Associate Prof. Banu Bozkurt, MD, FEBO. Selcuk University Faculty of Medicine, Department of Ophthalmology, Konya, Turkey

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1 Associate Prof. Banu Bozkurt, MD, FEBO Selcuk University Faculty of Medicine, Department of Ophthalmology, Konya, Turkey

2 Reduction of IOP to the target therapeutic Lowering IOP range protects is not always against successful glaucomatous in halting optic the nerve and progression visual field of loss damage

3 NORMAL VISION Physiological loss Progression rate REVERSE FUTURE THERAPIES STOP Serious functional inability Untreated DECREASE BLINDNESS DIAGNOSIS DEATH

4 Future therapies Neuroprotection Preventing neuron loss Stop visual field progression Neuroregeneration Neuron reactivation Reverse visual field defect EGS. Terminology and Guidelines for Glaucoma, 3rd edition, 2008

5 PubMed 360 papers on Neuroprotection in Glaucoma Randomized clinical trials Experimental glaucoma models Optic nerve crush injury In vitro studies RGC cultures

6 Oxidative stress Impaired ocular perfusion Axonal Transport failure Autoimmunity Inflammation Neurotrophic factor deprivation Excitotoxic Damage Weinreb & Khaw. Lancet 2004;363:

7 Excitotoxicity NMDA rec antagonist; Memantine, MK801 Neurotrophin Deprivation Brain Derived Neurotrophic Factor, CNTF, GDNF, PEDNF, Gene therapy Mitochondrial Dysfunction Coenzyme Q10 Oxidative stress Vitamin E, Ginkgo Biloba Inflammation Cop-1, Tumour necrosis factor-alpha blocker Apoptosis inhibitors Erythropoetin Neuroregeneration ROCK inhibitors

NTs promote development, differentiation and survival of RGC Exogenous supplementation of BDNF and ciliary NT factor enhance survival of RGCs after optic nerve injuries and glaucoma models In rat

8 NTs promote development, differentiation and survival of RGC Exogenous supplementation of BDNF and ciliary NT factor enhance survival of RGCs after optic nerve injuries and glaucoma models In rat model of glaucoma, less RGC death was observed with NGF eyedrops Three patients with advanced glaucoma treated once daily for 3 months showed improvement in visual field, visual acuity, contrast sensitivity Lambiase A, et al. Proc Natl Acad Sci U S A 2009; 106: 13469

9 Glutamate is an essential neuro-transmitter in CNS and retina Ganglion cells and glial cells were shown to produce glutamate in IOP and ischemia models Elevated levels of glutamate in the vitreous in humans and monkeys with glaucoma. Inhibitors of NMDAR and Ca channel blockers

An uncompetitive antagonist of Effective Phase the NMDAR III trial: neuroprotective that 2 oral was doses approved

in treating glaucoma Alzheimer s patients with controlled IOP.

However; Blocks only excessive NMDAR showed activity no beneficial effect in patients with glaucoma. Hare WA, et al.

I: functional measures. Invest Ophthalmol Vis Sci 2004; 45: 2625 Yucel YH, et al.

10 An uncompetitive antagonist of Effective Phase the NMDAR III trial: neuroprotective that 2 oral was doses approved agent of memantine by monkey vshypertension an arm of glaucoma oral the placebo FDA for models. in treating glaucoma Alzheimer s patients with controlled IOP. 4 years; disease 6 mo and intervals, vascular visual dementia field progression Low affinity, open channel blocker However; Blocks only excessive NMDAR showed activity no beneficial effect in patients with glaucoma. Hare WA, et al. Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, I: functional measures. Invest Ophthalmol Vis Sci 2004; 45: 2625 Yucel YH, et al. Memantine protects neurons from shrinkage in the lateral geniculate Allergan, Inc. Report on Fourth Quarter Operating Results: nucleus in experimental glaucoma. Arch Ophthalmol 2006; 124: 217 Memantine Update, January 30, 2008.

11 NO is a neuronal messenger critical for normal retinal neurotransmission and phototransduction. Unregulated, it reacts with the superoxide anion to form peroxynitrite, a highly ROS. In glaucoma, overstimulation of NMDAR activates NO synthetase (NOS) by reactive astrocytes and microglia in the ONH. Aminoguanidine is a potent inhibitor of inducible NOS; Its effectiveness in animal models of glaucoma remains inconclusive.

Vitamin C ve E ( -tocopherol) Melatonin was

12 Vitamin C ve E ( -tocopherol) Melatonin was shown to inhibit RGCs loss in the NO-induced retinal damage model. Ginkgo Biloba has been used to treat Alzheimer s disease and LTG; increases retinal blood flow Its extract EGb761 was shown to decrease IOP-induced RGCs loss.

Coenzyme Q10: An important component of the mitochondrial electron transport chain. Potentiates energy production to overcome the consequences of excessive glutamate.

13 Coenzyme Q10: An important component of the mitochondrial electron transport chain. Potentiates energy production to overcome the consequences of excessive glutamate. Inhibits the transcription factor NF-, responsible for inflammation and autoimmune disease. Inhibits opening of the mitochondrial permeability transition pore (PTP), involved in cell death pathways. Retinal protection after ischemia/reperfusion in the rat glaucoma model Russo R, et al. 2008; Osborne NN. Prog Brain Res 2008.

14 Microglial cell activation with release of proinflammatory mediators (TNF-α), which create an inflammatory microenvironment for neurones Apoptosis via caspase 8 and secondary degeneration Blocking antibodies that interfere with TNF-α soluble receptor(s) TNF-α converting enzyme inhibitor(s). Infliximab, a TNF-α receptor blocker, was shown to decrease neuronal death in glaucoma Tezel G. TNF-alpha signalling in glaucomatous degeneration. Prog Brain Res 2008; 173: 409; Bozkurt B, et al. Association of tumour necrosis factor-alpha -308 G/A polymorphism with primary open-angle glaucoma. Clin Experiment Ophthalmol. 2012

15 TNF- Mechanisms of neural injury in glaucoma. In: Neuroprotection for glaucoma: a pocket guide. Levin, Weinreb, Di Polo (Eds), Ethis, New York, 2007

16 Increase production of Bcl-2 and Bcl-XL Brimonidine Caspase inhibitors Calpeptin, Calpain specific inhibitor Tatton W, Surv Ophthalmol 2003; 48: Chaudhary P, Brain Res Mol Brain Res 1999; 67:

A natural cytokine used to treat anemia. Intravitreal injections of EPO have been shown to inhibit caspase-3 activation and death signals and rescue RGCs in axotomized rats and OHT models.

17 A natural cytokine used to treat anemia. Intravitreal injections of EPO have been shown to inhibit caspase-3 activation and death signals and rescue RGCs in axotomized rats and OHT models. Dose toxicity studies of IV injections of recombinant EPO in rats and rabbits were shown to be safe based on electroretinography, FFA and histopathology. Tsai JC. Curr EyeRes. 2005;30: ; Tsai JC. J Glaucoma. 2007;16:

18 Recent discoveries of the molecular mechanisms underlying glaucoma A number of molecules have been shown to be directly neuroprotective in experimental glaucoma So far none of these molecules has found its way into clinical practice. Too many challenges in translating advances from the basic science laboratory into real and proven benefits in humans

Can in-vitro studies be a true model for chronic Human glaucoma clinical in humans?

(chronic An animal disease) model cannot properly simulate Variability human between

ocular and systemic If lucky medications to find a molecule Which tests is the best for

19 Can in-vitro studies be a true model for chronic Human glaucoma clinical in humans? trials Which Timing animal? (chronic An animal disease) model cannot properly simulate Variability human between disease. patients: Have Which comorbidities, glaucoma model? ocular and systemic If lucky medications to find a molecule Which tests is the best for monitoring the Difficulty in formulating pharmacologic/biotherapetic dosages disease? Delivery Functional regimens or in humans structural damage Reliability The need for minimal side effects

20 1. Should have a receptor in retina 2. Should reach a concentration in the vitreus and retina to activate its receptor 3. Its efficacy in promoting cell survival and inhibiting death signals should be shown in experimental studies. 4. Its efficacy should be demonstrated in randomised controlled clinical trials.

22 Fosfatidil-inositol-3 (PI3) kinaz ekstrasellüler sinyalle regüle kinaz TattonW, et al. Surv Ophthalmol 2003; 48: 25 Wheeler LA, et al. Invest Ophthalmol 2001; 42: 411; Lai RK, et al. Vis Neurosci 2002; 19: 175

23 Mean treated IOP was similar for brimonidine- and timolol-treated patients at all time points. Statistically fewer brimonidine-treated patients (9.1%) had visual field progression by pointwise linear regression than timolol-treated patients (39.2%; p=.001). More brimonidine-treated (28.3%) than timolol-treated (11.4%) patients discontinued study participation because of drug-related adverse events (P=.008).

24 Is neuroprotection so far away? Although there are substantive barriers; we still have hope.. Clinical trials for glaucoma neuroprotection are not impossible. Quigley HA. Curr Opin Ophthalmol. 2012; 23:

25 Thank you very much for your interest

CHAPTER 2 LITERATURE REVIEW. Glaucoma is a devastating, worldwide disease. In just the United States there are over 2

CHAPTER 2 LITERATURE REVIEW. Glaucoma is a devastating, worldwide disease. In just the United States there are over 2 CHAPTER 2 LITERATURE REVIEW Introduction Glaucoma is a devastating, worldwide disease. In just the United States there are over 2 million estimated cases with 120,000 of those responsible for blindness.