Life Extension Magazine

Life Extension Magazine July 2010

Report

Halt the Stealth Threat of Parkinson’s Disease

By Julius Goepp, MD

Green Tea

The B Complex

Vitamin B6 in physiologically active form is the prerequisite for the production of dopamine. Deficiencies and disorders in B vitamin and folate metabolism have thus been implicated in many neurological disorders, including PD, and studies as early as the 1970’s were directed at demonstrating the effects of supplementation—initially with discouraging results.52-54

As our understanding of the role of the toxic amino acid homocysteine grew, however, more targeted and mechanism-based studies became possible. Homocysteine levels are closely related to folate, vitamin B6, and vitamin B12 status, and elevated homocysteine is found in cardiovascular disease and a variety of neurological and psychiatric disturbances, including PD.55-57 Paradoxically, levodopa treatment of PD can itself lead to elevations in homocysteine, potentially worsening the condition. This has prompted researchers to recommend B complex supplements in those taking the drug.58

Definitive demonstration of the value of this approach came from Singapore in 2005, where neurologists supplemented PD patients who were stable and on their best doses of levodopa with pyridoxine, a common form of vitamin B6. Mean motor and activities of daily living scores improved significantly following supplementation, and deteriorated again when the supplements were stopped.59 Low serum folate is also found in PD patients, especially those taking levodopa;57 Canadian researchers have demonstrated that a folate/B12 supplement could decrease plasma homocysteine levels in patients taking levodopa.60

A review paper in 2007 points to recent work with the active form of vitamin B6, pyridoxal-5’ phosphate (P5P), noting that a number of neurological disorders including PD offer attractive therapeutic targets for this substance.61 Because of the association of elevated homocysteine and its deleterious effects with both PD itself and levodopa therapy, supplementation with folate, B6, and B12 is warranted.62-65

One note of caution regarding B6 supplements is if a PD patient is being treated with levodopa alone without the decarboxylase inhibitor carbidopa. Vitamin B6 may cause levadopa to convert to dopamine in the bloodstream before it crosses the blood-brain barrier (where it beneficially converts to dopamine in the brain). For safety’s sake, it is best to take vitamin B6 supplements at a time of the day furthest from the last dose of a levadopa (L-dopa)-containing medication and to have one’s blood tested periodically to make sure that excess dopamine does not accumulate in the bloodstream.

Carnitine

Carnitine serves as a co-factor in fatty acid metabolism—it helps to “shuttle” large fat molecules into the cellular powerhouses known as the mitochondria, where they are metabolized for energy. This makes carnitine a valuable weapon against PD.5,66 A small but burgeoning body of data indicates carnitine as a promising preventive for PD through its support of brain energy management.

Carnitine

Researchers at Mount Sinai Medical Center have successfully prevented experimentally-induced PD in monkeys by pre-treating them with acetyl-L-carnitine (ALC), a readily-absorbed form of the nutrient.67 Italian researchers have led the way in studies of carnitine as a neuroprotective agent in the brains of methamphetamine users, who develop an acute form of brain injury resulting from the same basic mitochondrial destruction and free radical damage observed in PD.66,68 This work has been extended in similar studies by researchers at the US National Center for Toxicological Research.69

In the most exciting recent development in this area of research, Chinese nutritional scientists in Shanghai explored the combination of ALC with another energy-related nutrient, lipoic acid, in preventing PD-like changes in human neural cells in culture.70 They found that either nutrient, or the combination, applied for 4 weeks prior to a PD-inducing chemical, protected the cells from mitochondrial dysfunction, oxidative damage, and accumulation of the dangerous alpha-synuclein protein characteristic of PD.

Most notably, the combination of supplements was effective at 100- to 1,000-fold lower concentrations than were required for either acting alone—powerful evidence for a synergy that led the researchers to conclude, “This study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for PD.”70

Green Tea

According to internationally-noted Israeli neuroscientist Sylvia Mandel, “Tea consumption is inversely correlated with the incidence of dementia and Al zheimer’s and Parkinson’s diseases.”71 Green tea contains valuable antioxidant polyphenols known to be protective against a host of chronic and age-related conditions.

This has given rise to a tremendous scientific interest in green tea and its active compound epigallocatechin gallate or EGCG as a neuroprotectant in PD, especially because these compounds penetrate into brain tissue extremely well compared to many drugs.72-74 Israeli researchers showed in 2001, for example, that they could prevent the cellular changes associated with PD in mice by pre-treating them with either green tea extracts or EGCG ahead of inducing the condition by chemical injection,73 work that has subsequently been repeated and extended in laboratories around the world.75-80 The Israeli team also demonstrated that green tea extracts can prevent activation of the inflammation-producing nuclear factor-kappaB (NF-kB) system in brain cell cultures triggered to develop PD-like changes.81 EGCG’s specific anti-inflammatory properties have been further shown to protect cultured brain tissue from the loss of dopaminergic cells as well.16 An entirely distinct component of green and black teas, L-theanine, is a unique amino acid that can cross the blood-brain barrier.82 Korean scientists have recently shown it may prevent the dopaminergic cell death characteristic of PD.83

Another potential benefit of green tea extracts is their ability to sustain dopamine levels in ailing brain tissue, reducing the severity of symptoms.84

The multiple beneficial compounds found in green tea form a combination therapy all their own, maximize their neuroprotective effects in PD and other neurodegenerative conditions.71,80,85-89

Resveratrol

Since dopamine itself is an oxidant compound which can contribute to the early demise of its own neurons, scientists have studied the antioxidant potential of resveratrol to prevent this paradoxical destruction. They found that human neural tissue treated with dopamine underwent rapid cell death as a result of loss of mitochondrial function, but that exposing the cells to resveratrol for just one hour prior to dopamine treatment prevented cell loss and preserved mitochondrial function.90 Canadian scientists showed in 2008 that they could prevent neuronal cell death caused by inflammation through the use of resveratrol.91

That anti-inflammatory action was further dramatically explored by Chinese researchers, who first administered a PD-inducing chemical to rats, and then gave them resveratrol orally each day for 10 weeks.92 They found that even as early as 2 weeks into supplementation, the diseased rats demonstrated significant improvement in their movement disorders, and examination of their brains showed marked reduction in mitochondrial and dopaminergic cell damage. Remarkably, they also found a reduction in expression of the inflammatory markers cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-alpha). They were led to conclude that “resveratrol exerts a neuroprotective effect on [a chemically]-induced Parkinson’s disease rat model, and this protection is related to the reduced inflammatory reaction.”

As with green tea extracts, it appears that resveratrol’s promise for PD prevention may reside in its multi-modal mechanisms of action, targeting oxidative stress, inflammation, and other cellular processes fundamental in regulating brain function.93

Additional Interventions

The explosion of knowledge about the many interrelated probable causes of Parkinson’s disease in the past decade has led to a number of other nutrient molecules’ being explored for their neuroprotective, anti-parkinsonian potential. Vitamin D, for example, a known neurohormone with neuroprotective effects throughout the life span, has been shown to prevent many of the changes associated with PD in laboratory and animal studies; it is also known to be deficient in a large proportion of PD sufferers.94-99 Curcumin, a derivative of the spices turmeric and cumin, is a natural inhibitor of inflammation through its potent modulation of the inflammatory NF-kappaB system; it prevents chemically-induced changes in lab models of PD, and exerts significant neuroprotection.100-107 And the pineal hormone melatonin, an antioxidant in its own right, may help to preserve cells’ ability to make dopamine and to reduce accumulation of destructive alpha-synuclein proteins. It is also invaluable as a sleep aid for PD victims, who often suffer from distressing sleep disturbances.108-114

Summary

While its precise cause remains unknown—and there is no cure—aging is the single most important risk factor for Parkinson’s disease (PD). Symptoms manifest in PD victims as early as age 50 (earlier in rare instances). The risk of onset continues to rise with advancing age. Incidence increases dramatically at age 60. Slowed movement, tremors, mild cognitive impairment, and difficulty standing up are the early warning signs. End-stage PD is marked by dementia, near-total immobility, personality and mood disorders, and death. These are the result of multiple, interacting destructive processes triggered by oxidant stress, mitochondrial dysfunction, and inflammation. Together these processes selectively and irreversibly destroy vital movement-controlling cells deep in the brain, resulting in loss of control and gradual decline in movement and activity. Nutritional interventions acting through multiple mechanisms can slow or prevent the accumulation of brain cell damage that produces Parkinson’s disease. In particular, nutrients that enhance brain energy utilization, prevent mitochondrial dysfunction, protect against oxidant damage, and tame inflammation are among the leading contenders for anti-Parkinson’s therapies. The most promising among these include creatine, omega-3 fatty acids, coenzyme Q10, B vitamins (particularly B6 and pyridoxal-5’phosphate), carnitine, lipoic acid, green tea extract, and resveratrol.

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References

1. Hindle JV. Ageing, neurodegeneration and Parkinson’s disease. Age and Ageing. 2010;39(2):156-61

2. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003 Jun 1;157(11):1015-22.

3. Bennett DA, Beckett LA, Murray AM, et al. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med. 1996 Jan 11;334(2):71-6.

4. Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008 Apr;79(4):368-76.

5. Kidd PM. Parkinson’s disease as multifactorial oxidative neurodegeneration: implications for integrative management. Altern Med Rev. 2000 Dec;5(6):502-29.

6. Zhou C, Huang Y, Przedborski S. Oxidative stress in Parkinson’s disease: a mechanism of pathogenic and therapeutic significance. Ann N Y Acad Sci. 2008 Dec;1147:93-104.

7. Gonzalez-Fraguela ME, Cespedes EM, Arencibia R, et al. Indicators of oxidative stress and the effect of antioxidant treatment in patients with primary Parkinson disease. Rev Neurol. 1998 Jan;26(149):28-33.

8. Shadrina MI, Slominskii PA. Mitochondrial dysfunction and oxidative damages in the molecular pathology of Parkinson’s disease. Mol Biol (Mosk). 2008 Sep-Oct;42(5):809-19.

9. Hattoria N, Wanga M, Taka H, et al. Toxic effects of dopamine metabolism in Parkinson’s disease. Parkinsonism Relat Disord. 2009 Jan;15 Suppl 1:S35-8.

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

11. Chaturvedi RK, Beal MF. PPAR: a therapeutic target in Parkinson’s disease. J Neurochem. 2008 Jul;106(2):506-18.

12. Zhang J, Perry G, Smith MA, et al. Parkinson’s disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol. 1999 May;154(5):1423-9.

13. Martignoni E, Blandini F, Godi L, et al. Peripheral markers of oxidative stress in Parkinson’s disease. The role of L-DOPA. Free Radic Biol Med. 1999 Aug;27(3-4):428-37.

14. Nicholls DG. Oxidative stress and energy crises in neuronal dysfunction. Ann N Y Acad Sci. 2008 Dec;1147:53-60.

15. Beal MF. Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann N Y Acad Sci. 2003 Jun;991:120-31.

16. Li R, Huang YG, Fang D, Le WD. (-)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury. J Neurosci Res. 2004 Dec 1;78(5):723-31.

17. Dutta G, Zhang P, Liu B. The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol. Oct 2008 Oct;22(5):453-64.

18. Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 2009 Apr;8(4):382-97.

19. Wyss M, Schulze A. Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience. 2002;112(2):243-60.

20. Beal MF. Bioenergetic approaches for neuroprotection in Parkinson’s disease. Ann Neurol. 2003;53 Suppl 3:S39-47; discussion S47-38.

21. Fernandez-Espejo E. Pathogenesis of Parkinson’s disease: prospects of neuroprotective and restorative therapies. Mol Neurobiol. 2004 Feb;29(1):15-30.

22. Schapira AH. Progress in neuroprotection in Parkinson’s disease. Eur J Neurol. 2008 Apr;15 Suppl 1:5-13.

23. Klein AM, Ferrante RJ. The neuroprotective role of creatine. Subcell Biochem. 2007;46:205-43.

24. NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology. 2006 Mar 14;66(5):664-71.

25. NINDS NET-PD Investigators A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results. Clin Neuropharmacol. 2008 May-Jun;31(3):141-50.

26. Schapira AH. Molecular and clinical pathways to neuroprotection of dopaminergic drugs in Parkinson disease. Neurology. 2009 Feb 17;72(7 Suppl):S44-50.

27. Youdim KA, Martin A, Joseph JA. Essential fatty acids and the brain: possible health implications. Int J Dev Neurosci. 2000 Jul-Aug;18(4-5):383-99.

28. Montine KS, Quinn JF, Zhang J, et al. Isoprostanes and related products of lipid peroxidation in neurodegenerative diseases. Chem Phys Lipids. 2004 Mar;128(1-2):117-24.

29. Saugstad LF. Infantile autism: a chronic psychosis since infancy due to synaptic pruning of the supplementary motor area. Nutr Health. 2008;19(4):307-17.

30. Saugstad LF. Are neurodegenerative disorder and psychotic manifestations avoidable brain dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(2):89-101.

31. Calon F, Cole G. Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):287-93.

32. Wu Y, Tada M, Takahata K, Tomizawa K, Matsui H. Inhibitory effect of polyunsaturated fatty acids on apoptosis induced by etoposide, okadaic acid and AraC in Neuro2a cells. Acta Med Okayama. 2007 Jun;61(3):147-52.

33. Bousquet M, Saint-Pierre M, Julien C, Salem N, Jr., Cicchetti F, Calon F. Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease. FASEB J. 2008 Apr;22(4):1213-25.

34. Samadi P, Gregoire L, Rouillard C, Bedard PJ, Di Paolo T, Levesque D. Docosahexaenoic acid reduces levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys. Ann Neurol. 2006 Feb;59(2):282-8.

35. Whelan J. (n-6) and (n-3) Polyunsaturated fatty acids and the aging brain: food for thought. J Nutr. 2008 Dec;138(12):2521-2.

36. LeWitt PA. Neuroprotection for Parkinson’s disease. J Neural Transm Suppl. 2006(71):113-22.

37. Weber CA, Ernst ME. Antioxidants, supplements, and Parkinson’s disease. Ann Pharmacother. 2006 May;40(5):935-8.

38. Storch A. Coenzyme Q10 in Parkinson’s disease. Symptomatic or neuroprotective effects? Nervenarzt. 2007 Dec;78(12):1378-82.

39. Hargreaves IP, Lane A, Sleiman PM. The coenzyme Q10 status of the brain regions of Parkinson’s disease patients. Neurosci Lett. 2008 Dec 5;447(1):17-9.

40. Rakoczi K, Klivenyi P, Vecsei L. Neuroprotection in Parkinson’s disease and other neurodegenerative disorders: preclinical and clinical findings. Ideggyogy Sz. 2009 Jan 30;62(1-2):25-34.

41. Dhanasekaran M, Karuppagounder SS, Uthayathas S, et al. Effect of dopaminergic neurotoxin MPTP/MPP+ on coenzyme Q content. Life Sci. 2008 Jul 18;83(3-4):92-5.

42. Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol. 2008 Nov;4(11):600-9.

43. Muller T, Buttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson’s disease. Neurosci Lett. 2003 May 8;341(3):201-4.

44. Young AJ, Johnson S, Steffens DC, Doraiswamy PM. Coenzyme Q10: a review of its promise as a neuroprotectant. CNS Spectr. 2007 Jan;12(1):62-8.

45. Galpern WR, Cudkowicz ME. Coenzyme Q treatment of neurodegenerative diseases of aging. Mitochondrion. 2007 Jun;7 Suppl:S146-53.

46. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50.

47. Shults CW, Flint Beal M, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol. 2004 Aug;188(2):491-4.

48. Hosoe K, Kitano M, Kishida H, Kubo H, Fujii K, Kitahara M. Study on safety and bioavailability of ubiquinol (Kaneka QH) after single and 4-week multiple oral administration to healthy volunteers. Regul Toxicol Pharmacol. 2007 Feb;47(1):19-28.

49. Langsjoen PH, Langsjoen AM. Supplemental ubiquinol in patients with advanced congestive heart failure. Biofactors. 2008;32(1-4):119-28.

50. Abdin AA, Hamouda HE. Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism. Neuropharmacology. 2008 Dec;55(8):1340-6.

51. Cleren C, Yang L, Lorenzo B, et al. Therapeutic effects of coenzyme Q10 (CoQ10) and reduced CoQ10 in the MPTP model of Parkinsonism. J Neurochem. 2008 Mar;104(6):1613-21.

52. Yahr MD, Duvoisin RC, Cote L, Cohen G. Pyridoxine, DOPA, and Parkinsonism. Adv Biochem Psychopharmacol. 1972;4:185-94.

53. McGeer PL, Zeldowicz L, McGeer EG. A clinical trial of folic acid in Parkinson’s disease. Can Med Assoc J. 1972 Jan 22;106(2):145-6 passim.

54. Schwarz J, Trenkwalder C, Gasser T, Arnold G, Oertel WH. Folinic acid therapy fails to improve early Parkinson’s disease: a two week placebo controlled clinical trial. J Neural Transm Park Dis Dement Sect. 1992;4(1):35-41.

55. Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 1994 Aug;48(2):137-52.

56. Martignoni E, Tassorelli C, Nappi G, Zangaglia R, Pacchetti C, Blandini F. Homocysteine and Parkinson’s disease: a dangerous liaison? J Neurol Sci. 2007 Jun 15;257(1-2):31-7.

57. Obeid R, McCaddon A, Herrmann W. The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med. 2007;45(12):1590-606.

58. Siniscalchi A, Mancuso F, Gallelli L, Ferreri Ibbadu G, Biagio Mercuri N, De Sarro G. Increase in plasma homocysteine levels induced by drug treatments in neurologic patients. Pharmacol Res. 2005 Nov;52(5):367-75.

59. Tan EK, Cheah SY, Fook-Chong S, et al. Functional COMT variant predicts response to high dose pyridoxine in Parkinson’s disease. Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 5;137B(1):1-4.

60. Postuma RB, Espay AJ, Zadikoff C, et al. Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study. Neurology. 2006 Jun 27;66(12):1941-3.

61. Amadasi A, Bertoldi M, Contestabile R, et al. Pyridoxal 5’-phosphate enzymes as targets for therapeutic agents. Curr Med Chem. 2007;14(12):1291-324.

62. Zoccolella S, Iliceto G, deMari M, Livrea P, Lamberti P. Management of L-Dopa related hyperhomocysteinemia: catechol-O-methyltransferase (COMT) inhibitors or B vitamins? Results from a review. Clin Chem Lab Med. 2007;45(12):1607-13.

63. Qureshi GA, Qureshi AA, Devrajani BR, Chippa MA, Syed SA. Is the deficiency of vitamin B12 related to oxidative stress and neurotoxicity in Parkinson’s patients? CNS Neurol Disord Drug Targets. 2008 Feb;7(1):20-7.

64. Muller T. Role of homocysteine in the treatment of Parkinson’s disease. Expert Rev Neurother. 2008 Jun;8(6):957-67.

65. Dos Santos EF, Busanello EN, Miglioranza A, et al. Evidence that folic acid deficiency is a major determinant of hyperhomocysteinemia in Parkinson s disease. Metab Brain Dis. 2009 Jun;24(2):257-69.

66. Virmani A, Gaetani F, Imam S, Binienda Z, Ali S. The protective role of L-carnitine against neurotoxicity evoked by drug of abuse, methamphetamine, could be related to mitochondrial dysfunction. Ann N Y Acad Sci. 2002 Jun;965:225-32.

67. Bodis-Wollner I, Chung E, Ghilardi MF, et al. Acetyl-levo-carnitine protects against MPTP-induced parkinsonism in primates. J Neural Transm Park Dis Dement Sect. 1991;3(1):63-72.

68. Virmani A, Gaetani F, Binienda Z. Effects of metabolic modifiers such as carnitines, coenzyme Q10, and PUFAs against different forms of neurotoxic insults: metabolic inhibitors, MPTP, and methamphetamine. Ann N Y Acad Sci. 2005 Aug;1053:183-91.

69. Wang C, Sadovova N, Ali HK, et al. L-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture. Neuroscience. 2007 Jan 5;144(1):46-55.

70. Zhang H, Jia H, Liu J, et al. Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson’s disease. J Cell Mol Med. 2008 Jun 20.

71. Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim MB. Targeting multiple neurodegenerative diseases etiologies with multimodal-acting green tea catechins. J Nutr. 2008 Aug;138(8):1578S-1583S.

72. Weinreb O, Mandel S, Amit T, Youdim MB. Neurological mechanisms of green tea polyphenols in Alzheimer’s and Parkinson’s diseases. J Nutr Biochem. 2004 Sep;15(9):506-16.

73. Levites Y, Weinreb O, Maor G, Youdim MB, Mandel S. Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem. 2001 Sep;78(5):1073-82.

74. Pan T, Jankovic J, Le W. Potential therapeutic properties of green tea polyphenols in Parkinson’s disease. Drugs Aging. 2003;20(10):711-21.

75. Levites Y, Amit T, Youdim MB, Mandel S. Involvement of protein kinase C activation and cell survival/ cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action. J Biol Chem. 2002 Aug 23;277(34):30574-80.

76. Choi JY, Park CS, Kim DJ, et al. Prevention of nitric oxide-mediated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease in mice by tea phenolic epigallocatechin 3-gallate. Neurotoxicology. 2002 Sep;23(3):367-74.

77. Nie G, Cao Y, Zhao B. Protective effects of green tea polyphenols and their major component, (-)-epigallocatechin-3-gallate (EGCG), on 6-hydroxydopamine-induced apoptosis in PC12 cells. Redox Rep. 2002;7(3):171-7.

78. Mandel S, Maor G, Youdim MB. Iron and alpha-synuclein in the substantia nigra of MPTP-treated mice: effect of neuroprotective drugs R-apomorphine and green tea polyphenol (-)-epigallocatechin-3-gallate. J Mol Neurosci. 2004;24(3):401-16.

79. Guo S, Bezard E, Zhao B. Protective effect of green tea polyphenols on the SH-SY5Y cells against 6-OHDA induced apoptosis through ROS-NO pathway. Free Radic Biol Med. 2005 Sep 1;39(5):682-95.

80. Guo S, Yan J, Yang T, Yang X, Bezard E, Zhao B. Protective effects of green tea polyphenols in the 6-OHDA rat model of Parkinson’s disease through inhibition of ROS-NO pathway. Biol Psychiatry. 2007 Dec 15;62(12):1353-62.

81. Levites Y, Youdim MB, Maor G, Mandel S. Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol. 2002 Jan 1;63(1):21-9.

82. Yamada T, Terashima T, Kawano S, et al. Theanine, gamma-glutamylethylamide, a unique amino acid in tea leaves, modulates neurotransmitter concentrations in the brain striatum interstitium in conscious rats. Amino Acids. 2009 Jan;36(1):21-7.

83. Cho HS, Kim S, Lee SY, Park JA, Kim SJ, Chun HS. Protective effect of the green tea component, L-theanine on environmental toxins-induced neuronal cell death. Neurotoxicology. 2008 Jul;29(4):656-62.

84. Chen D, Wang CY, Lambert JD, Ai N, Welsh WJ, Yang CS. Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies. Biochem Pharmacol. 2005 May 15;69(10):1523-31.

85. Mandel SA, Amit T, Weinreb O, Reznichenko L, Youdim MB. Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases. CNS Neurosci Ther. 2008 Winter;14(4):352-65.

86. Li R, Peng N, Du F, Li XP, Le WD. Epigallocatechin gallate protects dopaminergic neurons against 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity by inhibiting microglial cell activation. Nan Fang Yi Ke Da Xue Xue Bao. 2006 Apr;26(4):376-80.

87. Ramassamy C. Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets. Eur J Pharmacol. 2006 Sep 1;545(1):51-64.

88. Avramovich-Tirosh Y, Reznichenko L, Mit T, et al. Neurorescue activity, APP regulation and amyloid-beta peptide reduction by novel multi-functional brain permeable iron- chelating- antioxidants, M-30 and green tea polyphenol, EGCG. Curr Alzheimer Res. 2007 Sep;4(4):403-11.

89. Zhao B. Natural antioxidants protect neurons in Alzheimer’s disease and Parkinson’s disease. Neurochem Res. 2009 Apr;34(4):630-8.

90. Lee MK, Kang SJ, Poncz M, Song KJ, Park KS. Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. Exp Mol Med. 2007 Jun 30;39(3):376-84.

91. Bureau G, Longpre F, Martinoli MG. Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation. J Neurosci Res. 2008 Feb 1;86(2):403-10.

92. Jin F, Wu Q, Lu YF, Gong QH, Shi JS. Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats. Eur J Pharmacol. 2008 Dec 14;600(1-3):78-82.

93. Pallas M, Casadesus G, Smith MA, et al. Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res. 2009 Feb;6(1):70-81.

94. Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V. Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol. 2008 Oct;65(10):1348-52.

95. Newmark HL, Newmark J. Vitamin D and Parkinson’s disease--a hypothesis. Mov Disord. 2007 Mar 15;22(4):461-8.

96. Sanchez B, Relova JL, Gallego R, Ben-Batalla I, Perez-Fernandez R. 1,25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially restores tyrosine hydroxylase expression in substantia nigra and striatum. J Neurosci Res. 2009 Feb 15;87(3):723-32.

97. Sato Y, Honda Y, Iwamoto J. Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease. Neurology. 2007 Mar 20;68(12):911-915.

98. Sato Y, Iwamoto J, Kanoko T, Satoh K. Alendronate and vitamin D2 for prevention of hip fracture in Parkinson’s disease: a randomized controlled trial. Mov Disord. 2006 Jul;21(7):924-9.

99. Smith MP, Fletcher-Turner A, Yurek DM, Cass WA. Calcitriol protection against dopamine loss induced by intracerebroventricular administration of 6-hydroxydopamine. Neurochem Res. 2006 Apr;31(4):533-9.

100. Chen J, Tang XQ, Zhi JL, et al. Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOS pathway. Apoptosis. 2006 Jun;11(6):943-53.

101. Jagatha B, Mythri RB, Vali S, Bharath MM. Curcumin treatment alleviates the effects of glutathione depletion in vitro and in vivo: therapeutic implications for Parkinson’s disease explained via in silico studies. Free Radic Biol Med. 2008 Mar 1;44(5):907-17.

102. Mythri RB, Jagatha B, Pradhan N, Andersen J, Bharath MM. Mitochondrial complex I inhibition in Parkinson’s disease: how can curcumin protect mitochondria? Antioxid Redox Signal. 2007 Mar;9(3):399-408.

103. Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE. Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol. 2008 Apr;115(4):479-89.

104. Rajeswari A, Sabesan M. Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model of Parkinson’s disease induced by MPTP neurodegeneration in mice. Inflammopharmacology. 2008 Apr;16(2):96-9.

105. Sethi P, Jyoti A, Hussain E, Sharma D. Curcumin attenuates aluminium-induced functional neurotoxicity in rats. Pharmacol Biochem Behav. 2009 Jul;93(1):31-9.

106. Yang S, Zhang D, Yang Z, et al. Curcumin protects dopaminergic neuron against LPS induced neurotoxicity in primary rat neuron/glia culture. Neurochem Res. 2008 Oct;33(10):2044-53.

107. Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT. 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 Oct;39(10):1119-25.

108. Capitelli C, Sereniki A, Lima MM, Reksidler AB, Tufik S, Vital MA. Melatonin attenuates tyrosine hydroxylase loss and hypolocomotion in MPTP-lesioned rats. Eur J Pharmacol. 2008 Oct 10;594(1-3):101-8.

109. Dowling GA, Mastick J, Colling E, Carter JH, Singer CM, Aminoff MJ. Melatonin for sleep disturbances in Parkinson’s disease. Sleep Med. 2005 Sep;6(5):459-66.

110. Klongpanichapak S, Phansuwan-Pujito P, Ebadi M, Govitrapong P. Melatonin inhibits amphetamine-induced increase in alpha-synuclein and decrease in phosphorylated tyrosine hydroxylase in SK-N-SH cells. Neurosci Lett. 2008 May 16;436(3):309-13.

111. Lin CH, Huang JY, Ching CH, Chuang JI. Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats. J Pineal Res. 2008 Mar;44(2):205-13.

112. Ma J, Shaw VE, Mitrofanis J. Does melatonin help save dopaminergic cells in MPTP-treated mice? Parkinsonism Relat Disord. 2009 May;15(4):307-14.

113. Medeiros CA, Carvalhedo de Bruin PF, Lopes LA, Magalhaes MC, de Lourdes Seabra M, de Bruin VM. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease. A randomized, double blind, placebo-controlled study. J Neurol. 2007 Apr;254(4):459-64.

114. Saravanan KS, Sindhu KM, Mohanakumar KP. Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model. J Pineal Res. 2007 Apr;42(3):247-53.

115. Murakami K, Miyake Y, Sasaki S, et al. Dietary intake of folate, vitamin B6, vitamin B12 and riboflavin and risk of Parkinson’s disease: a case-control study in Japan. Br J Nutr. 2010 Mar 26:1-8.

116. de Lau LM, Koudstaal PJ, Witteman JC, Hofman A, Breteler MM. Dietary folate, vitamin B12, and vitamin B6 and the risk of Parkinson disease. Neurology. 2006 Jul 25;67(2):315-8.