# Neurorotrophic Factors in Glaucoma and Innovative Delivery Systems
## 2 Neuroprotection: Insights on Biochemical Pathways and Treatment Opportunities  
Neuroprotection for glaucoma refers to any intervention aiming at preserving retinal ganglion cells and related signal transduction pathways. Mean increase of IOP is still considered as the most common risk factor for glaucoma progression, and it is well known that its reduction allows slowing or halting the disease progression in most cases [16]. However, up to 20% of patients with glaucoma show disease progression despite optimal IOP control [17]. In addition, 30-90% of patients showing glaucomatous optic disc damage and visual field loss have normal values of IOP, suggesting that multiple factors may contribute to the pathogenesis of RGCs death in glaucoma [16; 18; 19; 20; 21]. Several studies demonstrated that neuronal death represents the ultimate process in the pathophysiology of glaucoma damage, and, in this scenario, neuroprotective therapeutical approaches appear as crucial to prolong RGC life and possibly improve visual function [22; 23].  
The rationale for neuroprotectants is to act against the main pathways involved in the apoptotic ganglion cell death process, including: (i) the deprivation of NTs resulting from the blockage of the retrograde axonal transport from the lateral geniculate nucleus of the thalamus; (ii) the abnormal increase of excitatory neurotransmitters and reactive oxygen species; (iii) the deregulation of ion channel activities; and (iv) the loss of intracellular self-repair processes. All of these different cellular mechanisms invariably lead to RCG loss and glial cells activation.  
Several classes of neuroprotective agents have been studied in glaucoma, most notably NTFs, glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, \(\alpha_{2}\)-adrenergic agonists, antioxidant and free radical scavengers, and calcium channel blockers. Among them, only meantime, a non-competitive NMDA receptor antagonist, and brimonidine, a topical \(\alpha_{2}\)- agonist, were evaluated in large randomized controlled trials (RCTs). Specifically, the efficacy of meantime in reducing glaucoma progression was evaluated through two long-term, phase III RCTs conducted by Allergan (Irvine, CA). The results of these studies show that daily treatment with 10 or 20 mg of mementine for 48 months was not proven to significantly delay glaucomatous damage progression, when compared with placebo [3]. Neuroprotective properties of brimonidine were investigated in a multi-center, phase II RCT and compared with topical timolol in patients with low-pressure glaucoma (Low Pressure Glaucoma Treatment Study, LoGTS) [4]. The potential mechanisms of neuroprotective effects of brimonidine include upregulation of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) in RGCs, activation of cell survival pathways and antiapoptotic genes, and modulation of NMDA receptor.  
In LoGTS, twice-daily treatment with topical 0.2% brimonidine tartrate for four years appeared to have beneficial effect on visual function independently of IOP lowering when compared with 0.5% timolol maleate eye drops. Nevertheless, problems related with the study design, patient adherence to treatment, the occurrence of adverse events leading to significant drop-out, the different profiles and diurnal effects of used drugs, and the missing data on visual acuity and vertical cup-discratio questioned the reliability of the study. A recent Cochrane systematic review concluded that results were not decisive, and that additional clinical trials are strongly recommended to demonstrate whether neuroprotective agents, including brimonidine eye drops, may be beneficial for patients with glaucoma [24].