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Alpha-lipoic Protects Brain Cells (neurons)-Antioxidant Mechanisms For Alzheimer’s Prevention

Posted Jan 14 2009 5:43pm

By Ralph Sanchez, L.Ac.,CNS,D.Hom.

Alpha lipoic acid (ALA), a naturally occurring nutrient found in many foods and available in supplemental form, is also synthesized in humans where it serves in energy metabolism and as a vital antioxidant. ALA is a unique antioxidant in that it is both water and fat-soluble, which enables ALA to confer its antioxidant benefits to all the cells and cell structures of the body. Another important characteristic of ALA is that it is part of the antioxidant team that includes vitamin E, C, coenzyme Q10 and glutathione. ALA regenerates theses antioxidants as they are metabolized in their protective antioxidative roles. As an antioxidant, the protective benefits of ALA are well documented in the research literature. However, just this month (12-08), scientists have been able to describe some of the mechanisms behind ALA’s brain protective (neuroprotective) function with respect to peroxynitrite, (1) a potent oxidant,* nitrative agent** and pro-inflammatory molecule that induces cellular damage and death (apoptosis). (2) Peroxynitrite mediates its toxic effects by reacting with structural and functional proteins and fats of the cell, as well as its DNA.

DNA Helix

DNA Helix

Peroxynitrite’s damage to DNA is induced by “strand breaks”. There are many forms of DNA damage with double-strand breaks (DSBs) being the most severe. Single strand breaks are an easier fix for the repair mechanisms involved in DNA maintenance. Recall the strand double helix image of DNA from your science class? Well now picture it being broken…that is a strand break (see images below), and peroxynitrite mediated damage is one of the mechanisms responsible for your DNA malfunctioning, and the toxic pathways that leads to brain cell (neurons) damage and death. (3) Most vulnerable is the DNA of the cell’s mitochondria. Mitochondrial DNA is more susceptible to toxic insults, and once this cellular energy factory is overwhelmed by peroxynitrite-mediated reactions, the eventual demise of the brain cell is not far behind. (4) Besides DNA damage, peroxynitrite elevations in the brain is linked to neurofibrillary tangles (5), and the neurotoxicity of beta-amyloid peptide (BAP). (6) The oxidative stress induced by peroxynitrite and other oxidative factors, is a key component to the disease process associated with Alzheimer’s disease. (7)

DNA Strand Break

The role of ALA in buffering the neurotoxic effects of peroxynitrite is a recent revelation, yet there is plenty of similar evidence demonstrating the same benefits to other antioxidants-both from foods and nutraceuticals. Glutathione, the body’s primary antioxidant, counters peroxynitrite reactions, and protects against DNA single strand breaks. (8) Carotenoids (lycopene, beta-carotene) and ascorbates (vit C as mineral ascorbates) are able to neutralize peroxynitrite oxidation. (9) Quercetin and EGCg from green tea, rutin, and resveratrol and cocoa have neuroprotective benefits including protection from peroxynitrite. (10, 11) Ellagic acid in strawberries, blueberries and raspberries are protective from oxidative and nitrative damage from peroxynitrite. (12) Grape Seed Polyphenols*** have also demonstrated in research to have peroxynitrite scavenging properties, (13) inhibition of beta amyloid plaque formation, and the protection from other oxidative stress reactants associated with beta amyloid toxicity on brain cells. (14, 15)

A diet rich in these natural antioxidants as well as supplementing with a blend of these nutraceuticals will provide invaluable protection to your brain and the rest of your body as well. The pathways of oxidative stress and nitrative stress, require antioxidants that are effective scavengers for the varying oxidative or nitrative reactions. For examples of these types of formulations (i.e. Detox Antiox, Quercetin + Nettles, Resveratrol Synergy ), please visit the Antioxidant section of
Note that it links you to my Health and Wellness store @

* Oxidant: A substance (i.e. peroxynitite) that is capable of oxidizing another substance through oxygen mediated reactions. In the process, the oxidizing agent (i.e. peroxynitite) accepts electrons and the oxidized substance loses electrons. Oxidation is a normal component of energy metabolism and immune system defenses. However, in the case of certain oxidants like peroxynitrite, the reactions taking place are at the expense of cellular structures and DNA, as well as mitochondrial DNA.

** Nitration: Just as the biochemical reactions of oxidation are a potentially damaging process in the body, nitration also can exert ” Nitrative Stress”. The same proteins, lipids, and cellular DNA damaged by oxidative reactions, are also mediated by nitrative reactions. “Oxidative Stress” involves reactions mediated by oxygen containing molecules, while “Nitrative Stress” involves reactions mediated by nitrogen containing molecules.
Note: Peroxynitrate (ONOO) contains both oxygen and nitrogen compounds and is a potent oxidation and nitration agent.

*** Oxidative Stress: Oxidative stress is a physiological condition whereby there is an imbalance between protective antioxidants and oxidative free radicals and other oxidants. The “oxidative balance” between antioxidants and the free radicals and oxidants that they quench, is a key element in optimizing health and buffering against the aging process and some of the degenerative diseases associated with it.

**** Polyphenols:
Plant chemicals (phytochemicals) that function as antioxidants. They are found in wine, tea, chocolate, and some fruits and vegetables.

1. Alpha-lipoic acid potently inhibits peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation: implications for the neuroprotective effects of alpha-lipoic acid.
Jia Z, Zhu H, Vitto MJ, Misra BR, Li Y, Misra HP.
Mol Cell Biochem. 2008 Dec 11.

2. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention
L Virág, E Szabó, P Gergely, C Szabó
Toxicol Lett (2003) 140: 113-24.

3. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures
E Bonfoco, D Krainc, M Ankarcrona, P Nicotera, and S A Lipton
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7162-6.

4. Peroxynitrite reactions and formation in mitochondria.

R Radi, A Cassina, R Hodara, C Quijano, L Castro
Free Radic Biol Med (2002) 33: 1451-64.

5. Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.
Zhang, Y-J., Xu, Y-F., Liu, Y-H., Yin, J., Li, H-L., Wang, Q., Wang, J-Z.
FASEB J. 20, 1431–1442 (2006)

6. Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia.
Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD.
J Neurosci. 2002 May 1;22(9):3484-92.

7. Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease

Mark A. Smith, Peggy L. Richey Harris, Lawrence M. Sayre, Joseph S. Beckman, and George Perry
J. Neurosci., April 15, 1997, 17(8):2653–2657

8. Selenium-Containing Compounds Protect DNA from Single-Strand Breaks Caused by Peroxynitrite
Ivan Roussyn, Karlis Briviba, Hiroshi Masumoto and Helmut Sies 1
Archives of Biochemistry and Biophysics Volume 330, Issue 1, 1 June 1996, Pages 216-218

9. Effect of lycopene and beta-carotene on peroxynitrite-mediated cellular modifications.
Muzandu Kaampwe, Ishizuk, Mayumi, Sakamoto Kentaro Q.
Shaban Zein, Bohi Khlood El, Kazusaka Akio, Fujita Shoichi
Toxicology and Applied Pharmacology. 215(3), 2006, 330-340

10. Protection of peroxynitrite-induced DNA damage by dietary antioxidants.

Hye Kyung Moon, Eun Sun Yang, and Jeen Woo Park
Arch Pharm Res Vol 29, No 3, 213-217, 2006

11. Protection against peroxynitrite by cocoa polyphenol oligomers
G . Arteel                                                                           FEBS Letters , Volume 462 , Issue 1 - 2 , Pages 167 - 170
12. Prevention of peroxynitrite-induced oxidation and nitration reactions by ellagic acid
Katsunari Ippoushi, Atsuko Takeuchi, and Keiko Azuma
Food Chemistry. Volume 112, Issue 1, 1 January 2009, Pages 185-188

13. Procyanidins from grape seeds protect endothelial cells from peroxynitrite damage and enhance endothelium-dependent relaxation in human artery: new evidences for cardio-protection
Giancarlo Aldini, Marina Carini, Angela Piccoli, Giuseppe Rossoni and Roberto Maffei Facino
Life Sciences. Volume 73, Issue 22, 17 October 2003, Pages 2883-2898

14. Effects of Grape Seed-derived Polyphenols on Amyloid β-Protein Self-assembly and Cytotoxicity
Kenjiro Ono, Margaret M. Condron, Lap Ho, Jun Wang, Wei Zhao, Giulio M. Pasinetti, and David B. Teplow
J. Biol. Chem., Vol. 283, Issue 47, 32176-32187, November 21, 2008

15. Grape-Derived Polyphenolics Prevent A-beta Oligomerization and Attenuate Cognitive Deterioration in a Mouse Model of Alzheimer’s Disease
Jun Wang, L. Ho, W. Zhao, K. Ono, C. Rosensweig, L. Chen, N. Humala, D.B. Teplow, G.M. Pasinetti
Journal of Neuroscience. June 2008, Volume 28, Pages 6388-6392

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