In 1988 McGeer and colleagues (Neurology 38,1285-91) observed an activation of the microglia insubstantia nigra pars compacta (SNpc) and striatumof brains from patients with Parkinson's disease. Inthe years that followed several studies performed inthe cerebrospinal fluid and during post-mortemanalysis in parkinsonian patients revealed increasedlevels of cytokines, suggesting the activation of aproinflammatory response. Moreover, Langstonand his group described the presence of activemicroglia in the SNpc of three patients who hadbeen exposed to MPTP several years before death.These results suggested that the inflammatoryresponse may increase negative feed-back into thedamaged area of the cerebral parenchyma, induc-ing an imbalance that could perpetuate and/oraccelerate neuronal death over a period of years.Similar results have been obtained in parkinsonianmonkeys, rats and mice. For these reasons, severalgroups have treated parkinsonian animals with dif-ferent anti-inflammatory drugs and obtained prom-ising results. However, it is still not known whetherinflammatory changes are responsible for activenerve cell death or whether they play a protectiverole in neurodegeneration. These changes are puta-tively related to neuronal loss and suggest that anti-inflammatory treatment for parkinsonian patientscould have beneficial effects in the progression ofthe disease by slowing down the process of neuronalloss.

Keywords: Inflammation; Microglia; MPTP; Cytokines;Lymphocyte infiltration; Blood vessels

INTRODUCTION

The mechanism of dopaminergic cell death in parkin-sonism remains unknown, although different hypothe-ses have been proposed to explain this dramatic phe-nomenon. The production of free radicals, excytotoxi-city and mitochondrial affectation may activate apop-totic pathways and may induce cell loss (Dexter et al.,1989; Gotz et al., 1994; Jenner and Olanow, 1998).However, there is evidence that inflammatory changescould induce neuronal loss in parkinsonism (Hirsch etal., 1998; McGeer et al., 2001; Hunot and Hirsch,2003; Liu and Hong, 2003; Teismann et al., 2003b).Since the discovery of active microglial antigens in thestriatum and Substantia nigra pars compacta (SNpc)(McGeer et al., 1988), this hypothesis has claimedmuch attention. In 1999 Langston and colleaguesdetected microglial activation in the SNpc fromhumans intoxicated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) several years after their lastexposure. The idea that the inflammatory responsecould be related with the progression of the disease hasopened up new challenges in the treatment ofParkinson's disease (PD).

MICROGLIAL ACTIVATION

Results published concerning PD patients have shownthat microglial activation plays a crucial role in theinflammatory response. Microglia are the mainimmune cell types of the brain parenchyma, and theiractivation is characterized by the expression of majorhistocompatibility complex class II antigen (II MHC)and by an increase in immunoreactivity to surface anti-

F.P. Graham Publishing Co.

Neurotoxicity Research, 2003, VOL. 5(6). pp. 411-418

Parkinson's Disease and Inflammatory ChangesCARLOS BARCIAa,b,*, ANDRÉS FERNÁNDEZ BARREIROa,c, MÁXIMO POZAa,d and MARÍA-TRINIDADHERREROa,b,*

aExperimental Neurology and Neurosurgery Group, School of Medicine, Campus Espinardo, University of Murcia, 30071Murcia, Spain; bDepartment of Human Anatomy and Psychobiology, School of Medicine, Campus Espinardo, University ofMurcia, 30071 Murcia, Spain; cDepartment of Neurology, Hospital Virgen de la Arrixaca, Murcia, Spain; dDepartment ofNeurosurgery, Hospital Virgen de la Arrixaca, Murcia, Spain. barcia@um.es; mtherrer@um.es

(Received 08 July 2003; Revised 06 August 2003; In final form 06 August 2003)

*Corresponding authors. Tel.: +34 968 36 46 83; Fax: +34 968 36 76 54; E-mail: barcia@um.es; mtherrer@um.esISSN 1029 8428 print/ ISSN 1476-3524 online. © 2003 FP Graham Publishing Co., www.fpgrahamco.com

C. BARCIA et al. 412

gen and an increase in the number of cell bodies(Kreutzberg, 1996; McGeer et al., 1988; Langston etal., 1999). The expression of II MHC antigen (HLA-DR in human), which has been described in PDpatients and MPTP-intoxicated subjects, correspondsto damaged tissue and may be related with neuronaldamage (Graeber et al., 1994). These deleterious fea-tures of microglial activation have also been describedin cultures and have been demonstrated into in vitromodels of PD (Liya et al., 2000; Le at al., 2001; Wilmset al., 2003). In line with this, our group has foundincreased expression of the same microglial antigen inparkinsonian monkeys one year after the last MPTPadministration. Similar findings have been made inMPTP-treated mice and 6-OHDA intoxicated rats(Czlonkowska et al., 1996; Kurkowska-Jastrzebska etal., 1999; Carreno-Muller et al., 2003). Microglialreaction is normally observed surrounding the surviv-ing neurons, which suggests that it might be relatedwith neuronal loss and could perpetuate the chronicprogression of the disease (FIGs. 1 and 2).

EXPRESSION OF CYTOKINES

The cytotoxic effect of microglia can be modulated bycytokines (Loughlin et al., 1993), which play a crucialrole in inflammatory changes and are capable of devel-oping and maintaining neurodegenerative diseases(Merril and Benveniste, 1996). In physiological condi-tions, the levels of cytokines are very low or unde-tectable in the central nervous system (CNS) but, in thecase of injury, infection or autoimmune disease, theyincrease enormously (Rothwell and Hopkins, 1995;Merrill and Benveniste, 1996). Cytokine production ismediated by neuroglial resident cells (Campbell, 2001)and can activate lymphocytes, macrophages, astro-cytes, oligodendrocytes, microglial cells and even neu-rons (Fargeas et al., 1992; Benveniste, 1995). Includedamong the cytokines are interleukins (IL1, IL6 andIL10), interferon (IFN-α/ß and IFN-γ), Tumor NecrosisFactor (TNF), Transforming Growth Factor-ß (TGF-ß),etc. and the chemokine family. Increased levels ofcytokines have been described in the cerebrospinalfluid (CSF) of patients with PD (Mogi et al., 1994;1996; Blum-Degen et al., 1995; Stypula et al., 1996).Moreover, in post-mortem studies of brains frompatients with idiopatic PD an increase in IL-1ß, TNF-αand IFN-γ has been found (Boka et al., 1994; Hunot etal., 1997). In addition, such changes have beendescribed in the CSF of 6-OHDA lesioned rats (Mogiet al., 1999) and in plasma levels of parkinsonian mon-

keys (Barcia et al., 2002a). IL-1ß is related with neu-rodegenerative processes and was initially seen as anindicator of astrocyte hyperplasia and hypertrophy(Giulian and Lachman, 1985). IL-1ß immunoreactivityin reactive perivascular microglia cells has beenobserved in different neurodegenerative diseases andexperimental models (Bauer et al., 1993; Kiefer et al.,1993; Tyor et al., 1993; Van Dam et al., 1995) and maybe important in PD pathogenesis. On the other hand,TNF is a proinflammatory cytokine that plays a crucialrole in the inflammatory reaction in CNS (Fiers, 1991).The significance of TNF in the pathogenesis of degen-erative diseases in vivo has been described widely(Akassoglou et al., 1997). TNF, then seems to play arole in microglia/macrophage induction, destructionand degeneration functions (Taupin et al., 1997). Thisis closely related with chronic inflammatory diseases,suggesting that TNF activates these cells and maintainsthese responses (Campbell, 2001). Finally, IFN-γ mayactivate T lynphocytes, natural killer cells, to facilitategliosis and induce MHC II (Campbell, 2001). Evidencefrom neurodegenerative disorders and experimentalmodels confirms the potential active role of IFN-γ indegenerative processes and proinflammatory reactionsin the brain (Egwuagu et al., 1994; Renno et al., 1998).They are toxic for cells (Geiger et al., 1994; Corbin etal., 1996) and potentially harmful compounds for theprogression of neurodegeneration in parkinsonism(FIG. 2).

ADHESION PHENOMENA AND CELLINFILTRATION

The inflammatory reaction in parenchyma is mediatedby resident brain cells, such as neuroglia, but can bealso mediated by infiltrated leukocytes in the brainparenchyma (Campbell, 2001). Leukocytes associatedwith the inflammatory response can cross the brainblood barrier and be introduced in the brain parenchy-ma in response to chemotactic signaling expressed bycells of the CNS (Tani and Ransohoff, 1994). This canoccur in different processes which are involved in theexpression of adhesion receptors in leukocytes,endothelial cells and glial cells (Hickey, 1991). ActiveT cells inside the cerebral parenchyma can initiatesome events, such as endothelial cells activation,cytokines (e.g. TNF-α, IL-1ß and IFN-γ) induction andlymphocyte- and monocyte-recruitment (FIG. 2).Different types of adhesion molecules are involved inthe extravasation of cells into the brain, for example,vascular adhesion molecules (VCAM-1-VLA-4) and

INFLAMMATION AND PARKINSON'S DISEASE 413

DA neuron

BV

Astrocyte

Microglia

Figure 1. Representation of cerebral parenchyma of SNpc. In control subjects (left) notethe normal number of dopaminergic (DA) neurons, microglia, astrocytes and bloodvessels (BV). In parkinsonism we can observe an increase in the number of astrocytes,activated microglia and increased BV related with DA neuronal loss.

Control Parkinsonism

Figure 2. Putative role of inflammatory changes in parkinsonism. MPTP- like insult induces neuronalloss. Cell death can activate the astrocyte proliferation and induce the microglial activation. Astrocytesand microglia release cytokines that may induce new neuronal loss or growth factors (such as vascularendothelial growth factor [VEGF]) that induce BV formation. Cytokines can activate the adhesionphenomena and peripheral cells of blood flow can entry inside of the cerebral parenchyma becomingnew activated microglial cells.

INFLAMMATION AND PARKINSON'S DISEASE 415

intercellular adhesion molecules (ICAM-1-LFA-1 orICAM-1-Mac1). An increase of ICAM-1 moleculeshas been described in MPTP-treated parkinsonian mice(Kurkowska-Jastrzebska et al., 1999) and in MPTP-treated monkeys (Barcia et al., 2002a). VCAM andICAM-1 may be expressed in damaged areas by lym-phocytes, monocytes, granulocytes, endothelial cells,dendritic cells, and astrocytes, induced by cytokines(TNF-α, IL-1ß, IFN-γ) (Hurwitz et al., 1992;Rosenman et al., 1995; Akassoglou et al., 1997;Horwitz et al., 1999). The increased cytokine levelsdescribed in PD, therefore, could induce the expressionof these molecules and facilitate the recruitment ofblood cells into the cerebral parenchyma in a chronicprocess of neurodegeneration.

THE ROLE OF VASCULARIZATION

The enhanced number of blood vessels (BV) in injuredareas is also a hallmark of the inflammatory reaction.Changes in BV in the area suffering neurodegenerationcould represent an important inflammatory reactionrelated with neuronal loss (FIG. 1). An increase in thenumber of endothelial cells has been described in theSNpc of patients with PD (Faucheux et al., 1999) andmorphometric studies have described an increase ofBV in the SNpc of MPTP-treated monkeys and MPTP-treated mice (Barcia et al., 2002b; Sáez-Cassanelli etal., 2002). BV may be formed by different processes(Risau, 1997; Carmeliet, 2001), for example VascularEndothelium Growth Factor (VEGF) seems to play acrucial role in their formation (Dvorak et al., 1995;Eriksson and Alitalo, 1999; Ferrara, 1999) and may ini-tiate BV formation in adults after hypoxia, metabolicstress, hypoglycemia and inflammatory responses(Alon et al., 1995; Stone et al., 1995; Benjamin et al.,1998; Cameliet, 2001; Kerbel, 2000) or increase theexpression of adhesion molecules (Jain et al., 1996;Pinedo et al., 1998; Seljelid et al., 1999). The BVchanges in cerebral parenchyma seen in parkinsonism,therefore, could be related with the inflammationinduced by neuronal loss. Moreover, increased num-bers of BV and BV walls with openings or endothelialfenestrae, might facilitate the extravasation of proin-flammatory cells through the production of adhesionmolecules like ICAM-1 and VCAM. The increasednumber of BV and the overexpression of adhesion mol-ecules may also be related to the inflammatory changesassociated with neuronal degeneration in PD.However, whether these changes in vascularizationhave a detrimental or beneficial effect, or indeed a

combination of the two, remains to be determined inparkinsonian syndromes.

CONCLUSIONS

These findings support the idea that inflammatorychanges are related with neuronal loss. However, evenif it is unclear whether the inflammatory phenomenonis sufficient to induce cell death, a maintained inflam-matory response could be responsible for perpetuatingcell nerve degeneration (Hirsch at al., 1998; Langstonet al., 1999). Furthermore, different cytokines arereleased by microglial cells and macrophages (Lee etal., 1993), and these could induce cell death (Hirsch etal., 1998; Jenner and Olanow., 1998). Antiinflam-matory treatment has been used in experimentalparkinsonism with promising results. In fact, it hasbeen suggested that several antiinflammatory drugs canprotect against the neurodegeneration induced byMPTP in mice (Kurkowska-Jastrzebska et al., 1999;Teismann and Ferger, 2001). More recently it has beendescribed that the inhibitor of cyclooxygenase-2(COX-2) can play a neuroprotective role withoutdiminishing the inflammatory reaction, suggesting thatCOX-2 may play a critical deleterious role in theinflammatory process (Teisman et al., 2003a). Takentogether, these results provide evidence that the inflam-matory response is activated and maintained in SNpcand could play a crucial role in degeneration and nervecell death. The results, therefore, open up pathways andtargets for new strategies in PD therapy.

AcknowledgementsSupported by Fundación Séneca PJ 38876-01Ministerio de Ciencia y Tecnología (SAF2001-0479),and FIS 2002-1335.

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