# The Potential of Visible and Far-Red to Near-Infrared Light in Glaucoma Neuroprotection
## 3 Pathophysiology of Glaucoma: Increased IOP, Mitochondrial Dysfunction, and Altered Ion Fluxes  
The following parameters are risk factors in relation to glaucoma: Older age and frailty, African descent, familiarity with glaucoma, diabetes [16], use of systemic or topical corticosteroids [17], myopia, ocular diseases, reduced central corneal thickness [18], trauma and surgery [19], smoking, ischemic event, hypertension, and vasospasm [20]. These all contribute to an increase in the eye pressure, which is the most important risk factor for glaucoma [2]. Eye pressure is thought to cause direct damage to neurons and to the optic  
Figure 1: A comprehensive search strategy of scientific articles and clinical studies for this review paper. nerve [21]. Indeed, the disease is characterized by the progressive degeneration of both RGCs, the projection neurons of the eyead axons. The balance between the secretion of aqueous humor by the ciliary body and its drainage through two independent pathways--the trabecular meshwork (TM) and uveoscleral outflow pathway--is very important, as progressive resistance to outflow results in a gradual increase in IOP [17], which triggers glaucomatous pathogenesis [22]. An increased resistance to aqueous outflow through the trabecular meshwork is reported in patients suffering from open-angle glaucoma. In contrast, access to the drainage pathways is anatomically obstructed in patients with angle-closure glaucoma [17]. Notably, similarly to endothelial-like cells, TM cells also lie in the collagen meshwork beams, and they are significantly decreased; moreover, they show both mitochondrial permeability transition pore alteration and mitochondrial release of calcium, both of which are increased in glaucoma patients compared to healthy subjects [22]. The dysfunction of calcium regulation by these cells may cause the failure to control IOP by TM tissue. Due to its sensitivity to high IOP, progressive and chronic stress is conveyed or transduced through the optic nerve head to the unmyelinated RGC axon segment. This is executed in complex ways that include mechanical, inflammatory, and bioenergetic components [23]. However, in individuals with normal IOP and in patients whose IOP is effectively controlled by medical treatment, but who continue to suffer progressive neuron loss and visual field deterioration, glaucomatous RGCs and axon loss occur [24]. This suggests that other not fully understood mechanisms beyond pressure-mediated damage are involved in neurodegeneration [5; 21]. Indeed, there is the possibility that pathophysiological stress, such as that induced by elevated IOP, triggers secondary immune or autoimmune responses, leading to RGC and axon damage after the initial insult is gone. In fact, evidence suggests that the transient elevation of IOP is sufficient to induce autoreactive T lymphocytes and T-cell infiltration into the retina in mice; the importance of this mechanism was demonstrated by the lack of T-cell autoreactivity in germ-free mice, even after long-term experimentally induced IOP elevation. This T-cell infiltration leads to a prolonged phase of RGCs degeneration that also persists after IOP returns to a normal level [21], suggesting an autoimmune component in glaucoma. Importantly, mitochondrial failure has been implicated in the aetiology of retinitis pigmentosa and in retinal degeneration in glaucoma in a way that is similar to neurodegenerative diseases such as Alzheimer's and Parkinson's [25]. In some illnesses, a specific loss of RGCs is a common feature. Indeed similarities exist between glaucoma and mitochondrial optic neuropathies, such as [PERSON]'s hereditary optic neuropathy and autosomal dominant optic atrophy [26]. [PERSON] et al. found a high density of voltage-gated Na\({}^{+}\) channels and increased numbers of mitochondria in the pre-laminar optic nerve, which reflects the higher energy requirements for electrical conduction in unmyelinated axons in the pre-laminar and laminar optic nerve [27].