Signal transduction mechanisms of neuroprotective substances in animal models of glaucoma and the role of the protein high-mobility group box-1 (HMGB-1)

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Neuroprotection is a challenge in glaucoma therapy and is offered as subsidiary treatment to IOP-lowering procedures. Different substances have been shown to be neuroprotective such as neurotrophins, the hemopoietic factor GM-CSF, anti-VEGF and the aplha2-adrenergic agonist brimonidin. However, the signal transduction mechanisms of these substances remain unknown in the retina. The first goal of this proposal is to scrutinise cell signalling associated with neuroprotective activity within the retina in glaucoma models. The second goal is to unravel whether neuroprotection involves the nuclear protein high-mobility group-box-1 (HMGB-1) discovered in acutely and chronically degenerating retina. The initial studies revealed a strong expression of HMGB-1 in the retina exposed to IOP-elevation-induced ganglion cell death. We generated both in vivo glaucoma models and in vitro organotypic culture models under adjustable and maintained high pressure and showed that progressive ganglion cell survival/death is associated with HMGB-1 regulation. We propose that neuron survival will be monitored using neuroprotective drugs (e.g. GM-CSF, brimonidin, anti-VEGF) aiming to provide information, where and how HMGB-1 interferes with the cell signalling cascades which culminate to beneficial outcomes in glaucoma.