Neurodegenerative diseases of the retina and potential for protection and recovery

Abstract

Recent advances in our understanding of the mechanisms in the cascade of events resulting in retinal cell death in ocular pathologies like glaucoma, diabetic retinopathy and age-related macular degeneration led to the common descriptive term of neurodegenerative diseases of the retina. The final common pathophysiologic pathway of these diseases includes a particular form of metabolic stress, resulting in an insufficient supply of nutrients to the respective target structures (optic nerve head, retina). During metabolic stress, glutamate is released initiating the death of neurones containing ionotropic glutamate (N-methyl-D-aspartat, NMDA) receptors present on ganglion cells and a specific type of amacrine cells. Experimental studies demonstrate that several drugs reduce or prevent the death of retinal neurones deficient of nutrients. These agents generally block NMDA receptors to prevent the action of glutamate or halt the subsequent pathophysiologic cycle resulting in cell death. The major causes for cell death following activation of NMDA receptors are the influx of calcium and sodium into cells, the generation of free radicals linked to the formation of advanced glycation endproducts (AGEs) and/or advanced lipoxidation endproducts (ALEs) as well as defects in the mitochondrial respiratory chain. Substances preventing these cytotoxic events are considered to be potentially neuroprotective.

Keywords: Neurodegeneration; age-related macular degeneration; diabetic retinopathy; glaucoma; neuroprotection; retina; retinal ganglion cells..

Fig. (1)

Schematic drawing of a retinal ganglion cell (RGC) axon being non-myelinated from the retina to the lamina cribrosa (LC) and being myelinated after passing this structure (Fig. 1).

Fig. (2a)

Retinal microvessels (scanning electron micrograph of a vascular resin cast) showing the capillary meshwork between arteriole (arrow) and venule (arrowhead), being tighter on the venular side and wider on the arteriolar side reflecting different oxygen tension in these vessels and thus altered supply.

Fig. (2b)

Differential interference contrast microscopy (DIC) of an unstained retina whole mount of a freshly enucleated rat eye. RGCs (thin arrows), even mitochondria are visible: (arrowhead) and capillaries (thick arrows) can be kept well alive up to 9 hours (see 143, 145 and 164).

Fig. (3)

Schematic drawing indicating the reactions leading to advanced glycation endproducts (AGEs), cross-linking of protein-(lysil-residue) and reducing sugar groups (Maillard reaction). AGEs impair intracellular functional proteins and crosslink extracellular material. The time frame of the reversibility of these reactions depends on the toxicity of respective intermediary metabolic products (e.g. glyoxal).

Fig. (4)

Differential interference contrast microscopy (DIC) of living astrocytes treated with glyoxal, a reactive intermediate of AGE-production. This leads to accumulation of isolated and aggregated intracellular vesicles (arrows, a-c) in the axons of a neuron and to blockade of the axonal transport (arrowheads, c,d).

Fig. (5)

Differential interference contrast microscopy (DIC) of a cultured astrocyte, the mitochondria are clearly outlined (thin arrows). Arrowhead: membrane of the nucleus, thick arrows: nucleoli.

Fig. (6)

Cross section of single mitochondria (width: 0.5 µm) in an astrocyte: the function of the mitochondrial membrane is clearly indicated by the colour of a dye (JC1) indicating the degree of the membrane potential: red still intact; green compromised.

Fig. (7)

Schematic drawing and localization of the factors leading to neurodegenerative diseases in the retina (GFAP = glial fibrillary protein, APP = amyloid precursor protein, MMPs = matrix metallo-proteinases). Please see text for details.