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8.NON-PHARMACEUTICAL MEDICATIONS AND APPROACHES
Section leaders: Makoto Araie, Robert Ritch, Clement Tham
Contributors: Makoto Aihara, Aiko Iwase, Sandra Fernando, Michael S Kook, Simon Law, Robert Nussenblatt, Vincenzo Parisi, Nathan Radcliffe, Douglas Rhee, Kwok-Fai So, Raymond Chuen-Chung Chang, He Wei, Lori Ventura
Consensus statements
1.There is a paucity of clinical trial information examining neuroprotective effects of non-pharmaceutical compounds (alternative or complementary therapies) for glaucoma.
Comment: Bio-availability of these natural compounds has not been well studied, and clinical studies of their efficacy and safety are needed.
2.Exercise reduces IOP, but the extent, duration and clinical significance are unclear.
Comment: Exercise also can increase ocular blood flow, but the significance of this is unknown.
3.Acupuncture has been reported to lower IOP and increase ocular blood flow. Comment: The reported results are inconsistent and additional studies are needed before it is employed in clinical practice.
Quercetin and quercetin glycosides
Makoto Aihara
Background
Flavonoids comprise a large family of plant-derived compounds widely distributed in fruits and vegetables.1,2 Here is growing evidence from human nutrition studies that the absorption and bioavailability of specific flavonoids is much higher than originally believed.2,3 Flavonoids are believed to exert protective and/or beneficial effects on multiple disease states, including cancer, cardiovascular disease, and neurodegenerative disorders.2-5 These physiological benefits of flavonoids are generally thought to be derived from their antioxidant activity and free radical scavenging.6
Quercetin is an important flavonoid and is ordinarily present bound to a sugar as a glycoside. For example, quercetin 3-O-rutinoside (rutin) is one of the
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2010 © Kugler Publications, Amsterdam, The Netherlands
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quercetin glycosides, which is rich in buckwheat and tartary buckwheat, commonly ingested in Japan and other Asian countries, and amazingly accounting for as high as 1% of the total weight of buckwheat and tartary buckwheat.7,8 RGC death in glaucoma is believed to be induced by apoptotic mechanisms triggered by multiple stimuli, including ischemia, oxidative stress, or elevation of glutamate levels.9,10 Numerous studies have demonstrated that excessive glutamate induces RGC death in vitro and in vivo,11 and that the glutamate receptor antagonists MK801 or memantine can ameliorate RGC death caused by elevated intraocular pressure.12-16 Oxidative stress induced either by increased levels of reactive oxygen species (ROS) or mitochondrial dysfunction is also implicated in glaucomatous, ischemic, and hereditary optic neuropathies.17,18 Accordingly, flavonoids including quercetin may also have neuroprotective
potential in glaucoma.
Neuroprotection in non-retinal neurons
In in vitro culture studies, Quercetin showed an ameliorating effect on oxidative stress-induced PC12 cell death19 or midbrain culture of rat,20 and also other kinds of stress-induced cell death, such as beta-amyloid induced PC12 cell death21 or kainite/NMDA induced rat neuronal death.22 Quercetin also induced neuroprotective effect by modulating inflammatory responses in astroglia by IL1beta.23 In vivo, quercetin was effective in rat brain trauma model24 and cerebrovascular insults.25
Neuroprotection in retinal neurons
Only five studies describing the potential effects of flavonoids on RGC death induced by oxidative stress or pressure stress using RGC-5 transgenic cell lines or in vivo rodent models have been reported.26-30 Liu et al. reported a neuroprotective effect of quercetin on pressure-induced RGC-5 death.30
Drug delivery of quercetin and quercetin glycoside
A few reports have indicated that repeated intake of several hundred milligrams of quercetin-rutinoside resulted in a plasma concentration of 100nM or higher.31-33 Moreover, flavonoids can penetrate into the central nervous system through the blood-brain barrier.34 Interestingly, quercetin itself may not be effective in neurodegenerative disease such as Parkinson disease model rat,35 because it penetrates the blood brain barrier less efficiently than quercetin glycosides.25 This may be the reason for its beneficial effects in rat brain trauma or cerebrovascular insults.24,25
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Mechanism of neuroprotective action
Although the precise mechanism of action remains unclear, the beneficial activity of flavonoids is generally attributed to their antioxidative efficacy.8,22,24 The antioxidant capacity of flavonoids depends on the arrangement of functional groups surrounding the flavonol nucleus, which may directly affect glutathione metabolism, antioxidant capacity, or the ability to maintain low Ca2+ levels despite high levels of reactive oxygen species.1,8
Conclusion
Quercetin and its glycosides have neuroprotective effect and may have applications for glaucomatous optic neuropathy. However there was no clinical evidence to use them as a neuroprotective agent. The major concerns of quercetin intake as a supplement are its poor penetration into the retina25,34 and its specific inhibitory effect on HSP72 induction,36,37 which may lead to deteriorate neuroprotective effect by HSP72. Further studies are needed using glaucoma9 animal model and human studies.
References
1.Heim KE, Tagliaferro AR, Bobilya D. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 2002; 13: 572-584.
2.Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002; 22: 19-34.
3.Manach C, Williamson G, Morand C, et al. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 2005; 81: 230S-242S.
4.Middleton E Jr. Effect of plant flavonoids on immune and inflammatory cell function. Adv Exp Med Biol 1998; 439: 175-182.
5.Middleton EJ, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000; 52: 673-751.
6.Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med 2001; 30: 433-446.
7.Kim DW, Hwang IK, Lim SS, et al. Germinated buckwheat extract decreases blood pressure and nitrotyrosine immunoreactivity in aortic endothelial cells in spontaneously hypertensive rats. Phytother Res 2009; 23: 993-998.
8.Fabjan N, Rode J, Kosir IJ, et al. Tartary buckwheat (Fagopyrum tataricum Gaertn.) as a source of dietary rutin and quercitrin. J Agric Food Chem 2003; 51: 6452-6455.
9.Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res 1999; 18: 39-57.
10.Wax MB, Tezel G. Neurobiology of glaucomatous optic neuropathy: diverse cellular events in neurodegeneration and neuroprotection. Mol Neurobiol 2002; 26: 45-55.
11.Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res 1997; 37: 3483-3494.
12.Lipton SA. Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. Surv Ophthalmol 2003; 48 Suppl 1: S38-46.
13.Chaudhary P, Ahmed F, Sharma S. MK801-a neuroprotectant in rat hypertensive eyes. Brain Res 1998; 792: 154-158.
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14.Hare WA, WoldeMussie E, Lai RK, 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: 2625-2639.
15.Lagrèze WA, Knörle R, Bach M, Feuerstein TJ. Memantine is neuroprotective in a rat model of pressure-induced retinal ischemia. Invest Ophthalmol Vis Sci 1998; 39: 1063-1066.
16.WoldeMussie E, Yoles E, Schwartz M, et al. Neuroprotective effect of memantine in different retinal injury models in rats. J Glaucoma 2002; 11: 474-480.
17.Carelli V, La Morgia C, Valentino ML, et al. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta 2009; 1787: 518-528.
18.Tezel G. Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Brain Res 2006; 25: 490-513.
19.Dajas F, Rivera F, Blasina F, et al. Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox Res 2003; 5: 425-432.
20.Mercer LD, Kelly BL, Horne MK, Beart P. Dietary polyphenols protect dopamine neurons from oxidative insults and apoptosis: investigations in primary rat mesencephalic cultures. Biochem Pharmacol 2005; 69: 339-345.
21.Zhu JT, Choi RC, Chu GK, et al. Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: a comparison of different flavonoids in activating estrogenic effect and in preventing beta-amyloid-induced cell death. J Agric Food Chem 2007; 55: 2438-2445.
22.Silva B, Oliveira PJ, Dias A, Malva J. Quercetin, kaempferol and biapigenin from Hypericum perforatum are neuroprotective against excitotoxic insults. Neurotox Res 2008; 13: 265-279.
23.Sharma V, Mishra M, Ghosh S, et al. Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull 2007; 73: 55-63.
24.Schultke E, Kamencic H, Zhao M, et al. Neuroprotection following fluid percussion brain trauma: a pilot study using quercetin. J Neurotrauma 2005; 22: 1475-1484.
25.Ossola B, Kaariainen TM, Mannisto PT. The multiple faces of quercetin in neuroprotection. Expert Opin Drug Saf 2009; 8: 397-409.
26.Zhang B, Safa R, Rusciano D, Osborne NN. Epigallocatechin gallate, an active ingredient from green tea, attenuates damaging influences to the retina caused by ischemia/reperfusion. Brain Res 2007; 1159: 40-53.
27.Maher P, Hanneken A. Flavonoids protect retinal ganglion cells from ischemia in vitro. Exp Eye Res 2008; 86: 366-374.
28.Maher P, Hanneken A. Flavonoids protect retinal ganglion cells from oxidative stress-induced death. Invest Ophthalmol Vis Sci 2005; 46: 4796-4803.
29.Jung SH, Kang KD, Ji D, et al. The flavonoid baicalin counteracts ischemic and oxidative insults to retinal cells and lipid peroxidation to brain membranes. Neurochem Int 2008; 53: 325-337.
30.Liu Q, Ju WK, Crowston JG, et al. Oxidative stress is an early event in hydrostatic pressure induced retinal ganglion cell damage. Invest Ophthalmol Vis Sci 2007; 48: 4580-9.
31.Boyle SP, Dobson VL, Duthie SJ, et al. Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study. Eur J Clin Nutr 2000; 54: 774-782.
32.Erlund I, Kosonen T, Alfthan G, et al. Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol 2000; 56: 545-553.
33.Graefe EU, Wittig J, Mueller S, et al. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol 2001; 41: 492-499.
34.Youdim KA, Qaiser MZ, Begley DJ, et al. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med 2004; 36: 592-604.
35.Zbarsky V, Datla KP, Parkar S, et al. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease. Free Radic Res 2005; 39: 1119-1125.
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36.Kretz A, Schmeer C, Tausch S, Isenmann SS. Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo. Neurobiol Dis 2006; 21: 421-430.
37.Kwong JM, Lam TT, Caprioli J. Hyperthermic pre-conditioning protects retinal neurons from N-methyl-D-aspartate (NMDA)-induced apoptosis in rat. Brain Res 2003; 970: 119-130.
Methylcobalamin
Makoto Aihara
Background
Methylcobalamin is an active form of Vitamin B12 (cyanocobalamin). Vitamin B12 deficiency is well known to cause megaloblastic anemia and neuropathy. Humans have two vitamin B12-dependent enzymes (i.e., methionine synthase and methylmalonyl coenzyme mutase). Neuropathy occurs because of lack of methionine synthase and not by a lack of activity by methylmalonyl coenzyme mutase. Methylcobalamin is effective in enhancing myelinization in neural axons. Several reports have indicated enhancement of axonal regeneration or postsynaptic field potentials.1-3 In rat cultured cortical neurons, methylcobalamin protected against glutamate-induced cell death.4 Vitamin B12 has until now been used primarily for diabetic neuropathy and peripheral neuropathy in humans.
Ocular studies
In the eye, vitamin B12 deficiency induces optic nerve atrophy in monkeys.5 Also, in a patient with methionine synthase deficiency resembling methylcobalamine deficiency, the visual system was disturbed.6 Thus, methylcobalamin may have a neuroprotective effect on optic neuropathy, including glaucoma. However, only a few studies have been reported in ophthalmology. In rat retinal culture, methylcobalamin protected against glutamate-induced cell death.7 In in vivo experiments, only one report showed methylcobalamine to ameliorate optic nerve degeneration in the optic nerve crush rat model.8 There was no evidence of a beneficial effect of methylcobalamin in glaucomatous optic neuropathy.
References
1.Yamazaki K, Oda K, Endo C, Kikuchi T, Wakabayashi T. Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse. Neurosci Lett 1994; 170: 195-197.
2.Ikeuchi Y, Nishizaki T. Methylcobalamin induces a long-lasting enhancement of the postsynaptic field potential in hippocampal slices of the guinea pig. Neurosci Lett 1995; 192: 113-116.
3.Nishikawa Y, Shibata S, Shimazoe T, Watanabe S. Methylcobalamin induces a long-lasting enhancement of the field potential in rat suprachiasmatic nucleus slices. Neurosci Lett 1996; 220: 199-202.