-6) M did not result in increased cell death, and glutamate agonist-induced cell death was significantly suppressed by prior treatment at these low concentrations. Similar induction and suppression of cell death was also shown in cultured Muller cells. Based on our experiments and other published literature, we looked at three hypotheses for possible mechanisms for the neuroprotection of L-dopa, i.e., interactions with dopamine receptors, the anti-apoptotic action of NO, and the actions of neurotrophic or nerve growth factors. Neuroprotection appeared to occur through the D1 or D2 receptors. From data obtained from video-enhanced microscopic recordings, which can be used to observe real-time intracellular movement of particles, the movement after administration of a D1 receptor agonist was found to be remarkably different than that seen after D2 agonist administration. It is suggested that the action of dopamine on retinal cell death should be analyzed separately with respect to D1 and D2 receptors. We also discuss clinical application of these two agents in retinal and optic nerve ischemia.