excitotoxic damage to white matter

J. Anat.

(2007)

210

, pp693–702 doi: 10.1111/j.1469-7580.2007.00733.x

© 2007 The Authors Journal compilation © 2007 Anatomical Society of Great Britain and Ireland

Blackwell Publishing Ltd

REVIEW

Excitotoxic damage to white matter

Carlos Matute,

1

Elena Alberdi,

1

María Domercq,

1

María-Victoria Sánchez-Gómez,

1

Alberto Pérez-Samartín,

1

Alfredo Rodríguez-Antigüedad

2

and Fernando Pérez-Cerdá

1

1

Departamento de Neurociencias, Universidad del País Vasco, Leioa, and Neurotek-UPV/EHU, Parque Tecnológico de Bizkaia, Zamudio, Spain

2

Servicio de Neurología, Hospital de Basurto, Bilbao, Spain

Abstract

Glutamate kills neurons by excitotoxicity, which is caused by sustained activation of glutamate receptors. In recent

years, it has been shown that glutamate can also be toxic to white matter oligodendrocytes and to myelin by this

mechanism. In particular, glutamate receptor-mediated injury to these cells can be triggered by activation of

alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, kainate and

N

-methyl-

D

-aspartate glutamate receptor

types. Thus, these receptor classes, and the intermediaries of the signal cascades they activate, are potential targets

for drug development to treat white matter damage in acute and chronic diseases. In addition, alterations of

glutamate homeostasis in white matter can determine glutamate injury to oligodendrocytes and myelin.

Astrocytes are responsible for most glutamate uptake in synaptic and non-synaptic areas and consequently are the

major regulators of glutamate homeostasis. Activated microglia in turn may secrete cytokines and generate radical

oxygen species, which impair glutamate uptake and reduce the expression of glutamate transporters. Finally,

oligodendrocytes also contribute to glutamate homeostasis. This review aims at summarizing the current

knowledge about the mechanisms leading to oligodendrocyte cell death and demyelination as a consequence of

alterations in glutamate signalling, and their clinical relevance to disease. In addition, we show evidence that

oligodendrocytes can also be killed by ATP acting at P2X receptors. A thorough understanding of how oligodendro-

cytes and myelin are damaged by excitotoxicity will generate knowledge that can lead to improved therapeutic

strategies to protect white matter.

Key words

ATP; cell death; complement; glutamate; human; oligodendrocyte; pathology.

Introduction

Excitotoxic cell death can occur in virtually all neurons

which express ionotropic glutamate receptors (GluRs)

and it has been implicated in acute injury to the central

nervous system (CNS) and in chronic neurodegenera-

tive disorders (Choi, 1988; Lipton & Rosenberg, 1994;

Lee et al. 1999). In addition, glutamate can also be toxic

to glial cells including astrocytes (Haas & Erdo, 1991)

and oligodendrocytes (Yoshioka et al. 1995; Matute

et al. 1997; McDonald et al. 1998). This review will

focus on excitotoxicity in oligodendrocytes, as this cell

type is particularly vulnerable to glutamate insults. We

will first summarize current knowledge of GluRs and

glutamate transporters (GluTs) and then the mech-

anisms of glutamate excitoxicity to white matter and

its relevance to CNS diseases.

Glutamate signalling in oligodendrocytes

Glutamate signalling is carried out by GluRs and GluTs.

Glutamate activates ionotropic and metabotropic

receptors (for reviews, see Dingledine et al. 1999; Cull-

Candy & Leszkiewicz, 2004; Swanson et al. 2005). Glial

cells express most of these receptors (for recent reviews

Correspondence

Dr C. Matute, Departamento de Neurociencias, Universidad del País Vasco, E-48940 Leioa, and Neurotek-UPV/EHU, Parque Tecnológico de Bizkaia, E-48170 Zamudio, Spain. T: +34 946 013 244; F: +34 946 015 055; E: carlos., [email protected]

Accepted for publication

6 March 2007

White matter injury by glutamate, C. Matute et al.

© 2007 The AuthorsJournal compilation © 2007 Anatomical Society of Great Britain and Ireland

694

see, Belachew & Gallo, 2004; Kettenmann & Steinhäuser,

2005; Matute et al. 2006; Matute, 2006). In particular,

cells of the oligodendrocyte lineage express functional

alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic

acid (AMPA) and kainate-type receptors throughout

a wide range of developmental stages and species,

including humans (Figs 1 and 2). In addition, immature

and mature oligodendrocytes express

N

-methyl-

D

-

aspartate (NMDA) receptors which can be activated

during injury (Karadottir et al. 2005; Salter & Fern,

2005; Micu et al. 2006). Moreover, oligodendrocytes

also express receptors of all three groups of metabo-

tropic GluRs but their levels are developmentally

regulated and are very low in mature cells of this lineage

(Deng et al. 2004).

Glutamate uptake from the extracellular space by

specific GluTs is essential for the shaping of excitatory

postsynaptic currents and for the prevention of excito-

toxic death due to overstimulation of GluRs (Rothstein

et al. 1996). At least five GluTs have been cloned (Dan-

bolt, 2001; Huang & Bergles, 2004). Of these, glutamate

transporter 1 [GLT-1; excitatory amino acid transporter

2 (EAAT2) in the modern nomenclature] exhibits the

highest level of expression and is responsible for

most glutamate transport (Danbolt, 2001). GluTs are

expressed by astrocytes and oligodendrocytes. The

main transporter expressed by oligodendrocytes is

glutamate aspartate transporter (GLAST; EAAT1 in

the modern nomenclature; Fig. 3). The neuronal trans-

porter, termed excitatory amino acid carrier 1 (EAAC1;

EAAT3 in the modern nomenclature), is present in a

subpopulation of adult oligodendrocyte progenitor

cells (Domercq et al. 1999). It thus appears that all

macroglial cells differentially express the three major

GluTs present in the CNS. These transporters maintain

basal levels of extracellular glutamate in the range of

1–2

µ

M

and thus prevent over-activation of GluRs under

physiological conditions.

Oligodendrocyte vulnerability to excitotoxic insults by glutamate

Numerous studies carried out over the last few years

have shown that, in addition to neurons, glial cells can

die by excitotoxicity. The glial cell types which are

most vulnerable to excitotoxicity are those of the

oligodendrocyte lineage. However, there is evidence

that sustained activation of ionotropic GluRs can also

kill astrocytes and microglia.

The first evidence that oligodendrocytes are highly

vulnerable to glutamate was obtained in primary

cultures more than 10 years ago (Oka et al. 1993). After

a 24-h exposure to glutamate, oligodendroglial death

Fig. 1 Functional AMPA and kainate receptors in cultured human oligodendrocytes. (A) Cells originated from human cerebral cortex excised at surgery for tumour removal and were immunostained for the oligodendrocyte marker O1. Scale bar = 20 µm. (B) Sample whole-cell recordings of O1+ cells of the responses to AMPA and kainate (both at 1 mM). GYKI53655 (100 µM) was added in conjunction with kainate to activate selectively kainate receptors. (C) Increase in [Ca2+]i in oligodendrocytes exposed to AMPA (10 µM) with CTZ (100 µM) and kainate (3 µM) (arrow) in the presence of GYKI53655 (100 µM) from two to five O1+ cells.



695

was comparable with that described in neurons. How-

ever, oligodendroglial toxicity was not mediated by

GluRs, as in neurons, but rather by a transporter-related

mechanism involving the inhibition of cystine uptake,

which results in glutathione depletion and cellular

vulnerability to toxic-free radicals (Oka et al. 1993).

More recently, it was shown that prolonged activation

of GluRs is toxic to cells of an oligodendroglial cell line

(Yoshioka et al. 1996) and to oligodendrocytes

in vitro

and

in vivo

(Matute et al. 1997; McDonald et al. 1998;

Li & Stys, 2000). This toxicity is directly related to Ca

2+

influx subsequent to receptor activation, and it is

greatly attenuated in the absence of Ca

2+

in the culture

medium (Sánchez-Gómez & Matute, 1999).

Glutamate can also cause glial demise indirectly

by inducing the release of toxic agents. In microglia,

activation of AMPA and kainate receptors results in

the release of tumour necrosis factor-

α

(TNF-

α

), which

Fig. 2 Expression of AMPA and kainate receptors in oligodendrocytes of the human optic nerve. Double immunofluorescence labelling of AMPA (GluR2/3) and kainate (GluR5/6/7) receptor subunits in oligodendrocytes of the human optic nerve. Green and red fluorescence reveal subunit localization and oligodendrocyte labelling by the anti-APC antibody, an oligodendroglial marker, respectively. Arrows point to some double immunolabelled oligodendrocytes. Scale bar = 20 µm.

Fig. 3 Expression of glutamate transporter EAAT1 in oligodendrocytes of the human optic nerve. Photomicrographs depict same fields in each row with immunofluorescence labelling of EAAT1 transporter and of APC+ oligodendrocytes and GFAP+ astrocytes. Overlays (right column) show that EAAT1 co-localizes with the oligodendrocyte marker APC but not with GFAP+ cells. Arrows point to same somata in each row of photographs. Scale bar = 30 µm. Abbreviations: APC, adenomatous polyposis coli antigen; GFAP, glial fibrillary acidic protein. Modified from Vallejo-Illarramendi et al. (2006).



696

can potentiate glutamate neurotoxicity and kill oli-

godendrocytes, destroy myelin and damage axons

(Merrill & Benveniste, 1996). In turn, stimulation of the

mGluR2 receptor on primary rat microglia induces

microglial activation and results in a neurotoxic pheno-

type which secretes TNF-

α

(Taylor et al. 2005). This

toxicity can be neutralized by the activation of the

mGluR3 receptor, which is also present in microglia

(Taylor et al. 2005). Moreover, inflammatory cytokines

including TNF-

α

and interleukin-1

β

, which are commonly

released by reactive microglia, can impair glutamate

uptake and trigger excitotoxic oligodendrocyte

death (Takahashi et al. 2003). Indeed, inhibition of the

expression and functioning of GluTs in axonal tracts is

sufficient to induce oligodendroglial loss and demye-

lination, which demonstrates that the integrity of

oligodendrocytes and white matter depends on proper

GluT function (Domercq et al. 2005).

Mechanisms of glutamate damage to oligodendrocytes

Activation of AMPA, kainate or NMDA receptors in

oligodendrocytes leads to Ca

2+

influx (Fig. 4), an effect

which is totally abolished by selective receptor anta-

gonists or by removing this cation from the culture

medium. The mechanisms triggered by NMDA receptor-

mediated insults to oligodendrocytes have not yet

been clarified. However, the types of excitotoxic oligo-

dendrocyte death induced by activation of AMPA

and kainate receptors are known to depend on the

intensity and duration of glutamate exposure. A central

event to this process is accumulation of Ca

2+

within

mitochondria, which leads to the depolarization of

this organelle, increased production of oxygen free

radicals, and release of proapoptotic factors which

activate caspases (see Fig. 4).

Fig. 4 Molecular events triggered by glutamate receptor-mediated oligodendrocyte demise. Selective activation of AMPA receptors (AMPA-R) and kainate receptors (Kai-R) leads to Na+ and Ca2+ influx through the receptor channel complex. Subsequent depolarization activates voltage-gated Ca2+ channels (VGCC), which contributes to [Ca2+]i increase. Ca2+ overload induces rapid uptake by mitochondria, which results in attenuation of mitochondrial potential and an increase in the production of reactive oxygen species (ROS). Cytochrome c (Cyt c) is released from depolarized mitochondria, interacts with apoptotic protease-activating factor 1 (Apaf-1) and activates caspases. Other pro-apoptotic factors include apoptosis-inducing factor (AIF), which activates poly(ADP-ribose)polymerase-1 (PARP-1). In oligodendrocytes, insults channelled through Kai-R activate caspases 9 and 3, whereas those activating AMPA-R induce apoptosis by recruiting caspase 8, which truncates Bid, caspase 3 and PARP-1, or cause necrosis. In addition, Ca2+ influx triggered by Kai-R stimulation but not by AMPA-R activates calcineurin (CdP), which dephosphorylates Bad and facilitates apoptosis. Finally, activation of NMDA receptors (NMDA-R) also initiates oligodendrocyte death, which is entirely dependent on Ca2+ influx; however, the molecular mechanisms activated by these receptors are not yet known. Abbreviations: FADD, Fas-associated death domain; 14-3-3, phosphoserine-binding protein 14-3-3. Scheme based on Sánchez-Gómez et al. (2003).



697

Glutamate at non-toxic concentrations can also

induce oligodendrocyte death by sensitizing these

cells to complement attack (Alberdi et al. 2006). Thus, a

brief incubation with glutamate followed by exposure

to complement is lethal to oligodendrocytes

in vitro

and in freshly isolated optic nerves (Fig. 5A). Intri-

guingly, complement toxicity is induced by activation

of kainate, but not of AMPA, NMDA or metabotropic

GluRs, and is abolished by removing Ca

2+

from the

medium during glutamate priming. Dose–response

studies show that sensitization to complement attack is

induced by two distinct kainate receptor populations

displaying high and low affinities for glutamate.

Oligodendrocyte death by complement required the

formation of the membrane attack complex, which in

turn increased membrane conductance, induced Ca

2+

overload and mitochondrial depolarization as well as

a rise in the level of reactive oxygen species. Treat-

ment with the antioxidant Trolox and inhibition of

poly(ADP-ribose) polymerase-1, but not of caspases,

protected oligodendrocytes against damage induced

by complement (Fig. 5B,C). This novel mechanism of

glutamate-induced toxicity to oligodendrocytes is also

shared by neurons and may be relevant to glutamate

injury in acute and chronic neurological disease with

primary or secondary inflammation.

Fig. 5 Glutamate sensitizes cultured oligodendrocytes to complement attack by activating kainate receptors. (A) Oligodendrocyte viability (green calcein fluorescence) and death (propidium iodide red fluorescence) 24 h after pretreatment with vehicle or glutamate (Glu; 10 µM) for 10 min, followed by exposure to culture medium or complement (LTC). The histogram on the right illustrates oligodendrocyte death. Note that the culture medium alone (SATO) and heat-inactivated LTC (HI-LTC) were ineffective. *P < 0.01 compared with SATO, paired Student’s t-test. Scale bar = 40 µm. (B) Complement causes oxidative stress in glutamate (Glu)-sensitized oligodendrocytes. * and #: P < 0.05 compared with vehicle + LTC or Glu-pre + LTC, respectively, paired Student’s t-test. (C) PARP-1 inhibition with DPQ (30 µM) reduces cell death, whereas the pan-caspase inhibitor ZVAD-F (50 µM) was ineffective. In turn, the antioxidant Trolox (10 µM) fully protected oligodendrocytes from LTC toxicity. *P < 0.05, **P < 0.01 compared with Glu pre + LTC, paired Student’s t-test. Modified from Alberdi et al. (2006).



698

Clinical relevance of glutamate damage to white matter

In humans white matter constitutes about 50% of the

brain volume and consequently glutamate-induced

oligodendrocyte death is highly relevant to the patho-

physiology of CNS diseases. In addition, primary and/or

secondary glutamate damage to oligodendroglia in

grey matter may also contribute to the onset and

progression of acute and chronic brain and spinal cord

disorders. Thus, loss of oligodendrocytes and/or damage

to white matter occurs in stroke, traumatic injury,

neurodegenerative diseases, multiple sclerosis (MS)

(Matute et al. 2006) as well as in psychiatric diseases

(Davis et al. 2003). Here, we will only illustrate the

putative relevance of oligodendrocyte excitotoxicity to

ischaemia [stroke and periventricular leukomalacia

(PVL)] and MS.

Stroke

In humans, most cases of focal ischaemia and occlusion

of major cerebral arteries damage both grey and white

matter. Energy deprivation causes neuronal death,

axonal dysfunction and loss of oligodendrocytes which

are very sensitive to transient oxygen and glucose

deprivation (Dewar et al. 2003; Goldberg & Ransom,

2003; Stys, 2004). After 1 h under these conditions, the

viability of oligodendrocytes in mixed glial cultures

is severely impaired, an effect which is attenuated

by AMPA/kainate antagonists (McDonald et al. 1998).

In turn, immature oligodendrocytes are even more

sensitive to ischaemic injury than their mature counter-

parts (Fern & Möller, 2000). Thus, these cells may

release glutamate under ischaemic conditions by

reverse functioning of their GluTs (Domercq et al. 1999,

2005).

In vivo

models of stroke and cardiac arrest such as

permanent middle cerebral artery occlusion and brief

transient global ischaemia induce rapid oligoden-

droglial death (Mandai et al. 1997; Petito et al. 1998).

Interestingly, a few days after the insult, there is an

increase in the number of oligodendroglial cells in

areas bordering affected regions (Mandai et al. 1997),

as well as in the number of immature oligodendrocytes

surrounding the lateral ventricles (Gottlieb et al. 2000),

indicating that ischaemic damage to oligodendroglia can

be compensated for, at least in part, by the generation

and migration of new oligodendrocytes.

Preterm and perinatal ischaemia

PVL, the main substrate for cerebral palsy, is character-

ized by diffuse injury of deep cerebral white matter,

accompanied in its most severe form by focal necrosis.

The classical neuropathology of PVL has given rise to

several hypotheses about its pathogenesis, largely

relating to hypoxia-ischaemia and reperfusion in the

sick premature infant. These include free radical injury,

cytokine toxicity (especially given the epidemiological

association of PVL with maternofetal infection) and

excitotoxicity (Folkerth, 2006).

Injury to oligodendrocyte progenitors, caused in

part by glutamate and the subsequent derailment of

Ca

2+

homeostasis, contributes to the pathogenesis of

myelination disturbances in this illness (Back & Rivkees,

2004). In addition to this mechanism, glutamate-

induced depletion of glutathione and the subsequent

oxidative stress in PVL also contributes to damage to

oligodendrocytes (Haynes et al. 2003), which are sensi-

tive to oxidative stress in part because of their high lipid

and iron content. Notably, the vitamin K deficiency in

preterm infants is a risk factor for developing PVL, and

in turn its presence is protective against oxidative injury

to immature oligodendrocytes (Li et al. 2003).

Multiple sclerosis

In MS, the immune system attacks the white matter of

the brain and spinal cord, leading to disability and/or

paralysis. Myelin and oligodendrocytes are lost due

to the release by immune cells of cytotoxic cytokines,

autoantibodies and toxic amounts of glutamate

(Matute et al. 2001; Srinivasan et al. 2005). Excitotoxins

such as kainate infused onto the optic nerve cause

glutamate receptor-mediated MS-like lesions (Matute,

1998). In turn, experimental autoimmune encephalo-

myelitis (EAE), an animal model which exhibits the

clinical and pathological features of MS, is alleviated

by AMPA and kainate receptor antagonists (Pitt et al.

2000; Smith et al. 2000; Groom et al. 2003). Remarkably,

blockade of these receptors in combination with anti-

inflammatory agents is effective even at an advanced

stage of unremitting EAE, as assessed by increased

oligodendrocyte survival and remyelination, and cor-

responding decreased paralysis, inflammation, CNS

apoptosis and axonal damage (Kanwar et al. 2004).

The concentration of glutamate in cerebrospinal

fluid (CSF) is higher in patients with acute rather than



699

silent MS and in controls (Stover et al. 1997) and it is

associated with the severity and course of the disease

(Barkhatova et al. 1998). Notably, glutamate levels are

increased in acute MS lesions and in normal-appearing

white matter in MS patients (Srinivasan et al. 2005).

Potential cellular sources contributing to enhanced

glutamate levels in CSF include activated microglia,

which can release glutamate via the reversal of GluT

function, a process which is potentiated under path-

ological conditions (Noda et al. 1999). In addition,

oxidative stress may also contribute to the increase in

glutamate concentrations in the extracellular space, as

free radicals reduce the efficiency of GluTs (Volterra

et al. 1994). Other factors which may contribute to

perturbing glutamate homeostasis include altered

activity of the glutamate-producing enzyme glutami-

nase in activated macrophages/microglia in close

proximity to dystrophic axons (Werner et al. 2001), and

altered expression of the glutamate transporters EAAT-

1 and EAAT-2 in oligodendrocytes as a consequence of

enhanced exposure to the proinflammatory cytokine

TNF

α

(Pitt et al. 2003; Vallejo-Illarramendi et al. 2006).

Overall, these alterations probably lead to high

extracellular glutamate levels and an increased risk of

oligodendrocyte excitotoxicity in MS.

ATP can also induce oligodendrocyte death

Like glutamate, extracellular ATP is a major excitatory

neurotransmitter in the CNS, activating ionotropic

(P2X) and metabotropic (P2Y) receptors (Ralevic &

Burnstock, 1998; North, 2002). ATP-gated P2X channels

are formed by P2X1–P2X7 subunits and have marked

Ca

2+

permeability (North, 2002). P2X receptors are

expressed in CNS neurons, where they participate in

fast synaptic transmission and modulation. In addition,

P2X receptors mediate signalling cascades leading to

neurodegeneration after ischaemia (Le Feuvre et al.

2003). Recently, it has also been shown that spinal

cord injury is associated with prolonged P2X7 receptor

activation, which results in neuronal excitotoxicity

(Wang et al. 2004).

Differentiated oligodendrocytes

in vitro

express

functional P2X and P2Y receptors, the former with high

permeability to Ca

2+

(Alberdi et al. 2005). As a result,

we tested whether activation of these receptors can kill

these cells. Incubation of oligodendrocytes with ATP

or P2X agonists such BzATP, but not P2Y agonists, was

toxic to oligodendrocytes (Fig. 6). Toxicity was pre-

vented by removal of Ca

2+

from the culture media, and

by the non-selective P2X receptor antagonist PPADS,

as well as by oATP and BBG at concentrations that

selectively block P2X7 receptors (Fig. 6). This is consistent

with a predominant expression of P2X7 receptors in

differentiated oligodendrocytes, as shown by immuno-

chemistry (Matute et al. 2003).

The relevance of ATP excitoxicity to CNS damage to

the aetiology of acute and chronic diseases is unknown,

but the release of this neurotransmitter from dying

cells may well contribute to aggravate the extent of

ongoing damage in numerous pathological conditions.

Concluding remarks

Oligodendrocytes display great vulnerability to over-

activation of AMPA, kainate and NMDA receptors. The

Fig. 6 Activation of purinergic P2X receptor kills oligodendrocytes in vitro. Acute exposure to ATP (A) or to BzATP (B) induces cell death of differentiated oligodendrocytes obtained from optic nerves of 14-day-old rats. This is prevented by co-application of the broad-spectrum P2 antagonist PPADS, the P2X7 antagonist O-ATP and by omitting Ca2+ in the culture medium. Data represent the means ± SEM. *P < 0.05 and **P < 0.001, one-way ANOVA, Fischer’s PDLS test.



700

proper functioning of glutamate uptake is critical to

prevent glutamate-induced damage to oligodendro-

cytes, and drugs that regulate the function and

expression of GluTs have the potential to attenuate

glutamate insults to glial cells. Likewise, positive regu-

lators of the expression of GluTs also have a protective

potential, as they contribute to ischaemic tolerance

after ischaemic preconditioning (Romera et al. 2004).

These include tumour growth factor-

α

and epidermal

growth factor (EGF), which by signalling through EGF

receptors and activation of phosphoinositol-3-kinase

and nuclear factor-

κ

B, strongly enhance EAAT2 expres-

sion (Su et al. 2003). Remarkably, clinically used beta-

lactam antibiotics are also potent activators of GluT

expression and thus hold great therapeutic potential

(Rothstein et al. 2005).

Another set of molecular targets to prevent gluta-

mate insults to oligodendrocytes lie downstream of

GluRs activation. For instance, tetracyclines, which

attenuate mitochondrial damage subsequent to insults

including excitotoxicity, protect oligodendrocytes and

white matter, making these antibiotics promising can-

didates for the treatment of acute and chronic diseases

with oligodendrocyte loss (Domercq & Matute, 2004).

By contrast, drugs supporting the management of

Ca

2+

overload subsequent to GluRs and P2X receptor

activation may improve oligodendrocyte viability.

In summary, knowledge about the mechanisms

leading to glutamate and ATP receptor-mediated oligo-

dendrocyte injury will facilitate new pharmacological

strategies for the treatment of CNS disorders which

cause white matter damage.

Acknowledgements

We would like to thank Drs A. Carrasco, E. Areitio, J.

Lespuru, J. B. Ulibarri and J. Salazar (Neurosurgery

Deparment, Hospital de Basurto, Bilbao) for providing

surgical specimens for tissue culture. This work was

supported by the Ministerio de Educación y Ciencia,

Ministerio de Sanidad y Consumo, Gobierno Vasco and

Universidad del País Vasco.

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