# Neurorotrophic Factors in Glaucoma and Innovative Delivery Systems
## 2 Neuroprotection: Insights on Biochemical Pathways and Treatment Opportunities
### Neurotrophic Factors Rationale for Use in Glaucoma Treatment and Preliminary Results
#### 2.1.2 Brain Derived Neurotrophic Factor  
Among the other NTs, BDNF is of interest for its potential neuroprotective effect in several neuronal populations involved in glaucoma, peripheral sensory neuropathies, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD) [60; 61]. BDNF synthesis occurs locally by RGCs and astrocytes in the retina, as well as in the superior colliculus and the lateral geniculate nucleus in higher mammals from where it is retrogradely transported [62]. Experimental studies showed that hampered axonal transport of BDNF has been observed in glaucoma animal models, and that BDNF injection into the superior colliculus of neonatal hamster led to a 13-15-fold reduction in RGCs pyknosis, suggesting that BDNF plays a key role in promoting RGC survival [6]. Moreover, clinical and experimental studies demonstrated that BDNF/TrkB complex was downregulated in inner retina and optic nerve head in glaucoma [11; 63]. Similarly, TrkB was shown to be gradually downregulated in response to neuronal injury, with potential decreased responsiveness to existing levels of BDNF [64]. In addition, BDNF levels in the serum of primary open-angle glaucoma patients and in tears of normal tension glaucoma patients were significantly lower when compared with control group [65; 30; 66]. On this a basis, previous research on experimental animals demonstrated that exogenous, topical, or intravitreal BDNF was effective in activating RGCs pro-survival signaling pathways after ocular hypertensive damage [5; 67]. Specifically, results from experimental study on animal models of chronic ocular hypertension show that recombinant human BDNF eye drop treatment was effective in inducing recovery of pattern electroretinogram (P-ERG) and visual cortical evoked potentials (VEP) damage. Moreover, it was associated with an increase of RGCs survival, as assessed by Brn3 immunopositive cell density in the RGC layer using retinal immunocytochemistry [67]. Furthermore, three repeated intraocular injections of BDNF at concentration of 1.0 \(\upmu\)g/\(\upmu\)L in moderately chronic hypertensive eyes of rats, resulted in two weeks of lasting increase in RGC survival with no cumulative effect [5]. However, high-doses BDNF as exposed on cultured rat hippocampal neurons and intravitreally injected in animal models of optic nerve injury, caused a rapid and significant downregulation of TrkB expression which reduced BDNF effectiveness [68; 69]. In addition, studies showed that upregulated expression of BDNF/TrkB can be detrimental for neuronal homeostasis as it enhances glutamate excitotoxicity [70; 71]. In this respect, elevated BDNF levels were found to be expressed in muscle from ALS patients, suggesting possible negative action, and TrkB activation was observed to accelerate glutamate-induced death in rat neuroblastoma cells [70; 71]. In addition, no significant reduction in the number of RGCs was demonstrated in BDNF knock-out mice [72; 73]. Clinical trials using high-dose subcutaneous or intrathecal rhBDNF for neuroprotective intent in ALS did not provide favorable results [74; 75]. Several efforts have been consequently directed at selectively targeting TrkB with low molecular weight exogenous agents. Specifically, a flavonoid-based TrkB agonist 7,8-dihydroxyflavone (7,8 DHF) has been developed. This molecule was effective in activating TrkB downstream signaling and exerting neuroprotective effects in an animal model of PD and in excitotoxic and oxidative stress-induced RGC apoptosis in vitro [76; 77]. In addition, it has been demonstrated that highly specific TrkB agonist antibodies promoted RGC survival in vitro and in vivo in acute and chronic models of glaucoma [78; 79]. As an option to directly activate survival signaling downstream of TrkB, a cell permeable phosphine-borane complex was demonstrated to promote RGC protection in rat model of optic nerve injury by activating the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway [80].