Inflammation and Parkinson’s Disease Pathogenesis

Serge Przedborski, MD, PhD*

Department of Neurology, Pathology and Cell Biology, Columbia University, New York, New York, USA

Abstract: Inflammation is a neuropathological feature ofparkinsonian brains and also in experimental models of thedisease. It is believed that activated glial cells, which com-pose the majority of this inflammatory response contributeto the neurodegenerative process through the productionof toxic molecules. Therapeutic strategies geared toward

reducing inflammation and inhibiting the production ofthese glial-derived toxic molecules may be a promisingneuroprotective strategy for the treatment of Parkinson’sdisease and related conditions. � 2010 Movement DisorderSocietyKey words: Parkinson’s disease; MPTP; inflammation

Parkinson’s disease (PD) is the second most com-

mon degenerative disorder of the aging brain after Alz-

heimer’s disease.1 PD presents itself essentially as a

sporadic condition of unknown cause and for which

there is, thus far, no cure.1 Its cardinal features include

resting tremor, rigidity, akinesia, and postural instabil-

ity, forming a clinical picture readily identifiable.2 It is

now well-recognized that PD neurodegeneration is

multisystemic, involving many different neuronal path-

ways.3 Yet, the degeneration of the nigrostriatal path-

way and the ensuing deficit in brain dopamine remain,

for most clinicians and scientists, the prototypic altera-

tions of this disabling disease.1

Another well-known neuropathological feature of

PD is the presence of intraneuronal proteinaceous

inclusions, called Lewy bodies.4 Within the few spared

dopaminergic cells encountered in ventral midbrains of

PD patients, Lewy bodies are often large, can be multi-

ple, and generally occupy most of the cytoplasm.

Lewy bodies can be easily identified, either by classi-

cal histological dyes, such as hematoxylin and eosin,

or by immunohistochemistry, using antibodies raised

against alpha-synuclein or ubiquitin.4 While their path-

ogenic role remains controversial, Lewy bodies con-

tinue to be regarded as a neuropathological finding of

diagnostic value.

A third, and perhaps less well-recognized, neuro-

pathological feature of PD is the presence of a glial

response in all areas of the brain where signs of neuro-

degeneration can be found. It is on this last and partic-

ular aspect of PD neuropathology that this chapter is

centered. As discussed in-depth elsewhere,5 over the

past decades, the presence of a glial response in PD

brain tissues has drawn a major interest among

researchers, in part because of the idea that neuroin-

flammation, caused by activated glial cells, might play

an important role in the neurodegenerative process.

INFLAMMATION AND PD

It is important to stress the fact that the aforemen-

tioned glial response is a generic cellular response to

the degeneration of neighboring cells such as neurons

which is not exclusive to PD.5 Indeed, an identical

glial response can be observed in virtually all parkinso-

nian syndromes, including cases of familial PD linked

to alpha-synuclein or LRRK2 mutations6,7; cases of

multisystem atrophy or progressive supranuclear

palsy8,9; and toxic parkinsonisms related to compounds

like MPTP.10 Histological analyses have revealed that

Potential conflict of interest: None reported.

*Correspondence to: Dr. Serge Przedborski, BB-302, ColumbiaUniversity Medical Center, 650 West 168th Street, New York,New York 10032. E-mail: SP30@Columbia.edu

Received 22 March 2008; Accepted 27 March 2009Published online in Wiley InterScience (www.interscience.wiley.

com). DOI: 10.1002/mds.22638

S55

Movement DisordersVol. 25, Suppl. 1, 2010, pp. S55–S57� 2010 Movement Disorder Society

the composition of the glial reaction in PD and related

conditions is made of primarily astrocytes and micro-

glia and, to a much lesser extent, of T-cells. Con-

versely, there is no evidence of brain infiltration by B-

cells or polynuclear white cells in PD; the latter likely

reflects the lack of blood brain barrier damage. Based

on animal models of PD such as MPTP, 6-hydroxydo-

pamine (6-OHDA), or rotenone, it appears that the

glial response is triggered by the loss of neighboring

neurons and thus is most profound in the areas of overt

degeneration.

ROLE OF THE GLIAL REACTION IN PD

Several reviews of the subject of neuroinflammation

have clearly demonstrated that the glial reaction in

pathological situations of the CNS can play either a

beneficial or detrimental role.5,11–13 The former proper-

ties are thought to be possibly mediated by the produc-

tion of a variety of trophic factors, the uptake of any

excess of glutamate, or the removal of cell debris; the

latter can result from the production of a host of cyto-

toxic molecules ranging from reactive oxygen and

nitrogen species (ROS; RNS) to cytokines. In the case

of PD, epidemiological studies have shown that the use

of nonsteroidal anti-inflammatory drugs decreased the

risk of developing PD.14 Although risk factors cannot

be equated to pathogenic factors, these studies still pro-

vide a major impetus to the notion that inflammation

in PD can enhance the neurodegenerative process, pro-

moting both the progression and propagation of the

disease. According to this idea, it may be proposed

that, in a disease like PD, where not all neurons die at

the same time, the very first cells to succumb to the

pathological process activate the neighboring glial

cells. Once activated, glial cells, and especially micro-

glia, can engage in the production of toxic mole-

cules15,16 that can promote the demise of surrounding

compromised neurons.

INFLAMMATORY ENZYMES AND

DOPAMINERGIC NEURODEGENERATION

As indicated earlier, activated glia can produce a

host of toxic molecules including RNS and ROS. In

the context of inflammation, the main generators of

RNS and ROS are, respectively, the enzymes inducible

NOS (iNOS) and NADPH-oxidase. In the normal

CNS, iNOS is not expressed and NADPH-oxidase is

quiescent, but in patients with PD and in MPTP mice,

both iNOS and NADPH-oxidase are clearly expressed

and/or activated in glial cells in the ventral mid-

brain.17–19 These two inflammatory enzymes could

have a pathogenic role in PD, given the fact that their

lack in mutant mice is associated with a lesser loss of

dopaminergic neurons after MPTP administration.17,18

It should be noted, however, that not all inflammatory

enzymes identified in PD brain are potentially neuro-

toxic. For instance, myeloperoxidase (MPO) is an

enzyme known to be involved in dramatic inflamma-

tory events in the periphery. This enzyme was recently

identified in the CNS of PD patients and of MPTP

mice.20 Yet, the absence of MPO in mutant mice only

provided marginal attenuation against MPTP-induced

dopaminergic neurotoxicity.20

THE SINGULAR SITUATION OF

CYLCOOXYGENASE-2

Several investigators, including ourselves, have pre-

viously shown that cylcooxygenase-2 (COX-2) mRNA

and protein are highly expressed in tissues of both PD

patients and MPTP mice.21 To our surprise, this inflam-

matory enzyme was not detected in glial cells but rather

in dopaminergic neurons of PD and MPTP mouse tis-

sues.21 While this unexpected finding could suggest that

COX-2 reacted merely as a stress factor without any

pathogenic role, it is important to mention that nullify-

ing COX-2 activity, either by pharmacological agents

or genetic engineering, caused a clear attenuation of

MPTP-induced dopaminergic neurodegeneration.21 We

also found that the inflammatory response associated

with dopaminergic neurodegeneration in COX-2 knock-

out mice did not differ from that which has been

observed in their wild-type counterparts.21 This result

suggests that the beneficial role of COX-2 in the mouse

model of PD is not mediated by an inflammatory event,

but by an alterative mechanism that our ongoing studies

are attempting to identify. The take-home message here

is that not all inflammatory enzymes identified in PD

brain may be contributing to neurodegeneration neces-

sarily via an inflammatory mechanism.

DUAL PHENOTYPE OF GLIAL CELLS

T-cell alterations in PD blood22 and infiltration in

brain parenchyma of MPTP-treated mice23,24 have

been reported. Through their effector functions, T-cells

can interact with other resident cells, such as neurons

and glial cells. It has been demonstrated that upon vac-

cination against brain-derived proteins, T-cells can

gain access to the brain, where they can modulate the

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Movement Disorders, Vol. 25, Suppl. 1, 2010

phenotype of the resident glial cells. More importantly,

it was shown that in several pathological settings

affecting the brain, vaccination against copolymer-1,

which is thought to behave as an analogue of myelin

basic protein, can coax glial cells to shift from a nox-

ious to a beneficial phenotype. Using such an

approach, we have tested the effect of vaccination

using copolymer-1 against MPTP toxicity.25 Here,

MPTP mice received a suspension of splenocytes puri-

fied from mice previously vaccinated with copolymer-

1.25 After this infusion of copolymer-1 splenocytes,

there was a striking attenuation of MPTP-induced tox-

icity on dopaminergic neurons.25 In these mice, there

was coincidentally a marked attenuation of the micro-

glial reaction and a significant increase in the trophic

factor contents in the ventral midbrain.25 While we

have not formally tested this possibility, it is tantaliz-

ing to suggest that copolymer-1 T-cells, once in the

brain, inhibited the microglial activation and stimulated

the production of trophic factor by astrocytes.

CONCLUSION

A glial reaction is a consistent feature of neurode-

generation in all parkinsonian syndromes. Thanks to

the use of toxic models of PD, mounting evidence

indicates that neuroinflammation may contribute to the

neurodegenerative process of PD. Because neuroin-

flammation is a multifactorial phenomenon, should its

pathogenic role be confirmed, optimal therapeutic strat-

egy will thus have to call upon the use of a cocktail of

agents to abate several of the key inflammatory media-

tors. Finally, while vaccination is still in its infancy,

preclinical results support its potential value in the

treatment of complex disease such as PD and warrant

further investigations

Acknowledgments: This work was supported by NIH/NINDS Grants RO1 AG21617 and P01 NS11766-27A1, Mor-ris K. Udall Parkinson’s Disease Research Grant P50NS38370, the US Department of Defense Grant DAMD 17-03-1, MDA/Wings Over Wall Street, and the Parkinsons Dis-ease Foundation, USA. We thank Michael Shelley for his as-sistance in preparing this manuscript.

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