Brain 2011: 134; 1877–1881
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BRAIN
A JOURNAL OF NEUROLOGY
SCIENTIFIC COMMENTARY
Newly lesioned tissue in multiple sclerosis—a
role for oxidative damage?
The causes of lesion formation in multiple sclerosis remain uncertain. While an autoimmune pathogenesis is favoured by many
(Weiner, 2004; Frohman et al., 2006), innate immune mechanisms
have also been proposed (Barnett and Prineas, 2004; Marik et al.,
2007), in addition to roles for bacteria and viruses (Gay, 2007;
Salvetti et al., 2009). This issue of Brain includes two papers on
multiple sclerosis lesions, which may illuminate mechanisms
involved in their formation (Haider et al., 2011) and repair
(Zambonin et al., 2011).
Hans Lassmann and colleagues have explored their bank of multiple sclerosis tissue seeking information on oxidative damage
(Haider et al., 2011). The authors uncover abundant evidence of
oxidized lipids and DNA in active multiple sclerosis lesions, significantly adding to our understanding from earlier observations
(Graumann et al., 2003; Gray et al., 2008b; Zeis et al., 2009;
van Horssen et al., 2011). Lipid peroxides and oxidized nuclear
DNA were mainly present in oligodendrocytes, often associated
with evidence of apoptosis: a small number of reactive astrocytes
were also affected. Oxidized phospholipids were also ‘massively’
accumulated in some axonal spheroids and neurons, many of
which appeared to be degenerating.
Oxidative damage ensues when pro-oxidant factors (see below)
overwhelm the inherent anti-oxidant defences of cells and tissues,
resulting in oxidative stress and oxidative modification of biological
molecules such as enzymes, lipids and DNA, thereby preventing
normal cellular function and increasing the likelihood of cell death.
The profound oxidative damage found in oligodendrocytes and
axons is therefore important because it will undoubtedly contribute to the ongoing demyelination and axonal injury and degeneration, and perhaps may even be causative.
The existence of oxidative damage within active multiple sclerosis lesions is not in itself surprising, because the accompanying
inflammation can be intense and there are several recognized
sources of reactive oxygen species responsible for the protein,
lipid and DNA oxidation. For example, it is well established that
activated microglia are very effective producers of reactive oxygen
species, not least by virtue of the NADPH oxidase-mediated respiratory burst, in which large amounts of superoxide can be produced extracellularly as a defence mechanism against invading
microorganisms (Bedard and Krause, 2007). Activated microglia
can also produce nitric oxide in large quantities through expression
of the inducible form of nitric oxide synthase; and nitric oxide and
superoxide can combine to produce the strong oxidizing agent
peroxynitrite. Superoxide and nitric oxide are the lead agents in
cascades of reactive oxygen and nitrogen species that can damage
tissue—and importantly mitochondria—via multiple pathways
(Brunori et al., 2006; Rubbo et al., 2009). The microglia can be
activated in different ways, including by breakdown of the blood–
brain barrier (which occurs in inflammatory multiple sclerosis lesions), and release from the vasculature of agents such as thrombin and fibrin that are found deposited on microglia in multiple
sclerosis lesions (Marik et al., 2007). Alternatively, inflammation
can also result in dysregulated glutamate homeostasis in multiple
sclerosis lesions (Werner et al., 2001); and glutamate can activate
receptors on oligodendrocytes and neurons causing the formation
of reactive oxygen and nitrogen species by NADPH oxidase, and
nitric oxide synthase (Karadottir and Attwell, 2007; Stys and
Lipton, 2007; Brennan et al., 2009). It is, therefore, unsurprising
that the oxidative damage found in the multiple sclerosis lesions is
significantly correlated with ongoing inflammation, including the
presence of microglia, macrophages and T cells (Haider et al.,
2011).
The mechanisms by which oxidative damage can occur, impair
mitochondrial function, and contribute to tissue damage in neuroinflammatory disease, have been summarized in a number of
excellent reviews and papers (Andrews et al., 2005; Dutta et al.,
2006; Dutta and Trapp, 2007; Kalman et al., 2007; Gonsette,
2008; Mahad et al., 2009; Witte et al., 2009; 2010; Mao and
Reddy, 2010; Campbell and Mahad, 2011; Nakamura and Lipton,
2011; van Horssen et al., 2011). These studies describe the numerous ‘downstream’ consequences of oxidative and mitochondrial damage, including energy failure; but it is interesting to
look at the new findings by Haider and colleagues (2011) and
consider whether they might indicate earlier ‘upstream’ mechanism(s) contributing to the formation of newly lesioned tissue.
The immunoreactivity for oxidized lipids and DNA is not distributed uniformly across the lesions, as is clear from Fig. 1 (Haider
et al., 2011). It is helpful to realize that the chronic active lesion
Advance Access publication June 15, 2011
ß The Author (2011). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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| Brain 2011: 134; 1877–1881
illustrated has grown over time (weeks or months). Although the
lesion represents a continuum, it can helpfully be divided into
stages and this is what Haider and colleagues have done. The
centre of the lesion, termed the ‘late active’ region, is the oldest
and it contains demyelinated axons. The centre is surrounded by
the progressively younger regions of the ‘early active’ (active demyelination), then the ‘initial’ region [Gay et al., 1997; equivalent
to the ‘prephagocytic’ region (Barnett and Prineas, 2004) with the
pattern III pathology (Lucchinetti et al., 2000) of early demyelination], and these regions are surrounded by the ‘periplaque’ tissue,
eventually merging with the normal appearing white matter (see
Lassmann, 2011). Of these different regions, the periplaque has
the least obvious pathology, but is perhaps the most interesting
because it contains the advancing front suggesting that this contains the secrets of the earliest events responsible for converting
normal-appearing tissue into multiple sclerosis lesions. Here, the
new findings of Haider et al. (2011) regarding the distribution of
the oxidative damage are surprising, and perhaps informative, because although it is greatest in the ‘initial’ region, where microglial
activation is profound, the next most intense region is not inwards
towards the active region, which might have been expected, but
rather outwards into the periplaque region. The new findings
therefore imply significant oxidative stress in the periplaque; but
what are its origins?
It seems that lymphocytes are absent from the parenchyma in
the periplaque (Barnett and Prineas, 2004; Henderson et al.,
2009), and present at only a low density (around one per
vessel) in the perivascular spaces (Henderson et al., 2009). Thus,
if judged simply by their density, T cells appear not to play a
decisive role in orchestrating a pro-inflammatory environment
(see also Barnett and Prineas, 2004; Marik et al., 2007;
Henderson et al., 2009) unless their influence is propagated to
the advancing front from where the T cells are abundant in the
older portions of the lesion. However, expression of the neuronal
and inducible forms of nitric oxide synthase are both upregulated
in the periplaque (Liu et al., 2001; Zeis et al., 2009); and microglia
are reported to be activated, with enlarged cell bodies and thickened ramified processes (Henderson et al., 2009). Data on the
capacity for superoxide production, perhaps by the expression of
functional NADPH oxidase, appear to be lacking in the multiple
sclerosis literature, but the opportunity for oxidative damage is
enhanced by the expression in some microglia/macrophages of
myeloperoxidase (Gray et al., 2008a). If the microglia are appropriately equipped, the simplest explanation for the oxidative
damage is therefore that the activated microglial cells [and perhaps astrocytes (Liu et al., 2001; Abramov et al., 2004)] are responsible for the oxidative damage, producing reactive oxygen
and nitrogen species that affect oligodendrocytes and axons.
Although some reactive species, including superoxide, are charged
and their permeability across membranes is limited, others, including nitric oxide, pass membranes easily and so will gain access to
the intracellular space of oligodendrocytes and axons.
It is worth pausing here to note that although it is easy to
assume that the microglial cells become activated and then inflict
oxidative damage on the oligodendrocytes and axons, it remains
possible that the primary pathology is in the oligodendrocytes and
that the microglia are reacting to it; or, especially, that both
Scientific Commentary
mechanisms are operating together in mutual reinforcement.
Indeed, in another study the microglial cells surrounding newly
forming lesions remained unactivated in two cases of acute multiple sclerosis (Henderson et al., 2009), consistent with the microglia having a more reactive, than proactive, role. It is therefore
worthwhile considering whether the oligodendrocytes and axons
might not be innocent targets of the oxidative damage and lesion
formation, but whether they may be partly responsible. How
might this occur?
Oligodendrocytes and axons contain many mitochondria and
these can be an important source of reactive oxygen species. In
fact mitochondria produce some superoxide under normal conditions as a consequence of ‘leakage’ of electrons onto oxygen as
they move along the electron transport chain (Murphy, 2009a;
Stowe and Camara, 2009); and although this can be important
in physiological signalling (Murphy, 2009a), the production can
increase substantially under various conditions with inherent antioxidant defences thereby overwhelmed, resulting in oxidative
stress and damage (Andrews et al., 2005; Kalman et al., 2007;
Murphy 2009a; Stowe and Camara, 2009; Witte et al., 2010; van
Horssen et al., 2011). The slow rate of advance of multiple sclerosis lesions suggests that a status quo may initially be maintained
during which the antioxidant defences are capable of restraining
runaway oxidative damage (Zeis et al., 2008). Eventually however,
either by slow attrition, or the superimposition of other adverse
events (e.g. systemic infection), homeostasis is lost and the lesion
advances as the oligodendrocytes (especially) and axons succumb.
Perhaps, the most important determinants of mitochondrial
superoxide production are: (i) mitochondrial damage such that
normal function is prevented; (ii) whether the mitochondria have
a high proton motive force, namely a high membrane potential
and pH gradient; (iii) when the pool of coenzyme Q is reduced (iv)
a high nicotinamide adenine dinucleotide/NAD + ratio; and (v) an
unusually high or low oxygen concentration (Murphy, 2009a).
Condition (i) is likely to occur because nitric oxide (and some
other reactive oxygen and nitrogen species) from activated microglia will freely diffuse into the mitochondria of oligodendrocytes
and axons and then either modify the mitochondrial constituents
directly, or, in the case of nitric oxide, combine with mitochondrial
superoxide to form the strong oxidizing agent peroxynitrite. This
agent can permanently nitrate tyrosine residues (i.e. damage the
associated proteins), and there is good evidence for mitochondrial
damage and nitrotyrosine formation in multiple sclerosis lesions
(Liu et al., 2001; Mahad et al., 2009; Zeis et al., 2009). As the
mitochondria become damaged by the toxic environment their
own production of reactive oxygen species can increase, setting
up a vicious cycle.
Conditions (ii), (iii) and (iv) are all favoured when ATP production is low. This may occur in axons, if demand is reduced by
conduction block—expected in inflamed, demyelinated axons, especially if the main body of the lesion is proximal to the direction
of impulse conduction (Smith et al., 2006). The effects of inflammation on the mitochondrial membrane potential are difficult to
predict, but observations in vivo in experimental autoimmune encephalomyelitis (EAE) favour membrane depolarization (Qi et al.,
2006; Nikic et al., 2011), although membrane hyperpolarization
has been documented due to nitric oxide in a different
Scientific Commentary
preparation, operating through the reverse action of the ATPase
supported by upregulation of glycolysis (Beltran et al., 2002).
Which condition would prevail in the periplaque is not known,
but it might be expected that ATP production would be reduced
by inhibition of mitochondrial complex IV of the respiratory chain
by nitric oxide. Such inhibition has long been suspected in multiple
sclerosis lesions (Redford et al., 1997) because nitric oxide is a
potent inhibitor of this enzyme (Bolanos and Almeida, 2006)
and the nitric oxide concentration is expected to be high (Smith
and Lassmann, 2002).
Although oxygen concentration is an important determinant of
the mitochondrial production of reactive oxygen species [Murphy,
2009a: condition (v)], the concentration of oxygen within multiple
sclerosis lesions is not known. Hyperoxia is a well-established
cause of increased reactive oxygen species production and could
occur if mitochondrial utilization of oxygen is reduced by nitric
oxide-mediated inhibition of complex IV of the respiratory chain
(Hagen et al., 2003). A hypoxic environment is however favoured
by the very prominent expression of the hypoxia inducible factor
1 (HIF-1) within pattern III multiple sclerosis lesions
[Aboul-Enein et al., 2003: although HIF-1 accumulation is not
specific for hypoxia (Palmer et al., 2000; Bove et al., 2008;
Majmundar et al., 2010; Olson and van der Vliet 2011)]; and
also by separate evidence for hypoxia in an experimental pattern
III lesion in vivo (Desai et al., 2011). If the environment is hypoxic, it is not safe to assume that production of reactive oxygen
species will be low (due to reduced availability of oxygen), as
some evidence indicates that the mitochondrial release of reactive
oxygen species increases in hypoxia, and in fact this appears to be
necessary for the observed stabilization of HIF-1 to occur
(Klimova and Chandel, 2008). There are thus several reasons to
believe that the mitochondrial production of reactive oxygen species will increase in multiple sclerosis lesions.
Under the different conditions detailed above, the mitochondrial
superoxide production originates primarily from complex I of the
respiratory chain, and the superoxide is formed on the matrix side
of the inner mitochondrial membrane, namely in the same compartment as the mitochondrial DNA. Mitochondrial DNA is particularly vulnerable to oxidative damage (Yakes and Van Houten,
1997), and indeed mitochondrial DNA defects are well documented in multiple sclerosis (Mao and Reddy; 2010; Campbell
et al., 2011), reinforcing a view that the mitochondrial production
of reactive oxygen species in and around multiple sclerosis lesions
may be higher than normal.
If mitochondria are an important source of reactive oxygen species, as well as ATP, they can be viewed not only as helpful ‘saviours’ in a battle against impending energy deficits, but also as
risky components that increase the chance of triggering an oxidative firestorm with microglia (Campbell and Mahad, 2011; van
Horssen et al., 2011) even from a quiescent beginning.
Especially with this in mind, the new findings in a second paper
published in this issue of Brain, from Don Mahad and his colleagues, are very interesting. Zambonin et al. (2011) report that
established remyelinated axons in multiple sclerosis lesions contain
more mitochondria than normal, but fewer mitochondria than established demyelinated axons. If axonal mitochondria are a potential source of excessive production of reactive oxygen species, the
Brain 2011: 134; 1877–1881
| 1879
increased number of mitochondria in remyelinated [and demyelinated axons (Campbell and Mahad, 2011)] may place the axons
at increased danger for degeneration; and this is consistent with
findings in multiple sclerosis. Thus, some remyelinating and remyelinated axons in multiple sclerosis can have greater evidence of
axonal injury than occurs in established demyelinating lesions
(Kuhlmann et al., 2002).
In this commentary, it has been reasoned that it may be possible
to look beyond the boundary of the chronic active multiple sclerosis lesion into the periplaque region, in order to explore the earliest events as an existing lesion grows, but it is interesting to
wonder whether mechanisms responsible for the extension of
existing lesions might recapitulate those involved with the formation of new lesions. This question is difficult to answer in multiple
sclerosis tissue, so is there any evidence from experimental studies
that oxidative damage might occur in the normal nervous system
as an initial event in lesion formation? An unexpected finding
in EAE is pronounced oxidative and nitrative injury of tissue and
mitochondria as early as 3-days post-immunization, well before
the onset of obvious inflammation marked by the infiltration of
inflammatory cells (Qi et al., 2007a). This finding is intriguing,
not least because similar findings are reported in animals with experimental autoimmune uveitis (Saraswathy and Rao, 2008). The
source of the oxidative damage remains unclear, but innate immune mechanisms seem likely and this interpretation is supported
by other findings in EAE, although using a very different model
(Ponomarev et al., 2005). Although not conclusive, the experimental findings show that oxidative damage can be a very early
event in the formation of new autoimmune lesions.
In summary, new observations regarding oxidative damage in
chronic active multiple sclerosis lesions might reflect the early
events occurring as the tissue is lesioned in multiple sclerosis.
Thus, if the periplaque tissue can be interpreted as the advancing
edge of the slowly growing lesion, it is interesting that it exhibits
clear oxidative damage in the presence of activated microglial cells
expected to be releasing superoxide and nitric oxide and the cascade of reactive oxygen and nitrogen species that follows. Several
reasons are presented to suspect that reactive oxygen species produced by the glial and axonal mitochondria may add to the oxidative damage experienced by these cells, exacerbating the
mitochondrial damage, including damage to the mitochondrial
DNA. If so, anti-oxidant therapy could be beneficial in multiple
sclerosis and there is indeed supporting evidence for this approach
from experimental studies (Qi et al., 2007b; Nikic et al., 2011).
Such therapy may inhibit the growth of existing multiple sclerosis
lesions, and perhaps prevent the formation of new ones. It may also
prevent damage to demyelinated and remyelinated axons. As mitochondria are damaged in the disease process, and may also contribute to the oxidative stress, anti-oxidant therapies targeted directly
at mitochondria (Murphy, 2009b) may be particularly effective.
Acknowledgements
I am grateful to Michael Duchen, Michael Murphy and Jia
Newcombe for their expert comments on the manuscript.
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| Brain 2011: 134; 1877–1881
Funding
Work in the author’s laboratory is supported by grants from the
Brain Research Trust, the Medical Research Council and the
Multiple Sclerosis Society of Great Britain and Northern Ireland.
Kenneth J. Smith
Department of Neuroinflammation, UCL Institute of Neurology,
Queen Square, London WC1N 3BG, UK
Correspondence to:
Kenneth J. Smith,
Department of Neuroinflammation,
UCL Institute of Neurology,
Queen Square,
London WC1N 3BG, UK
E-mail: [email protected]
Advance Access publication June 15, 2011
doi:10.1093/brain/awr144
Reference
Aboul-Enein F, Rauschka H, Kornek B, Stadelmann C, Stefferl A,
Bruck W, et al. Preferential loss of myelin-associated glycoprotein reflects hypoxia- like white matter damage in stroke and inflammatory
brain diseases. J Neuropathol Exp Neurol 2003; 62: 25–33.
Abramov AY, Canevari L, Duchen MR. Beta-amyloid peptides induce
mitochondrial dysfunction and oxidative stress in astrocytes and
death of neurons through activation of NADPH oxidase. J Neurosci
2004; 24: 565–75.
Andrews HE, Nichols PP, Bates D, Turnbull DM. Mitochondrial dysfunction plays a key role in progressive axonal loss in Multiple Sclerosis.
Med Hypotheses 2005; 64: 669–77.
Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004; 55: 458–68.
Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007; 87:
245–313.
Beltran B, Quintero M, Garcia-Zaragoza E, O’Connor E, Esplugues JV,
Moncada S. Inhibition of mitochondrial respiration by endogenous
nitric oxide: a critical step in Fas signaling. Proc Natl Acad Sci USA
2002; 99: 8892–7.
Bolanos JP, Almeida A. Modulation of astroglial energy metabolism by
nitric oxide. Antioxid Redox Signal 2006; 8: 955–65.
Bove PF, Hristova M, Wesley UV, Olson N, Lounsbury KM, van der
Vliet A. Inflammatory levels of nitric oxide inhibit airway epithelial
cell migration by inhibition of the kinase ERK1/2 and activation of
hypoxia-inducible factor-1 alpha. J Biol Chem 2008; 283: 17919–28.
Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H,
et al. NADPH oxidase is the primary source of superoxide induced by
NMDA receptor activation. Nat Neurosci 2009; 12: 857–63.
Brunori M, Forte E, Arese M, Mastronicola D, Giuffre A, Sarti P. Nitric
oxide and the respiratory enzyme. Biochim Biophys Acta 2006; 1757:
1144–54.
Campbell GR, Mahad DJ. Mitochondria as crucial players in demyelinated axons: lessons from neuropathology and experimental demyelination. Autoimmune Dis 2011; 2011: 262847.
Campbell GR, Ziabreva I, Reeve AK, et al. Mitochondrial DNA deletions
and neurodegeneration in multiple sclerosis. Ann Neurol 2011; 69:
481–92.
Desai RA, Davies AL, Smith KJ. Evidence that hypoxia and energy insufficiency play a role in central inflammation. Neuropathol Appl
Neurobiol 2011; 37 (Suppl. 1): 7–8.
Scientific Commentary
Dutta R, McDonough J, Yin X, et al. Mitochondrial dysfunction as a
cause of axonal degeneration in multiple sclerosis patients. Ann
Neurol 2006; 59: 478–89.
Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in
multiple sclerosis. Neurol 2007; 68: S22–31.
Frohman EM, Racke MK, Raine CS. Multiple sclerosis–the plaque and its
pathogenesis. N Engl J Med 2006; 354: 942–55.
Gay F. Bacterial toxins and Multiple Sclerosis. J Neurol Sci 2007; 262:
105–12.
Gay FW, Drye TJ, Dick GW, Esiri MM. The application of multifactorial
cluster analysis in the staging of plaques in early multiple sclerosis.
Identification and characterization of the primary demyelinating
lesion. Brain 1997; 120: 1461–83.
Gonsette RE. Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity. J Neurol Sci 2008; 274: 48–53.
Graumann U, Reynolds R, Steck AJ, Schaeren-Wiemers N. Molecular
changes in normal appearing white matter in multiple sclerosis are
characteristic of neuroprotective mechanisms against hypoxic insult.
Brain Pathol 2003; 13: 554–73.
Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated activity
and microglial expression of myeloperoxidase in demyelinated cerebral
cortex in multiple sclerosis. Brain Path 2008a; 18: 86–95.
Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated myeloperoxidase activity in white matter in multiple sclerosis. Neurosci Lett
2008b; 444: 195–8.
Hagen T, Taylor CT, Lam F, Moncada S. Redistribution of intracellular
oxygen in hypoxia by nitric oxide: effect on HIF1alpha. Science 2003;
302: 1975–8.
Haider L, Fischer M-T, Frischer J, Hoeftberger R, Botond G, Esterbauer H,
et al. Oxidative damage and neurodegeneration in multiple sclerosis
lesions. Brain 2011; in press.
Henderson AP, Barnett MH, Parratt JD, Prineas JW. Multiple sclerosis:
distribution of inflammatory cells in newly forming lesions. Ann Neurol
2009; 66: 739–53.
Kalman B, Laitinen K, Komoly S. The involvement of mitochondria in
the pathogenesis of multiple sclerosis. J Neuroimmunol 2007; 188:
1–12.
Karadottir R, Attwell D. Neurotransmitter receptors in the life and death
of oligodendrocytes. Neuroscience 2007; 145: 1426–38.
Klimova T, Chandel NS. Mitochondrial complex III regulates hypoxic
activation of HIF. Cell Death Differ 2008; 15: 660–6.
Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W. Acute axonal
damage in multiple sclerosis is most extensive in early disease stages
and decreases over time. Brain 2002; 125: 2202–12.
Lassmann H. The architecture of inflammatory demyelinating lesions:
implications for studies on pathogenesis. Neuropathol Appl Neurobiol
2011; in press.
Liu JS, Zhao ML, Brosnan CF, Lee SC. Expression of inducible nitric oxide
synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol
2001; 158: 2057–66.
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M,
Lassmann H. Heterogeneity of multiple sclerosis lesions: Implications
for the pathogenesis of demyelination. Ann Neurol 2000; 47:
707–17.
Mahad DJ, Ziabreva I, Campbell G, Lax X, White K, Hanson PS, et al.
Mitochondrial changes within axons in multiple sclerosis. Brain 2009;
132: 1161–74.
Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the
response to hypoxic stress. Mol Cell 2010; 40: 294–309.
Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease? Biochim
Biophys Acta 2010; 1802: 66–79.
Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ. Lesion genesis in a
subset of patients with multiple sclerosis: a role for innate immunity?
Brain 2007; 130: 2800–15.
Murphy MP. How mitochondria produce reactive oxygen species.
Biochem J 2009a; 417: 1–13.
Murphy MP. Mitochondria–a neglected drug target. Curr Opin Investig
Drugs 2009b; 10: 1022–4.
Scientific Commentary
Nakamura T, Lipton SA. S-nitrosylation of critical protein thiols mediates
protein misfolding and mitochondrial dysfunction in neurodegenerative
diseases. Antioxid Redox Signal 2011; 14: 1479–92.
Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM,
et al. A reversible form of axon damage in experimental autoimmune
encephalomyelitis and multiple sclerosis. Nat Med 2011; 17: 495–9.
Olson N, van der Vliet A. Interactions between nitric oxide and
hypoxia-inducible factor signaling pathways in inflammatory disease.
Nitric Oxide 2011.
Palmer LA, Gaston B, Johns RA. Normoxic stabilization of hypoxiainducible factor-1 expression and activity: redox-dependent effect of
nitrogen oxides. Mol Pharmacol 2000; 58: 1197–203.
Ponomarev ED, Shriver LP, Maresz K, Dittel BN. Microglial cell activation
and proliferation precedes the onset of CNS autoimmunity. J Neurosci
Res 2005; 81: 374–89.
Qi X, Lewin AS, Sun L, Hauswirth WW, Guy J. Mitochondrial protein
nitration primes neurodegeneration in experimental autoimmune
encephalomyelitis. J Biol Chem 2006; 281: 31950–62.
Qi X, Lewin AS, Sun L, Hauswirth WW, Guy J. Suppression of mitochondrial oxidative stress provides long-term neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 2007a; 48: 681–91.
Qi X, Sun L, Lewin AS, Hauswirth WW, Guy J. Long-term suppression of
neurodegeneration in chronic experimental optic neuritis: antioxidant
gene therapy. Invest Ophthalmol Vis Sci 2007b; 48: 5360–70.
Redford EJ, Kapoor R, Smith KJ. Nitric oxide donors reversibly block
axonal conduction: demyelinated axons are especially susceptible.
Brain 1997; 120: 2149–57.
Rubbo H, Trostchansky A, O’Donnell VB. Peroxynitrite-mediated lipid
oxidation and nitration: mechanisms and consequences. Arch
Biochem Biophys 2009; 484: 167–72.
Salvetti M, Giovannoni G, Aloisi F. Epstein-Barr virus and multiple sclerosis. Curr Opin Neurol 2009; 22: 201–6.
Saraswathy S, Rao NA. Photoreceptor mitochondrial oxidative stress in
experimental autoimmune uveitis. Ophthalmic Res 2008; 40: 160–4.
Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis.
Lancet Neurol 2002; 1: 232–41.
Brain 2011: 134; 1877–1881
| 1881
Smith KJ, McDonald I, Miller D, Lassmann H. The pathophysiology of
multiple sclerosis. In: Compston A, Confavreux C, Lassmann H,
McDonald I, Miller D, Noseworthy J, et al. editors. McAlpine’s multiple
sclerosis. London: Churchill Livingstone; 2006. p. 601–59.
Stowe DF, Camara AK. Mitochondrial reactive oxygen species production
in excitable cells: modulators of mitochondrial and cell function.
Antioxid Redox Signal 2009; 11: 1373–414.
Stys PK, Lipton SA. White matter NMDA receptors: an unexpected new
therapeutic target? Trends Pharmacol Sci 2007; 28: 561–6.
van Horssen J, Witte ME, Schreibelt G, de Vries HE. Radical changes in
multiple sclerosis pathogenesis. Biochim Biophys Acta 2011; 1812:
141–50.
Weiner HL. Multiple sclerosis is an inflammatory T-cell-mediated autoimmune disease. Arch Neurol 2004; 61: 1613–5.
Werner P, Pitt D, Raine CS. Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage.
Ann Neurol 2001; 50: 169–80.
Witte ME, Bo L, Rodenburg RJ, Belien JA, Musters R, Hazes T, et al.
Enhanced number and activity of mitochondria in multiple sclerosis
lesions. J Pathol 2009; 219: 193–204.
Witte ME, Geurts JJ, de Vries HE, van der Valk P, van Horssen J.
Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 2010; 10: 411–8.
Yakes FM, Van Houten B. Mitochondrial DNA damage is more extensive
and persists longer than nuclear DNA damage in human cells following
oxidative stress. Proc Natl Acad Sci USA 1997; 94: 514–9.
Zambonin JL, Zhao C, Ohno N, Campbell GR, Engeham S, Ziabreva I,
et al. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain 2011; in press.
Zeis T, Graumann U, Reynolds R, Schaeren-Wiemers N. Normalappearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain 2008; 131: 288–303.
Zeis T, Probst A, Steck AJ, Stadelmann C, Bruck W, SchaerenWiemers N. Molecular changes in white matter adjacent to an active
demyelinating lesion in early multiple sclerosis. Brain Pathol 2009; 19:
459–66.