**11. Antioxidants**

Numerous studies have shown that mitochondrial metabolism results in the release of reactive oxidative species that cause damage to lipids, protein, resulting in cell death and neurode‐ generation [61]. Hypoxia and ischemia are found to play an important role in the cascade of events leading to oxidative stress, and stimulating delta-opioid receptors (DOR) [62]. DOR has been proven to reduce the build-up of harmful free radicals, glutamate, and pro-inflammatory cytokines [62]. It has been shown that naloxone, an opioid blocker given intraperitoneally 6mg/ kg in rabbits can reduce the retinal thickness thinning caused by ischemia [63]. Morphine has been used to pharmacological pre condition rabbit retina and has been shown to reduce acute IOP induced damage [64]

**12. Neurotrophic factors**

survival [13].

**12.1. Brain derived neurotrophic factor**

patients compared with controls [72].

**12.2. Ciliary derived neurotrophic factor**

future development for neuroprotection [4].

**13. Immune modulation**

**13.1. Anti-inflammatory agents**

*12.1.1. Role in neuroprotection*

Brain derived neurotropic factor is a neurotrophin derived from the brain (produced in the lateral geniculate body of primates) which moves in a retrograde fashion to bind TrkB receptors on RGC cell body and axon. Its retrograde transport is obstructed in acute and chronic glaucoma models, hence apoptosis occurs, as its neurotrophic support is important in RGC

Strategies for Neuroprotection in Glaucoma http://dx.doi.org/10.5772/53776 213

Eyes with chronic glaucoma exhibit loss of physiological neurotrophin levels particularly BDNF. Intravitreal injections of neurotrophins, eg BDNF has shown a reduction in apoptotic RGC death in adult rat models [71]. A recent study considered the cost effective use of serum BDNF as a biomarker for early POAG as its levels were significantly decreased in glaucoma

BDNF acts through Trk B receptors; phosphorylating kinase enzyme, activating phosphoino‐ sitol 3-kinase thereby inhibiting the activation of capsase 3, an important link in the apoptosis pathway (Figure 3). Experimentally BDNF has shown little effect on RGC survival in a single dose, but repeated intravitreal injections as well as virally mediated over expression has been shown to slow RGC loss [4]. It has been used at doses of 25-100ug/kg in clinical trials [73]

Ciliary derived neurotrophic factor (CNTF) is a secretor- protein expressed in cells of all retinal layers and the optic nerve head. The protein shows increased expression in retinal and optic nerve injuries, and is reduced in the presence of increased IOP [4]. The protein demonstrates neuroprotection in virally-mediated overexpression after intravitreal injection. In one study by Pease et al, CNTF showed a 15% less axonal death in experimental induced glaucoma, which was statistically significant over combined CNTF- BDNF and BDNF alone [74]. Intraocular delivery of neurotrophins, BDNF and CNTF, intravitreal or by viral transfer may be a potential

There is an inflammatory component to the neuronal retinal degeneration in glaucoma [75-78]. Studies have proved an age related susceptibility of glaucoma victims to progressive nerve damage and RGC loss even with single digit IOP [4]. Researchers have also established elements of the complement pathway such as C1q, as markers for astrocyte destruction that

#### **11.1. Coenzyme Q10 (Co Q10)**

Coenzyme Q10, either on its own or in combination with vitamin E (alpha -tocopherol ) have been shown to reduce intravitreal NMDA mediated damage in mice when adminsitered orally in 10mg/kg dosage [65]. In addition to its effect against oxidative stress its positive effect on the mitochondria may assist in the energy levels within the neuron, protecting it from apoptosis [66]. The RGC requires energy produced from mitochondria to ensure the conduc‐ tion of currents and normal function of the RGC. Agents that promote the ganglion cell mitochondrial energy production may be neuroprotective in glaucoma. Oral alpha-lipoic acid and nicotinamide have been suggested for further assessment for their neuroprotective effect on light induced neuronal apoptosis [67].

*Ginkgo biloba* may be useful for treating dementia associated with alzheimer and for vascular insufficiency. Although the mechanism of action remains unknown for its use in glaucoma, it is thought that it causes intracellular signaling and neutralizes reactive oxygen species [13, 68, 69]. It has been shown to reduce the RGC axonal loss in mice compared to controls in a dose dependent manner after intragastral administration [68]. In one prospective randomized placebo controlled cross over trial, Ginkgo biloba extract was used 40mg tds orally for 4 weeks, which resulted in a statistically significant decrease in the corrected pattern standard deviation in visual fields of those patients [70].

Visual field defects have been noted to improve in patients with normal tension glauco‐ ma after 4 weeks on gingko biloba and no ocular nor systemic adverse events occurred. Ginkgo biloba may exert multifactorial mechanisms which include increase ocular blood flow, anti oxidant activity, nitric oxide inhibition and improved cognitive function due to improved cerebral blood flow [70]. *Manganese Tetrakis* (4-benzoyl acid) porphyrin, a cell superoxide scavenger can prevent NO mediated motor neuron death in vitro [3]. *Cyclohex‐ imide (CHX),* a protein synthesis inhibitor has been used in doses of 50-500nM, to pre‐ vent neuronal death and protects against oxidative insults by inducing neuroprotective genes including bcl-2 [3].
