Even with clinical treatment to reduce intraocular pressure (IOP), visual field defects still progress in many patients. Recent research has shown that the optic nerve head (ONH) is a key location in this process, where mechanical, ischemic, and inflammatory stresses are associated with axonal transport defects and retinal ganglion cell (RGC) apoptosis. Glutamate, an excitatory neurotransmitter, causes excitotoxic damage in RGCs via N-methyl-d-aspartate receptors (NMDARs) in certain pathologic conditions, particularly ischemia. Activated NMDARs cause Ca2+ dysregulation, which activates the Ca2+-dependent cascade and results in RGC degeneration, calpain activation, the degeneration of neuronal processes, and, finally, apoptosis. Axonal transport damage induced by optic nerve crush (ONC) is commonly used as a model in glaucoma research. This model is known to induce deficits in neurotrophic factors in the central nervous system and ATP, to impair the mitochondria, to create oxidative stress and Ca2+ dysregulation, and to cause calpain activation. Additionally, hyperglycemia-induced dysfunction and pathology occurs earlier in the RGCs than in the retinal vessels. Previous reports also identified Ca2+ dysregulation and calpain activation in this process. Although various triggers induce RGC degeneration and apoptosis via various mechanisms, it is believed that they all result in Ca2+ dysregulation and calpain activation. Targeting this point of convergence thus holds promise as a neuroprotective therapy, especially for patients who do not respond to IOP-lowering treatment.
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