ceptors participate in mediating WM injury.8 Untilnow, however, the preponderance of evidence favoredthe idea that glutamate receptors on oligodendrocyteswere mainly, if not exclusively, to blame for the gluta-mate component of the injury (eg, Tekkok et al.2,9).

Stys and colleagues bring credible new evidencethat CNS axons themselves express glutamate recep-tors.5,6 Using an optical technique they have pio-neered to monitor intracellular [Ca2�] ([Ca2�]i) inindividual axons, they show that glutamate agonistscause slow increases in axonal [Ca2�]i. Pharmacolog-ical experiments and some immunohistochemical im-ages support the conclusion that myelinated axonssport several subtypes of glutamate receptors undertheir myelin sheaths, including kainate and AMPAtype receptors. When activated, these receptors admitCa2�, leading to a slight increase in axonal [Ca2�]i

that triggers further Ca2� release from intracellularorganelles. Some kainate type glutamate receptors ap-pear to physically co-localize with L-type Ca2� chan-nels, while others associate with the enzyme that gen-erates nitric oxide (NO), nitric oxide synthase.Activating these receptors leads to opening of the as-sociated Ca2� channels and NO production, bothevents contributing to more intracellular Ca2� accu-mulation. Whether glutamate receptors on centralmyelinated axons serve a physiological purpose re-mains unaddressed, an obvious goal of future re-search. These findings do lend themselves to a revisedtheory about WM injury. The authors propose thatglutamate released in WM under pathological condi-tions, for example ischemia or inflammation, wouldactivate axonal glutamate receptors leading to directaxon injury via Ca2� overload, as previously estab-lished.10 The work is elegant and pushes the tech-niques employed to their limits. It begs questionsabout glutamate source and how glutamate applied tothe extracellular space manages to reach glutamate re-ceptors buried under the myelin sheath, presumably aclosed compartment for all practical purposes. Morework will be necessary to determine the relative impor-tance of axon vs. oligodendrocyte glutamate receptor ac-tivation in explaining irreversible loss of WM functionduring ischemia or traumatic insult. Alternatively, acti-vation of these distinct receptor populations might beinextricably cooperative in producing WM injury.

These two papers, and the recent swell of others fo-cused on WM, establish one formidable fact: This partof the CNS is far more complex than we imagined,based on its primary function of conveying electrical sig-nals from one part of the brain to another. Intuitively,we expected no neurotransmitter receptors in this area,but now find evidence for glutamate receptors on everycell type tested. Their ‘physiological’ functions remainobscure, but they unequivocally can participate in harm.What Stys and his colleagues leave us to contemplate is

how precisely all these glutamate receptors collaborateunder injurious circumstances to excite axons to death.

Bruce R. Ransom, MD, PhD andSelva B. Baltan, MD, PhD

University of Washington School of Medicine,Department of Neurology, Seattle, WA

Potential conflict of interest: Nothing to report.

References1. McDonald JW, Althomsons SP, Hyrc KL et al. Oligodendro-

cytes from forebrain are highly vulnerable to AMPA/kainatereceptor-mediated Excitotoxicity. Nat Med 1998;4:291–297.

2. Tekkok SB, Goldberg MP. AMPA/kainate receptor activationmediates hypoxic oligodendrocyte death and axonal injury incerebral white matter. J Neurosci 2001;21:4237– 4248.

3. Agrawal SK, Fehlings MG. Role of NMDA and non-NMDAionotropic glutamate receptors in traumatic spinal cord axonalinjury. J Neurosci 1997;17:1055–1063.

4. Sanchez-Gomez MV, Matute C. AMPA and kainate receptorseach mediate Excitotoxicity in oligodendroglial cultures. Neu-robiol Dis 1999;6:475–485.

5. Ouardouz M, Coderre E, Basak A, et al. Glutamate receptorson myelinated spinal cord axons: I. GluR5 kainate receptors.Ann Neurol 2009;65:151–159.

6. Ouardouz M, Coderre E, Basak A, et al. Glutamate receptorson myelinated spinal cord axons: II. AMPA and GluR5 recep-tors. Ann Neurol 2009;65:160–166.

7. Zhang K, Sejnowski TJ. A universal scaling law between graymatter and white matter of the cerebral cortex. Proc Natl AcadSci U S A 2000;97:5621–5626.

8. Ransom BR, Acharya AB, Goldberg MP. Molecular pathophys-iology of white matter anoxic/ischemic injury. In: Stroke:Pathophysiology, Diagnosis, and Management. 4th edition. J.P.Mohr, Bennett M. Stein, D. Choi, editors. Churchill Living-stone, 2004:867–882.

9. Tekkok SB, Ye Z, Ransom BR. Excitotoxic mechanisms ofischemic injury in myelinated white matter. J Cereb BloodFlow Metab 2007;27:1540–1552.

10. Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxicinjury in mammalian CNS white matter: Role of Na� channelsand Na�-Ca2� exchanger. J Neurosci 1992;12:430–439.

DOI: 10.1002/ana.21659

Altered Redox Balance inDisease: Can We Changethe New Equilibria?

The oxidative stress theory of Alzheimer’s disease(AD)1 postulates that oxidative stress is the initiator ofAD pathogenesis2 and envisages that antioxidant-based

Perry et al: Altered Redox Balance in Disease 121

therapies are the best weapon to fight this neurodegen-erative disease. However, this theory has been criticizedbecause of the poor therapeutic effects of vitamin sup-plementation.3–5 In an elegant study, Sonnen and col-leagues6 directly analyzed the levels of lipid peroxida-tion products from a large series of patients and foundthat, although there are increases in the levels of oxi-dation products from patients with AD and other dis-ease conditions, there was not the expected decrease inresponse to vitamin/antioxidant supplementation. Theysuggest that vitamin E intake in these patients was ei-ther taken at insufficient levels to alter oxidant balance,or that other broader spectrum antioxidants may be re-quired.6 Although such an interpretation is consistentwith the results in animals where broad-spectrum anti-oxidants such as lipoic acid and acetyl L-carnitine dohave a benefit in maintaining normal function,7,8 theefficacy of antioxidants after the development of thedisease remains to be established.

The (apparent) inefficacy of antioxidants hasclouded the biological significance of oxidative damagein AD. Sonnen and colleagues’6 work suggests that theimportance of oxidative stress has yet to be tested. In-triguingly, there are epidemiological studies that showstrong linkage between AD reduction and a diet rich innutrients9–11 and that AD is marked by increased ox-idative damage, which contribute to a more complexand paradoxical view of the oxidative stress hypothe-sis.1

An alternative view is expressed in our questioningof the concept of oxidative stress as a simple equilib-rium between oxidants and antioxidants. Instead, webelieve in a finely tuned and robust system regulatingthe oxidant balance that primarily depends on meta-bolic reducing power and the complex interplay be-tween endogenous (glutathione) and exogenous (vita-mins) reductants.12 Beyond a deficiency in antioxidantvitamins, their excess is also detrimental,13–15 possiblybecause the prooxidant/antioxidant balance is a com-plex self-correcting system that regulates the system toa set point equilibria necessary to maintain physiology.Adding additional vitamins, often reductants, can ei-ther be without effect or instead create the instabilityunderlying increased morbidity.16 Even more impor-tant, the physiological/pathological accommodationsthat surely occur during chronic disease likely funda-mentally alter the set point to establish a new stableequilibrium point. In AD, the increase in redox-activemetals17,18 may alter the response to reductant vita-mins that conceivably could increase oxidative damagethrough redox-cycling. Although this may not bodewell for therapeutic-based or simple vitamins, it doessuggest that careful realignment of homeostasis may beable to fundamentally alter the system. Accordingly,others demonstrated that antioxidants work in con-junction with metabolic enhancers and metal chela-

tion.7,8 In this context, agents that blend antioxidants,metal chelators and metabolic enhancers, may findgreater efficacy in reestablishing a base equilibria to atime before the onset of AD.

George Perry, PhD

College of SciencesUniversity of Texas at San AntonioSan Antonio, TX

Xiongwei Zhu, PhD

Department of PathologyCase Western Reserve UniversityCleveland, OH

Paula I. Moreira, PhD

Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbra, Portugal

Mark A. Smith, PhD

Department of PathologyCase Western Reserve UniversityCleveland, OH

Potential conflict of interest: Nothing to report.

References1. Markesbery WR. Oxidative stress hypothesis in Alzheimer’s dis-

ease. Free Radic Biol Med 1997;23:134–147.2. Perry G, Castellani RJ, Hirai K, Smith MA. Reactive oxygen

species mediate cellular damage in Alzheimer disease. J Alzhei-mers Dis 1998;1:45–55.

3. Sano M, Ernesto C, Thomas RG, et al. A controlled trial ofselegiline, alpha-tocopherol, or both as treatment for Alzhei-mer’s disease. The Alzheimer’s Disease Cooperative Study.N Engl J Med 1997;336:1216–1222.

4. Gray SL, Anderson ML, Crane PK, et al. Antioxidant vitaminsupplement use and risk of dementia or Alzheimer’s disease inolder adults. J Am Geriatr Soc 2008;56:291–295.

5. Isaac MG, Quinn R, Tabet N. Vitamin E for Alzheimer’s dis-ease and mild cognitive impairment. Cochrane Database SystRev 2008:CD002854.

6. Sonnen JA, Larson EB, Gray SL, et al. Free radical damage tocerebral cortex in Alzheimer’s disease, microvascular brain in-jury, and smoking. Ann Neurol 2009;65:226–229.

7. Liu J, Head E, Gharib AM, et al. Memory loss in old rats isassociated with brain mitochondrial decay and RNA/DNAoxidation: partial reversal by feeding acetyl-L-carnitine and/orR-alpha -lipoic acid. Proc Natl Acad Sci U S A 2002;99:2356–2361.

8. Aliev G, Liu J, Shenk JC, et al. Neuronal mitochondrial ame-lioration by feeding acetyl-L-carnitine and lipoic acid to agedrats. J Cell Mol Med 2008 [Epub ahead of print]. In press.

9. Smith MA, Petot GJ, Perry G. Diet and oxidative stress: anovel synthesis of epidemiological data on Alzheimer’s disease. JAlzheimers Dis 1999;1:203–206.

10. Scarmeas N, Stern Y, Tang MX, et al. Mediterranean diet andrisk for Alzheimer’s disease. Ann Neurol 2006;59:912–921.

122 Annals of Neurology Vol 65 No 2 February 2009

11. Morris MC, Evans DA, Bienias JL, et al. Dietary intake ofantioxidant nutrients and the risk of incident Alzheimer dis-ease in a biracial community study. JAMA 2002;287:3230 –3237.

12. Perry G, Nunomura A, Hirai K, et al. Is oxidative damage thefundamental pathogenic mechanism of Alzheimer’s and otherneurodegenerative diseases? Free Radic Biol Med 2002;33:1475–1479.

13. Molotkov A, Fan X, Duester G. Excessive vitamin A toxicity inmice genetically deficient in either alcohol dehydrogenase Adh1or Adh3. Eur J Biochem 2002;269:2607–2612.

14. Becker P, Maurer B, Schirmacher P, et al. Vitamin A-inducedcholestatic hepatitis: a case report. Z Gastroenterol 2007;45:1063–1066.

15. Marsillach J, Ferre N, Camps J, et al. Moderately high folicacid supplementation exacerbates experimentally induced liverfibrosis in rats. Exp Biol Med (Maywood) 2008;233:38–47.

16. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis:high-dosage vitamin E supplementation may increase all-causemortality. Ann Intern Med 2005;142:37–46.

17. Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulationin Alzheimer disease is a source of redox-generated free radicals.Proc Natl Acad Sci U S A 1997;94:9866–9868.

18. Sayre LM, Perry G, Harris PL, et al. In situ oxidative catalysisby neurofibrillary tangles and senile plaques in Alzheimer’sdisease: a central role for bound transition metals. J Neurochem2000;74:270–279.

DOI: 10.1002/ana.21608

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