carnosine and subsequent controlled clinical trials performed in glaucomatous patients could shed light on its possible therapeutic role.

References

1.Babizhayev MA. Current ocular drug delivery challenges for N-acetylcarnosine: novel patented routes and modes of delivery, design for enhancement of therapeutic activity and drug delivery relationships. Recent Pat Drug Deliv Formul 2009; 3: 229-265.

2.Babizhayev MA, Burke L, Micans P, Richer SP. N-Acetylcarnosine sustained drug delivery eye drops to control the signs of ageless vision: glare sensitivity, cataract amelioration and quality of vision currently available treatment for the challenging 50,000-patient population. Clin Interv Aging 2009; 4: 31-50.

3.Reddy VP, Garrett MR, Perry G, Smith MA. Carnosine: a versatile antioxidant and antiglycating agent. Sci Aging Knowledge Environ 2005; pe12.

4.Rajanikant GK, Zemke D, Senut MC, et al. Carnosine is neuroprotective against permanent focal cerebral ischemia in mice. Stroke 2007; 38: 3023-3031.

5.Fujii T, Takaoka M, Tsuruoka N, et al. Dietary supplementation of L-carnosine prevents ischemia/reperfusion-induced renal injury in rats. Biol Pharm Bull 2005; 28: 361-363.

6.Liu YF, Liu HW, Peng SL. [Effects of L-canosine in preventing and treating rat cataract induced by sodium selenite]. Zhonghua Yan Ke Za Zhi 2009; 45: 533-536.

Carnitine

Vincenzo Parisi and Robert Ritch

Carnitine, an amino acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, liver), is essential for the intermediary metabolism of fatty acids. It plays an important role in such ocular tissues as the ciliary body, where muscle cells are present and may be an important energy reserve.1 After carnitine treatment, patients with Alzheimer’s disease improved on psychometric testing,2-4 and patients with chemotherapy-induced peripheral neuropathy showed amelioration of sensory amplitude and conduction velocity.5

In animal models, carnitine protects against selenite-induced cataract6 and ischemia-reperfusion retinal injury.7 It protects RPE cells against hydrogen peroxide-induced oxidative damage.8 Patients with early age-related macular degeneration showed improved visual function and fundus alterations after carnitine treatment.9

Carnitine prevents glutamate neurotoxicity in primary cultures of cerebellar neurons.10 and, by increasing the level of ATP, may improve mitochondrial function.11,12 Considerable evidence suggests that mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Parkinson’s disease and that acetyl- L-carnitine is beneficial in animal models of the disease.13 Mitochondrial dysfunction has been observed in patients with glaucoma.14 Thus, one could hypothesize that improved ganglion cell function and neural conduction along the optic nerve could occur after carnitine treatment in glaucoma patients.

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At present there is lack of information regarding controlled clinical trials performed in glaucomatous patients treated with carnitine.

References

1.Pessotto P, Valeri P, Arrigoni-Martelli E. The presence of L-carnitine in ocular tissues of the rabbit. J Ocul Pharmacol 1994; 10: 643-651.

2.Thal LJ, Calvani M, Amato A, et al. A 1-year controlled trial of acetyl-l-carnitine in earlyonset al.zheimer disease. Neurology 2000; 55: 805-810.

3.Hudson S, Tabet N. Acetyl-L-carnitine for dementia. Cochrane Database Syst Rev 2003; CD003158.

4.Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 2003; 18: 61-71.

5.De Grandis D. Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short review. CNS Drugs 2007; 21 Suppl 1: 39-43.

6.Geraldine P, Sneha B, Elanchezhian R, et al. Prevention of selenite-induced cataracttogenesis by acetyl-L-carnitine: an experimental study. Exp Eye Res 2006; 83: 1340-1349.

7.Kocer I, Kulacoglu D, Altuntas I, et al. Protection of the retina from ischemia-reperfusion injury by L-carnitine in guinea pigs. Eur J Ophthalmol 2003; 13: 80-85.

8.Shamsi FA, Chaudhry IA, Bouton ME, Al-Rajhi AA. L-carnitine protects human retinal pigment epithelial cells from oxidative damage. Curr Eye Res 2007 ; 32: 575-584.

9.Feher J, Kovacs B, Kovacs I, et al. Improvement of Visual Functions and Fundus Alterations in Early Age-Related Macular Degeneration Treated with a Combination of Acetyl-L- Carnitine, n-3 Fatty Acids, and Coenzyme Q10. Ophthalmologica 2005; 219: 154-166.

10.Llansola M, Erceg S, Hernandez-Viadel M, Felipo V. Prevention of ammonia and glutamate neurotoxicity by carnitine: molecular mechanisms. Metab Brain Dis 2002; 17: 389-397.

11.Evangeliou A, Vlassopoulos D. Carnitine Metabolism and Deficit - When Supplementation is Necessary? Curr Pharm Biotechnol 2003; 4: 211-219.

12.Kumaran S, Panneerselvam KS, Shila S, Sivarajan K, Panneerselvam C. Age-associated deficit of mitochondrial oxidative phosphorylation in skeletal muscle: Role of carnitine and lipoic acid. Vasc Med 2005; 280: 83-89.

13.Beal MF. Bioenergetic approaches for neuroprotection in Parkinson’s disease. Ann Neurol 2003; 53 Suppl 3: S39-47.

14.Kong GY, Van Bergen NJ, Trounce IA, Crowston JG. Mitochondrial dysfunction and glaucoma. J Glaucoma 2009; 18: 93-100.

Coenzyme Q10

Nathan Radcliffe

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a membrane bound mitochondrial antioxidant cofactor that participates in the electron transport chain. CoQ10 has been shown to improve mitochondrial function and is currently being evaluated in clinical trials for Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.1,2 In humans with Parkinson’s disease, there is evidence that CoQ10 can slow the rate of functional decline compared to placebo.3

CoQ10 has received interest in glaucoma because it is a free radical scavenger and inhibits apoptosis by blocking Bax.1,4 Mitochondrial dysfunction and

oxidative stress have been implicated in the development of glaucomatous optic neuropathy.5 In a rat model of pressure-induced retinal ischemia/reperfusion injury, CoQ10 administration inhibited glutamate increases and prevented retinal ganglion cell (RGC) apoptosis.6 Guo and Cordeiro have shown that CoQ10 inhibits staurosporine induced RGC apoptosis as visualized with the detection of apoptosing retinal cells technique.7 As a result of these and other studies, CoQ10 has received recent attention for a potential role for neuroprotection in glaucoma.8 However, there are no randomized clinical trials showing that CoQ10 is effective for glaucoma neuroprotection in humans, nor are there any experimental ocular hypertension/glaucoma animal studies demonstrating a neuroprotective effect of CoQ10.

References

1.Littarru GP, Tiano L. Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol. Biotechnol 2007; 37: 31-37.

2.Chaturvedi RK, Beal M. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 2008; 1147: 395-412.

3.Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q(10) in early Parkinson diseaseEvidence of slowing of the functional decline. Arch Neurol 2002; 59: 1541-1552.

4.Papucci L, Schiavone N, Witort E, et al. Coenzyme Q10 prevents apoptosis by inhibiting mitochondrial depolarization independently of its free radical-scavenging property. J Biol Chem 2003; 278: 28220-28228.

5.Tezel G. Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Brain Res 2006; 25: 490-513.

6.Nucci C, Tartaglione R, Cerulli A, et al. Retinal damage caused by high intraocular pressureinduced transient ischemia is prevented by coenzyme Q10 in rat. Int Rev Neurobiol 2007; 82: 397-406.

7.Guo L, Cordeiro MF. Assessment of neuroprotection in the retina with DARC. Prog Brain Res 2008; 173: 437-450.

8.Russo R, Cavaliere F, Rombolà L, et al. Rational basis for the development of coenzyme Q10 as a neurotherapeutic agent for retinal protection. Prog Brain Res 2008; 173: 575-582.

Folic acid

Nathan Radcliffe

Folic acid is an essential vitamin that is involved (in its active form tetrahydrofolate) in nucleotide biosynthesis and homocysteine (HCY) remethylation. Folate is found in green, leafy vegetables and in many breads and cereals fortified with folate. Folic acid deficiency (as well as certain medications and enzymatic deficiencies) can result in elevated levels of HCY. Hyperhomocysteinemia (HHCY) is a strong risk factor for atherosclerotic and thromboembolic disease. Elevated HCY levels are associated with several neurodegenerative diseases, including Alzheimer’s disease.1,2 Supplemental folic acid, combined with other B-vitamins (B-6 and B-12) can lower HCY levels by at least 30%.3 A number of large,

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randomized trials investigating the effects of lowering HCY with folate and B vitamins on cardiovascular and cerebrovascular endpoints have been performed without any strong evidence of benefit to HCY lowering.4 Additionally, a recent large scale randomized trial showed that high-dose B vitamin supplements did not slow cognitive decline in individuals with mild to moderate AD.5

Homocysteine is toxic to retinal ganglion cells (RGCs) through stimulation of N-methyl-D-aspartate (NMDA) receptors and this excitotoxic damage is possibly potentiated by simultaneous elevation of HCY and glutamate.6 An in vitro study of the effects of toxic concentrations of HCY on rat retinal tissues found HCY to be damaging to RGCs as well as to the outer and inner nuclear layers.7 These findings raise the question of whether HHCY could be involved in the pathophysiology of glaucomatous optic neuropathy.

While the findings about HCY levels in POAG are somewhat conflicting, they have not been consistently found to be higher than controls. Levels of HCY are elevated in exfoliation glaucoma while folate, vitamin B12 and B6 levels are reduced in this condition. In summary, while there are intriguing connections between glaucoma and folate deficiency/elevated HCY, there is currently no evidence from experimental animal studies or human clinical trials to substantiate folate supplementation for glaucoma, we do advocate treating those patients, particularly those with exfoliation syndrome, in whom HCY levels are elevated. Furthermore, the lack of an observed benefit to HCY lowering with folate and B-vitamin supplementation in large cardiovascular trials raises the possibility that HCY may be a marker, rather than a cause, of these pathologies.

References

1.Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002; 346: 476-483.

2.Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005; 82: 636-643.

3.Lobo A, Naso A, Arheart K, et al. Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12. Am J Cardiol 1999;

83:821-825.

4.Herrmann W, Herrmann M, Obeid R. Hyperhomocysteinaemia: a critical review of old and new aspects. Curr Drug Metab 2007; 8: 17-31.

5.Aisen PS, Schneider LS, Sano M, et al. Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 2008; 300: 1774-1783.

6.Moore P, El-sherbeny A, Roon P, et al. Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res 2001;

73:45-57.

7.Viktorov IV, Aleksandrova OP, Alekseeva NY. Homocysteine toxicity in organotypic cultures of rat retina. Bull Exp Biol Med 2006; 141: 471-474.

8.Vessani RM, Liebmann JM, Jofe M, Ritch R. Plasma homocysteine is elevated in patients with exfoliation syndrome. Am J Ophthalmol 2003; 136: 41-46.

9.Wang G, Medeiros FA, Barshop BA, Weinreb RN. Total plasma homocysteine and primary open-angle glaucoma. Am J Ophthalmol 2004; 137: 401-406.