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  • 1. Progress in Neurobiology 89 (2009) 277–287 Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: influence of microglia on the pathogenesis of Parkinson’s diseaseCaitrıona M. Long-Smith, Aideen M. Sullivan, Yvonne M. Nolan * ´Department of Anatomy and Neuroscience, University College Cork, Cork, IrelandA R T I C L E I N F O A B S T R A C TArticle history: Parkinson’s disease (PD) is characterised by degeneration of dopaminergic neurons in the substantiaReceived 14 May 2009 nigra pars compacta (SNpc). Inflammation may be associated with the neuropathology of PD due to theReceived in revised form 8 August 2009 following accumulating evidence: excessive microglial activation and increased levels of the pro-Accepted 10 August 2009 inflammatory cytokines tumour necrosis factor-a and interleukin-1b in the SNpc of patients with PD; the emergence of PD-like symptoms following influenza infection; the increased susceptibility to PDKeywords: associated with bacterial vaginosis; the presence of inflammatory mediators and activators in animalParkinson’s disease models of PD; the ability of anti-inflammatory drugs to decrease susceptibility to PD; and the emergingInflammation possibility of the use of microglial activation inhibitors as a therapy in PD. In this review, we will discussMicrogliaAnti-inflammatory therapies the role of inflammation in PD. We will focus on the influence of microglia in the pathogenesis of PD andInterleukin-1b discuss potential therapeutic interventions for PD, that target microglia.Cytokine ß 2009 Elsevier Ltd. All rights reserved.Animal modelsContents 1. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 1.1. Symptoms of Parkinson’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 1.2. Pathological features of Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 2. Microglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 2.1. Microglia in the healthy brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 2.2. Microglial activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 2.2.1. Activating stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 2.2.2. Consequences of microglial activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 2.2.3. Reactive microgliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 3. Role of inflammation in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 3.1. Inflammation in Parkinson’s disease patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 3.1.1. Activated microglia in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 3.1.2. Pro-inflammatory cytokines in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 3.2. Inflammation in animal models of Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 3.2.1. MPTP model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 3.2.2. 6-OHDA model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 3.2.3. LPS model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 4. Anti-inflammatory therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284Abbreviations: 6-OHDA, 6-hydroxydopamine; AD, Alzheimer’s disease; APC, antigen-presenting cells; ATP, adenosine triphosphate; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; COX, cyclooxygenase; DAT, dopamine transporter; GDNF, glial cell-line-derived neurotrophic factor; IL,interleukin; IL-1ra, IL-1R antagonist; LB, Lewy body; LPS, lipopolysaccharide; MHC, major histocompatibility complex; MMP-3, matrix metalloproteinase-3; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; NADPH, nicotinamide adenine dinucleotide phosphate; NF-kB, nuclearfactor kappa B; NO, nitric oxide; NOS, nitric oxide synthase; NSAID, non-steroidal anti-inflammatory drug; PD, Parkinson’s disease; PEP, post-encephalytic parkinsonism;PPARg, proliferator-activated receptor-g; ROS, reactive oxygen species; SAID, steroidal anti-inflammatory drug; SNpc, substantia nigra pars compacta; TLR, toll-like receptor;TNF-a, tumour necrosis factor-g; TNFR, TNF receptor. * Corresponding author. Tel.: +353 21 490 2787; fax: +353 21 427 3518. E-mail address: (Y.M. Nolan).0301-0082/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved.doi:10.1016/j.pneurobio.2009.08.001
  • 2. 278 C.M. Long-Smith et al. / Progress in Neurobiology 89 (2009) 277–2871. Parkinson’s disease premotor areas. Due to the involvement of non-motor areas, such as the olfactory system, in the early stages of the disease, it has Parkinson’s disease (PD) was first described in 1817 by Dr. been postulated that the use of olfactory testing may be a goodJames Parkinson, a London physician, in ‘An Essay on the Shaking early diagnostic tool for PD (Doty, 2007).Palsy’ (Parkinson, 1817). It is the second most common neurode- In the post-mortem PD brain, there are abundant roundgenerative disorder, after Alzheimer’s disease (AD). The incidence eosinophilic insoluble cytoplasmic inclusions called Lewy bodiesof PD is age-related; in developed countries, it affects approxi- (LBs) in perikarya, and dystrophic thread-like insoluble neuritesmately 1% of the population aged over 60 years (Nussbaum and (Lewy neurites) in neuronal and glial processes within the SNpcEllis, 2003) and increases sharply with age after 60 years, rising to (Braak et al., 1995). LBs were first described by Frederich Lewy inover 4% in the oldest populations (de Lau and Breteler, 2006). It has 1912 (Gibb and Poewe, 1986) and are also found in other diseases,been estimated that the number of people aged over 60 will such as dementia with LBs and diffuse LB disease (Braak et al.,increase within the next 50 years, from 11% of the total population 2003). LBs in PD patients have been shown to contain a-synucleinin 2007 to 22% in 2050 ( In 90–95% of cases, PD (Spillantini et al., 1997) and ubiquitin (Lowe et al., 1988) as well asoccurs in an idiopathic manner, whilst in the remaining 5–10% of several other proteins (Robinson, 2008). PD is also characterised bycases, a genetic mutation is present (Toulouse and Sullivan, 2008). the presence of an accumulation of activated microglia within theThere is currently no cure for PD, thus it is imperative that research SNpc (McGeer et al., 1988). However, the exact reasons for theon the causes and treatments of this disease is supported neurodegeneration and specific cellular manifestations of sporadicappropriately within the coming years, both for humanitarian PD are unknown.and economic purposes. There is currently no cure for this disease—current treatments for PD, such as L-DOPA, which is the mainstay of PD therapy, are1.1. Symptoms of Parkinson’s disease mainly aimed at replacing dopamine in the striatum and do not have any effect on the neurodegeneration. Furthermore, the PD primarily affects areas of the brain which are involved in majority of these drugs are effective for a limited number of years,motor control, and initially manifests clinically as a slight rhythmic and are associated with debilitating side effects. Thus, it istremor, usually of a limb (Fahn, 2003; Wolters, 2008). As the imperative that research on the causes and treatments of thisdisease progresses, bradykinesia, tremor at rest, gait disturbances, disease is supported appropriately within the coming years, bothpostural instability and rigidity develop. Loss of facial expression for humanitarian and economic purposes.and micrographia are also common. The symptoms usually start onone side of the body and later become bilateral. During the 2. Microgliaprogression of the disease, non-motor areas of the brain becomeaffected, potentially leading to depression, sleep disorders and Microglia are the resident immune-competent cells of the CNScognitive impairment. The Unified Parkinson’s Disease Rating Scale and have a role in monitoring the brain for immune insults and(UPDRS), which includes quantification of motor functions, ´ invading pathogens. Ramon and Cajal considered microglia to becomplications of therapy, activities of daily life, behaviour and part of the ‘third element’ of the CNS, being neither neuronal normood, is the most widely used standardised measure for staging astrocytic (Cajal, 1913). In the 1930s, Pio del Rio Hortega, a studentthe disease (Fahn and Elton, 1987). of Cajal, estimated that they make up approximately 12% of the cells in the brain (del Rio Hortega, 1932). Microglia have a1.2. Pathological features of Parkinson’s disease mesohaemopoietic origin and are likely to arise from myeloid tissue, however there is much controversy surrounding their PD is characterised by the degeneration of dopaminergic exact lineage (Cuadros and Navascues, 1998). Historically, theyneurons of the substantia nigra pars compacta (SNpc) in the were thought to invade the brain perinatally, from circulatingmidbrain, and loss of their ascending projection to the striatum. blood monocytes, yet microglial progenitors have been demon-This decrease in dopaminergic tone leads to the loss of control of strated in situ in the embryonic brain before the circulatoryvoluntary movements. By the time a patient has been diagnosed system has developed (Morris et al., 1991). It has been suggestedwith PD, approximately 80% of striatal dopamine has been lost and that microglial progenitors are recruited from the periphery uponthe disease is quite advanced. Although the loss of dopaminergic CNS damage (Ladeby et al., 2005b), while it has also been shownneurons within the SNpc is the primary pathological feature of PD, that microglia resident in the CNS can self-renew and undergoeswidespread neuronal loss also occurs in the locus coeruleus, the mitosis to increase the numbers of microglia in the affected areadorsal motor nucleus of the vagus and glossopharyngeal nerves, during insult (Ajami et al., 2007). Studies of microglial prolifera-the nucleus basalis of Meynert, and in later stages, neuronal loss tion in the hippocampus following a lesion of the perforantoccurs in the neocortex (Braak et al., 2003). However, the loss of pathway in mice also showed a large increase in microglialdopaminergic neurons in the SNpc is most acute and is responsible number and that the vast majority of the resultant microglialfor the majority of the clinical manifestations of the disease. It is of population was due to the proliferation of a subpopulation ofnote that the lateral SNpc shows more vulnerability than the endogenous microglia and that bone marrow-derived macro-medial part (Fearnley and Lees, 1991), possibly due to differential phages only contributed in small numbers (Ladeby et al., 2005a).mRNA profiles in cell death-related genes, mitochondrial complex I Due to the ability of microglia to self-renew under certaingenes, glutathione genes and pro-inflammatory cytokine genes, circumstances, microglia are thought of by some as an undiffer-amongst others (Duke et al., 2007). entiated population of cells in the adult brain. For example, after Braak et al. (2003) examined 110 brains from PD patients and stimulation with growth factors in vitro, microglia from adult micenoted that the disease progression followed a ‘predetermined were shown to differentiate to either a dendritic cell-likesequence’ of events, and which were categorised into what is now phenotype or a peripheral macrophage phenotype (Santambrogioknown as Braaks Staging. Stages 1 and 2 involve pathology in the et al., 2001). It is postulated therefore, that there may be twoolfactory structures, medulla oblongata and part of the pontine populations of microglia within the brain: those which developtegmentum. Stages 3 and 4 see the involvement of SNpc pathology pre-vascularisation and are generally amoeboid during develop-and affect some of the proencephalic areas. Stages 5 and 6 involve ment and those derived from blood monocytes post-natally,degeneration of higher-order sensory areas of the cortex and although the precise lineage has yet to be determined.
  • 3. C.M. Long-Smith et al. / Progress in Neurobiology 89 (2009) 277–287 2792.1. Microglia in the healthy brain transforming growth factor-b, and tumour necrosis factor-a (TNF- a) by microglia. These cytokines in turn potentiate microglial In the adult brain, the majority of microglia are postulated to be activation by binding to their receptors, which are expressed onin the ‘resting’ state, and have a characteristic ramified morphol- microglia (Kim and de Vellis, 2005). Mis-folded or aberrantogy. Kreutzberg (1996) proposed a classification system of the proteins such as amyloid-b are capable of activating microglia viastaging of microglia in vivo, from a resting ramified morphology scavenger receptors, which are up-regulated in the brains of ADwith small cell bodies and many slim branchings, containing up to patients (El Khoury et al., 1998), or via initiation of microglial20 spines, to an active amoeboid morphology with truncated phagocytosis of the pathological protein (Rogers et al., 2002). It hasbranches. Due to the difficulty in studying ‘resting’ microglia in a also been shown that microglial phagocytosis occurs in response tonon-pathogenic environment, little is known about their function. aggregated a-synuclein, the major component of LBs in PD (ZhangThis difficulty arises during dissection of microglia from tissue and et al., 2005). The serum factors thrombin and immunoglobulinsculturing them in vitro, which inevitably results in some level of initiate microglial activation through protease-activated receptoractivation due to trauma. In an attempt to produce a population of 1 and Fc receptors, respectively (Stangel and Compston, 2001; Suomicroglia that were in the resting state, one group prepared et al., 2002). ATP released from damaged neurons, has beenprimary cultures of rat microglia in a serine/glycine-free medium demonstrated to activate microglia (Davalos et al., 2005) byand the resulting cells appeared to be in a functionally resting binding to purinergic receptors, which are expressed on microgliastate. Moreover, when the cells were co-cultured with neurons, (Brautigam et al., 2005). Matrix metalloproteinase-3 (MMP-3),they facilitated neuronal survival (Tanaka et al., 1998). Another which degrades extracellular macromolecules, and neuromelanin,group added astrocyte-conditioned medium to murine microglial the neuronal pigment released from dying dopaminergic neuronscultures to induce a ramified, resting phenotype and found a in PD, have also been shown to induce microglial activation (Kimdramatic change of morphology from ‘‘ramified’’ to ‘‘resting’’ after et al., 2005; Wilms et al., 2003), although the exact mechanisms ofjust a few hours of treatment (Eder et al., 1999). Immunohisto- how these compounds regulate the activation process have yet tochemical staining of brain slices offers a better chance of capturing be determined.microglial cells in their normal surveillance mode. In vivo imaging It has also been suggested that activation of microglia occursstudies using two-photon microscopy have shown resting micro- due to a ‘‘switching-off’’ of an inhibitory effect that neurons exertglia in as normal a state as possible, and illustrated the ability of on microglia under resting conditions. Neurons express CD200, amicroglia to rapidly become activated and reorganise their cell-surface transmembrane glycoprotein, which binds to micro-architectural structure (Davalos et al., 2005; Nimmerjahn et al., glia expressing the receptor CD200R (Barclay et al., 2002), and2005). Some authors consider that microglia in the perinatal state helps maintain microglia in a quiescent state in the healthy brainare not resting, but are in an intermediate phase of activation (Hoek et al., 2000). A down-regulation of CD200 expression has(Hanisch, 2002). Indeed the presence of partially activated rat been shown in neurons exposed to inflammatory conditions, whilemicroglia in untreated cultures has been observed (Eder et al., inhibition of CD200 causes microglial activation, demonstrating a1999). neuronal-directed mechanism for regulation of microglial activa- Resting microglia, in contrary to what their name suggests, are tion (Lyons et al., 2007). The presence of neurons can also decreasenot static, dormant cells, they are proposed to constantly move and the microglial response to low-dose LPS-stimulation, demon-to monitor the area in which they reside for pathogens and changes strated by a decrease in nitric oxide (NO) and TNF-a production inin their microenvironment. Two studies that used time-lapse vitro (Chang et al., 2000). This finding concurs with the idea thatimaging in mice in vivo, showed that microglial cell bodies do not healthy neurons have an inhibitory effect on microglial activationmove during normal surveillance, but that the microglial processes while damaged neurons can promote their activation.extend and retract rapidly and dynamically (Davalos et al., 2005;Nimmerjahn et al., 2005). Following activation to engulf cellular 2.2.2. Consequences of microglial activationdebris, microglia release growth factors to support the surrounding Activated microglia have been shown to play key roles in bothneurons. Activation of microglia also occurs during development the developing and adult CNS. During CNS development theyand remodelling of the healthy brain. Apoptosis occurs during phagocytize neurons and cellular debris as a genetically deter-embryonic and early post-natal development of the brain; any mined event to prevent excessive cell production (Ashwell, 1990).neurons that have not successfully made synaptic connections are Upon activation in the adult CNS, microglia act primarily asdisposed of by microglia, and the remaining neurons are supported scavengers and in brain tissue remodelling to restore and protectby the growth factors produced by microglia (Batchelor et al., 1999). brain structures and functions. Resting microglia are rapidly activated after insults such as changes in the extracellular2.2. Microglial activation environment of the injured or diseased brain and undergo morphological changes from a resting, ramified shape to an active2.2.1. Activating stimuli amoeboid shape to facilitate proliferation, migration and phago- Microglia respond to activating stimuli in the extracellular cytosis (Nimmerjahn et al., 2005). Local microglia extend out theirenvironment which bind to a diverse selection of cell-surface processes to surround the area of insult (Davalos et al., 2005) andreceptors including receptors for endotoxin, cytokines, chemo- as a result damaged cells are engulfed by the microglia viakines, mis-folded proteins, serum factors and ATP. One of the most phagocytosis, removing any potentially damaging material fromcommonly used methods of activating microglia both in vitro and the area and protecting the neighbouring cells. Thus, microglia actin vivo is the application of the endotoxin lipopolysaccharide (LPS). as antigen-presenting cells (APCs) and present engulfed patho-LPS binds to toll-like receptor (TLR) 4, a member of the TLR family genic material to invading T-cells to generate an adaptive immuneof receptors involved in detecting microbial infection, of which response; the presence of major histocompatibility complexmicroglia are reported to express nine of the 12 members (Jack (MHC) class II antigen expression on activated microglia corrobo-et al., 2005). LPS-induced activation of microglia results in the rates this theory (Hickey and Kimura, 1988; McGeer et al., 1988).production of cytokines and chemokines such as interleukin (IL)- The ability of endogenous microglia to act as APCs has recently1b, IL-1 receptor antagonist (IL-1ra), IL-6, IL-8, IL-10, IL-12, IL-18, been questioned however, with some suggesting that perivascularmacrophage colony stimulating factor, macrophage inflammatory macrophages or invading dendritic cells are responsible for thisprotein (MIP)-1a, MIP-1b, monocyte chemoattractant protein-1, task (Perry, 1998).
  • 4. 280 C.M. Long-Smith et al. / Progress in Neurobiology 89 (2009) 277–287 Microglia, in common with other cells of the myeloid lineage, (Hu et al., 2008) and recent work has shown that necrotic neuronshave the ability to secrete a multitude of immunomodulatory activate microglia in a manner dependent on the TLR-associatedmolecules such as cytokines, chemokines, neurotrophins and adapter molecule myeloid differentiation primary response genereactive oxygen and nitrogen species, which communicate signals (MyD88) (Pais et al., 2008). However, a mediating stimulusto surrounding cells (Garden and Moller, 2006). Cytokines are low between the neurons and microglia has not yet been determined inmolecular-weight proteins that are usually classified as either pro- this paradigm. Interruption to brain homeostasis due to microglialor anti-inflammatory and are thought to signal both by paracrine ‘priming’, which occurs during the aging process itself, has alsoand autocrine methods. While pro-inflammatory cytokines have been suggested as a factor that amplifies the microglial response.the ability to elicit a sustained immune response, anti-inflamma- In this regard (Perry et al., 2007), have proposed that chronictory cytokines act to down-regulate an immune response by exposure to pro-inflammatory signals from systemic infection thatbinding to appropriate receptors expressed on microglia and occur throughout an individual’s lifetime, promotes an exagger-initiating an autocrine signalling process. Cytokines have numer- ated microglial response that contributes to neuronal deteriorationous effects on CNS function including growth promotion, inhibi- instead of facilitating a protective homeostatic response. Ongoingtion and proliferation of astrocytes and oligodendrocytes (Hanisch, research thus highlights that degenerating neurons have the2002), modulation of neurotransmitter release (Zalcman et al., capacity to reactivate microglia and that activated microglia are1994), long-term potentiation (Nolan et al., 2005), and behavioural capable of augmenting neuronal loss in neurodegenerativealterations such as memory impairment (Yirmiya et al., 2002), diseases, and as such, this cycle of perpetuating deterioration inanhedonia (Konsman et al., 2002) and anxiety (Anisman and CNS function is a potential target for therapeutic intervention.Merali, 1999). Chemokines act primarily as chemoattractants todraw additional microglia to the site of injury, while neurotrophic 3. Role of inflammation in Parkinson’s diseasefactors such as nerve growth factor, brain-derived neurotrophicfactor and glial-derived neurotrophic factor released from micro- 3.1. Inflammation in Parkinson’s disease patientsglia have been proposed to participate in the survival andregeneration of neurons (Batchelor et al., 2002; Nagata et al., The first evidence for a role for inflammation in PD came from a1993) as well as to prolong the existence of microglia and to post-mortem study – in 1998, McGeer and colleagues foundregulate their function (Elkabes et al., 1996). Activated microglia activated microglia and T-lymphocytes in the SNpc of a PD patient.can also produce and release both reactive oxygen and nitrogen Since then, there have been numerous studies which support a rolespecies due to catalysis by nicotinamide adenine dinucleotide for neuroinflammatory processes in PD (Hirsch and Hunot, 2009;phosphate (NADPH) oxidase (Babior, 1999) and these highly McGeer and McGeer, 2004; Orr et al., 2002; Tansey et al., 2007). Inreactive free radicals can kill surrounding pathogens. It has also addition to the presence of activated microglia and pro-inflam-been reported however, that microglial-derived free radicals can matory cytokines (both of which are discussed below), enzymescause neuronal cell death and so they have been implicated in the associated with inflammation, such as inducible nitric oxidepathogenesis of neurodegenerative conditions (Chao et al., 1992). synthase (iNOS) and cyclooxygenase 2 (COX2), have been found in the post-mortem PD brain (Hunot et al., 1996; Knott et al., 2000).2.2.3. Reactive microgliosis Support for an involvement of neuroinflammation in PD comes Activation of microglia is vital to normal brain function in order from studies which show a link between infection and neurode-to control the neuronal microenvironment. Mild activation has generation. Neurodegenerative diseases tend to be exacerbated byapparent beneficial effects on the surrounding cells but when systemic infections, and activated microglia may be involved inmicroglia are continuously activated or over-activated; damaging this process. For example, system infection has been shown toeffects ensue to inappropriately kill otherwise viable cells, induce microglial activation in multiple sclerosis (MS) (Perry,particularly neurons. Due to the possible involvement of micro- 2004). Also, periods of worsening dementia are known to emergeglial-mediated inflammation in PD and other neurodegenerative in AD patients following infections such as pneumonia, anddiseases, it has been postulated that a vicious cycle of inflamma- patients suffering from MS experience a deterioration of symptomstion may occur, regardless of the initial insult. When the microglia following similar infections (Cunningham et al., 2005; Perry et al.,become activated, whether through direct activation via a toxin, 2007). Therefore, it is possible that the added insult of infectionpathogen or endogenous protein, or indirectly via signals from exacerbates the ongoing inflammatory and degenerative pro-damaged neurons, these activated microglia may persist due to cesses. It is not clear whether or not PD patients suffer from apositive feedback from dying neurons, even if the initial insult has worsening of symptoms after experiencing systemic infection.ceased. Thus, microglial activation, and hence neuroinflammation, However, there are two lines of evidence which suggest thatmay be propagated and prolonged inappropriately to amplify the infection can increase the risk of developing PD. The first is thedestruction of neurons; a process referred to as reactive micro- observation of parkinsonism following encephalitis. Towards thegliosis and which is a common characteristic of neurodegenerative end of World-War-1, a pandemic of influenza virus caused andiseases (Gao and Hong, 2008). unusually large increase in the number of cases of post- As of yet, it is unclear what mechanisms propel reactive encephalytic parkinsonism (PEP), or von Economo encephalitismicrogliosis but there is some evidence to suggest that toxic (Rail et al., 1981). Similarly, people who are infected with Japanese-factors released from dying neurons into the microglial micro- encephalitis virus for a prolonged period are likely to develop PEPenvironment are responsible. The active form of MMP-3 that is (Ogata et al., 2000). Japanese-encephalitis-induced parkinsonismreleased from injured dopaminergic neurons was shown to induce shares many similarities with PD and has been used to create athe production of superoxide in microglia and consequently model of PD in rats (Ogata et al., 1997). The second line of evidenceaugment neuronal demise (Kim et al., 2007). The aggregated for a link between systemic infection and the risk of developingproteins a-synuclein and amyloid-b, which are both products of parkinsonism comes from animal studies. Rat fetuses exposed toneuronal degeneration in PD and AD, respectively, activate LPS were found to have fewer than normal dopaminergic neuronsmicroglia and in turn induce neuronal cell death (Floden et al., at birth and were more susceptible to subsequent 6-hydroxydo-2005; Zhang et al., 2005). Macrophage antigen complex-1, a pamine (6-OHDA; a neurotoxin used to model PD in rats) exposuremicroglial surface receptor and member of the b2 intergrin family in adulthood (Ling et al., 2002; Ling et al., 2004). The authorshas also recently been identified as mediating reactive microgliosis hypothesised that children born to mothers who experienced
  • 5. C.M. Long-Smith et al. / Progress in Neurobiology 89 (2009) 277–287 281bacterial vaginosis during pregnancy were at a higher risk of culture models however, and also from epidemiological studiesdeveloping PD in later life and that they may be more susceptible support the notion that microglia contribute to the disease processto additional insults which may precipitate the development of at an early stage (Liu, 2006).this disease. Similarly, a recent study by (Gao et al., 2008) showedthat formylmethionyl-leucyl-phenylalanine, a bacterial-derived 3.1.2. Pro-inflammatory cytokines in Parkinson’s diseasechemoattractant involved in systemic infection, caused the death The pro-inflammatory cytokines, IL-1b, TNF-a, IL-2 and IL-6,of dopaminergic neurons in mouse midbrain cultures via the are expressed at very low levels in healthy brain, but have beenactivation of microglia. found at much higher levels in PD patients, in the post-mortem It is thought that oxidative stress plays an important role in brain as well as in serum and cerebrospinal fluid in vivo (Boka et al.,dopaminergic neuronal death in PD (Jenner et al., 1992). Basal 1994; Dobbs et al., 1999; Mogi et al., 1994a; Mogi et al., 1994b;levels of lipid peroxidation are increased in the SN of PD patients Stypula et al., 1996). The death-signalling receptor, TNFR-1, has(Dexter et al., 1989), which suggests that this area of brain is been found to be expressed on dopaminergic neurons in humanparticularly vulnerable to excess free radicals and ROS which may SNpc (Boka et al., 1994; Mogi et al., 2000). Animal studies supportbe produced by activated microglia as part of an inflammatory an involvement of these pro-inflammatory cytokines in PD. Forresponse. example, induction of chronic expression of IL-1b in adult rat SNpc using a recombinant adenovirus resulted in dopaminergic cell3.1.1. Activated microglia in Parkinson’s disease death after three weeks (Ferrari et al., 2006). A study using The presence of inflammation is generally indicated by the neutralising antibodies to IL-1b and TNF-a showed that approxi-accumulation of activated microglia in damaged areas of the brain. mately 50% of LPS-induced dopaminergic neuronal cell death inParticularly high numbers of activated microglia have been found primary cultures of rat midbrain was mediated by the productionin the brains of PD patients’ post-mortem, predominantly in the of these two cytokines (Gayle et al., 2002). In support of a role forSNpc in the vicinity of the degenerating dopaminergic neurons, but IL-1b in the demise of dopaminergic neurons, we have found thatalso in the hippocampus, transentorhinal cortex, cingulate cortex LPS-stimulated primary cultures of rat microglial cells release IL-and temporal cortex where neuronal loss is also prevalent (Banati 1b (Fig. 1b), that IL-1R1 is expressed on primary cultures ofet al., 1998; Imamura et al., 2003; McGeer et al., 1988; Sawada midbrain dopaminergic neurons (unpublished observation), andet al., 2006). Indeed in PD with dementia, hippocampal volume as that treatment of these dopaminergic neurons with IL-1b results indetected by MRI studies is diminished (Laakso et al., 1996). While significant cell death, comparable to that induced by 6-OHDAincreased levels of activated microglia have been found in SNpc of (Fig. 1c). Taken together, these findings support the hypothesisthe general elderly population (Beach et al., 2007), it is possible that release of IL-1b from activated microglia are involved inthat this ‘normal’ aging pattern is exacerbated in PD. It is likely that dopaminergic neuronal degeneration (Fig. 1a).nigral neurons which are under stress or are damaged, in thepresence of already ‘‘primed’’ microglia, can exacerbate microglial 3.2. Inflammation in animal models of Parkinson’s diseaseactivation and induce them to release neurotoxic factors.Substances which are produced by dying dopaminergic neurons 3.2.1. MPTP modeland which can activate microglia include: a-synuclein aggregates Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neu-(Zhang et al., 2005), ATP (Davalos et al., 2005), MMP-3 (Kim et al., rotoxin which rapidly induces severe parkinsonian-like symptoms2007; Kim et al., 2005) and neuromelanin (Wilms et al., 2003). As in humans by selectively killing dopaminergic neurones of thementioned earlier, the dopaminergic neurons of the SNpc are SNpc (Langston et al., 1983; Langston and Ballard, 1983). MPTPparticularly susceptible to degeneration. Rodent nigral neurons itself is not toxic, but it crosses the blood–brain barrier (BBB) and ishave been shown to be more vulnerable than either hippocampal spontaneously oxidised to 1-methyl-4-phenylpyridinium (1-or cortical neurons to LPS-induced degeneration in vivo and in vitro, MPP+) by monoamine oxidase-B, mainly in glial cells. MPP+ isand this was shown to be due to the higher number of activated released into the extracellular space and actively taken up intomicroglia per unit area in the SNpc compared with the other two dopaminergic neurons by the dopamine transporter (DAT),brain areas (Kim et al., 2000). Indeed, the SNpc contains the highest whereby it potently inhibits mitochondrial complex I of theconcentration of microglia of any brain area (McGeer et al., 1988). electron transport chain, causing an increase in production ofIt is also of note that activated microglia present in the reactive oxygen species (ROS) and a drop in ATP levels, leading tohippocampus and cerebral cortex of PD patients may also cell death (Przedborski and Vila, 2003). Peripheral injection ofcontribute to the non-motor symptoms of the disease, the most MPTP in monkeys or mice is commonly used to model PD.debilitating of which is dementia (Emre, 2003). While substantial Activated microglia have been demonstrated in the brains of bothresearch has been carried out on the role of hippocampal monkeys (McGeer et al., 2003) and mice (Liberatore et al., 1999)inflammation in cognitive impairment (Lynch, in press), to date after systemic injection of MPTP. Infiltration of T-lymphocytes hashowever, there is limited information on the contribution of also been detected in the brains of MPTP-treated mice (Brochardinflammatory processes to the intellectual demise specific to PD. It et al., 2009; Kurkowska-Jastrzebska et al., 1999). It is thought thathas been postulated that a vicious cycle of inflammation may ROS produced by microglial NADPH play an important role inexacerbate the debilitating effects of dopaminergic neuron loss in MPTP-induced neurotoxicity (Gao et al., 2003; Wu et al., 2003). ItPD, regardless of whether the inflammation is a cause or has recently been proposed that angiotensin II is responsible forconsequence of the disease (Block and Hong, 2007). Evidence of the inflammation induced by MPTP in mouse mesencephalicinflammation from post-mortem PD brains is primarily from dopaminergic neurones in vitro and in vivo (Joglar et al., 2009).terminal stage cases and so it remains unknown if microglialactivation occurs only at this late stage of the disease as a 3.2.2. 6-OHDA modelconsequence of substantial neuronal loss, or at an earlier stage of 6-OHDA is a hydroxylated analogue of dopamine, which isdisease progression to precipitate or possibly even prevent actively taken up into dopaminergic neurons via DAT on the nerveneuronal loss. It has also been suggested that the observed terminals and selectively kills these cells via the generation of freemicroglial activation reflects their state in the final hours of radicals and oxidative stress. Intracerebral application of 6-OHDApatients’ lives rather than in the months or years before (McGeer to nigrostriatal dopaminergic neurones, by injection at the site ofand McGeer, 2008). More recent findings from animal and tissue their cell bodies, processes or terminals, induces degeneration of
  • 6. 282 C.M. Long-Smith et al. / Progress in Neurobiology 89 (2009) 277–287Fig. 1. . (a) Schematic representation of the impact of microglial activation on dopaminergic neuronal deterioration through release of IL-1b. (b) IL-1b released frommicroglial-enriched primary cultures of post-natal rat cortex which were treated with 0, 50, 100 or 500 ng/ml LPS for 24 h (n = 2). (c) Percentage of dopaminergic (tyrosinehydroxylase-positive) neurons in embryonic rat midbrain neuronal-enriched cultures after treatment for 1 h in the absence or presence of IL-1b (10 ng/ml) or 6-OHDA(40 mM) (n = 3). Data expressed as means with standard errors, *p < 0.05, **p < 0.01, ***p < 0.001, vs. control (ANOVA with post-hoc Dunnett’s test).nigral dopaminergic neurones and depletion of striatal dopamine dopaminergic neurons and that the toxicity of LPS occurs vialevels, and is the most widely used animal model of PD. We have microglial activation (Bronstein et al., 1995; Gayle et al., 2002).recently shown a significant increase in the number of activated Although many in vitro studies have supported an involvement ofmicroglia, identified using immunocytochemistry for MHC class II, NO in microglial-mediated dopaminergic neuronal death due toin the SNpc of 6-OHDA-lesioned rats at 10 and 28 days post-lesion LPS-treatment (Chao et al., 1992; Gibbons and Dragunow, 2006),(Crotty et al., 2008). The presence of activated microglia in the others have suggested that NO is not involved (Castano et al., 1998;brains of 6-OHDA-lesioned rats has previously been reported by Gayle et al., 2002). The pro-inflammatory cytokines IL-1b and TNF-other groups (Akiyama and McGeer, 1989; Depino et al., 2003; He a are thought to be involved in LPS-mediated toxicity (Gayle et al.,et al., 2001). The study by Depino et al. in 2003, which showed 2002). In support of a role for pro-inflammatory cytokines in themicroglial cell activation in the 6-OHDA-lesioned rat brain, found neurotoxic action of LPS, we have found a dose-dependent releaseno increase in IL-1b at the protein level, although IL-1b mRNA was of IL-1b in rat microglial cultures following LPS-treatmentincreased, and no increase in TNF-a at either mRNA or protein (Fig. 1b). Furthermore, blockade of the soluble form of the TNF-level. In support of a role for pro-inflammatory cytokines in the a receptor has been reported to reduce microglial activation in theneuronal death induced by 6-OHDA, blockade of the soluble form in vivo LPS model of PD (McCoy et al., 2006). Also, Ling and co-of the TNF-a receptor, but not the transmembrane form, was found workers found that the decreased numbers of nigral dopaminergicto attenuate the death of dopaminergic neurons in 6-OHDA- neurons in rats after prenatal exposure to LPS, was accompanied bylesioned rats (McCoy et al., 2006). elevated levels of TNF-a in the striatum (Ling et al., 2004). A recent study by (Koprich et al., 2008) showed that injection of3.2.3. LPS model a non-toxic low-dose of LPS into adult rat SNpc resulted in Intranigral injection of LPS in rats in vivo results in dopami- microglial activation and increased levels of IL-1b, without causingnergic neuronal loss and can be used as a model of PD (Castano death of dopaminergic neurons in vivo, but that subsequentet al., 1998). Systemic administration of LPS has also been found to injection of 6-OHDA into the striatum resulted in a large loss ofinduce progressive degeneration of nigral dopaminergic neurones dopaminergic neurons compared with that in animals treated within rats (Qin et al., 2007). Furthermore, it has been reported that 6-OHDA alone. This exacerbation of 6-OHDA-induced neuronalprenatal exposure to LPS in rats results in the development of loss by LPS appeared to be partly mediated by IL-1, since treatmentfewer than normal nigral dopaminergic neurons (Ling et al., 2004). with LPS plus IL-1ra rescued some of the dopaminergic neuronsIn vitro studies on rat mesencephalic cultures suggest that from 6-OHDA-induced death (Koprich et al., 2008). Another recentdopaminergic neurons are twice as sensitive to LPS as non- study showed that 6-OHDA injection into the adult rat striatum
  • 7. C.M. Long-Smith et al. / Progress in Neurobiology 89 (2009) 277–287 283plus a subsequent non-toxic LPS injection into the SNpc caused an While steroidal anti-inflammatory drugs (SAIDS) such asincreased level of dopaminergic neuronal death and motor deficits dexamethasone have been reported to have protective effects incompared with those induced by either toxin alone (Godoy et al., rodent models of PD (Castano et al., 2002; Kurkowska-Jastrzebska2008). In that study, increased levels of IL-1b, but not TNF-a, were et al., 2004), the potential side-effects preclude their long-termfound in the SNpc of the 6-OHDA plus LPS-treated group. Both of clinical usage. Non-steroidal anti-inflammatory drugs (NSAIDS)these studies postulated that the initial insult caused priming of such as aspirin, ibuprofen and indomethacin inhibit COX activity tomicroglia, while the second insult resulted in fully activated block the production of the pro-inflammatory lipid mediators,microglia. prostaglandins. It has also been shown that NSAIDS scavenge ROS in neuronal cells (Grilli et al., 1996), inactivate the pro-4. Anti-inflammatory therapies inflammatory transcription factor nuclear factor kappa B (NF- kB) (Kopp and Ghosh, 1994) and activate the peroxisome As the evidence accumulates for a detrimental role of inflamma- proliferator-activated receptor-g (PPARg), a member of thetion in the pathogenesis of PD, a host of anti-inflammatory agents are nuclear receptor superfamily and mediator of anti-inflammatorynow under investigation (Table 1). Indeed data generated from use activity, in microglia (Bernardo et al., 2005). Numerous experi-of non-steroidal anti-inflammatory drugs, microglial inhibitors and mental cell and animal models of PD have demonstrated thatanti-inflammatory cytokines in animal and cellular studies, have NSAID pre-treatment protects against 6-OHDA- and MPTP-supported the notion that control of neuroinflammation is a strategy induced dopaminergic neuronal degeneration and associatedworth pursuing in the effort to retard or even prevent degeneration symptoms (Esposito et al., 2007). While epidemiological studiesof dopaminergic neurons in PD. It should be noted however that have determined that the use of NSAIDS is associated with aagents which exert their effect by absolute inhibition of microglial decreased risk of developing PD (Ton et al., 2006), there is noactivation may in the long-term be detrimental rather than evidence of their efficacy in the treatment of the disease.therapeutic to PD patients, because a reduction in the beneficial Other agents currently under investigation for their potentialeffects of microglial activation such as immune surveillance and neuroprotective effects in models of PD primarily act to suppresstissue repair, may render the patient defenceless if exposed to CNS microglial activation and inhibit the production of neurotoxicinjuries or other harmful stimuli. factors and pro-inflammatory cytokines. Minocycline is a tetra-Table 1Neuroprotective effects of anti-inflammatory agents in animal models of Parkinson’s disease. Agent Mode of action Species PD model Effects References Dexamethasone SAID Mouse MPTP 1. Prevented striatal dopamine depletion Kurkowska-Jastrzebska 2. Protected dopaminergic neurons in SN et al. (2004) Rat LPS 1. Prevented striatal dopamine depletion Castano et al. (2002) 2. Protected dopaminergic neurons in SN Aspirin NSAID Mouse MPTP Prevented striatal dopamine depletion Aubin et al. (1998) Rat 6-OHDA Prevented striatal dopamine depletion Di Matteo et al. (2006) Salicylic acid NSAID Mouse MPTP 1. Attenuated akinesia and catalepsy Mohanakumar et al. (2000) 2. Prevented dopamine depletion and changes in dopamine turnover in nucleus caudatus putamen Indomethacin NSAID Mouse MPTP 1. Prevented striatal dopamine depletion Kurkowska-Jastrzebska 2. Protected dopaminergic neurons in SN et al. (2002) Celecoxib NSAID Rat 6-OHDA Reversed striatal dopaminergic neuronal Sanchez-Pernaute et al. (2004) fibre and nigral dopaminergic neuronal cell loss Minocycline Microglial activation Mouse MPTP 1. Protected dopaminergic neurons in SN Du et al. (2001) inhibitor 2. Prevented dopamine depletion in the striatum and nucleus accumbens Rat 6-OHDA 1. Reduced apomorphine-induced rotations Quintero et al. (2006) 2. Protected dopaminergic neurons in SN Rat LPS Protected dopaminergic neurons in SN Tomas-Camardiel et al. (2004) Interleukin-10 Anti-inflammatory Rat LPS Protected dopaminergic neurons in SN Arimoto et al. (2006) cytokine Rat 6-OHDA 1. Protected dopaminergic neurons in SN Johnston et al. (2008) 2. Prevented striatal dopamine depletion 3. Reduced apomorphine-induced rotations Naloxone Opioid receptor Rat LPS Protected dopaminergic neurons in SN Liu et al. (2000b) antagonist Pioglitazone PPARg agonist Mouse MPTP Protected dopaminergic neurons in SN Dehmer et al. (2004) Rat LPS 1. Prevented striatal dopamine depletion Hunter et al. (2007) 2. Protected dopaminergic neurons in SN Rosiglitazone PPARg agonist Mouse MPTP 1. Prevented errors in beam traversal test Schintu et al. (2009) 2. Protected dopaminergic neurons in SN 3. Partially prevented striatal dopamine depletion VP025 Phosphotidylglycerol Rat 6-OHDA 1. Protected dopaminergic neurons in SN Crotty et al. (2008) phospholipid 2. Prevented striatal dopamine depletion 3. Reduced apomorphine-induced rotations Rat Proteasome 1. Attenuated impairment on accelerating rotarod Fitzgerald et al. (2008) inhibition 2. Prevented striatal dopamine depletion
  • 8. 284 C.M. Long-Smith et al. / Progress in Neurobiology 89 (2009) 277–287cycline analog, which due to its lipophilicity, can easily cross the VP025 has also been shown to attenuate motor impairments andBBB where it is reported to have anti-inflammatory and loss of striatal dopamine in the proteasome inhibitor model of PDneuroprotective activity (Kim and Suh, 2009). As well as inhibiting (Fitzgerald et al., 2008). This compound, which is designed tomicroglial activation, proliferation and subsequent release of pro- interact with APCs, was shown to prevent activation of microgliainflammatory mediators (Griffin et al., 2006; Tikka et al., 2001; (Crotty et al., 2008) suggesting a combined anti-inflammatory andTikka and Koistinaho, 2001), minocycline is reported to exert a neuroprotective mechanism, a phenomenon that is apparent in theneuroprotective action by inhibiting both the release of the numerous potential therapeutically beneficial compounds underapoptotic mediator cytochrome c from mitochondria (Zhu et al., investigation for the treatment of PD.2002) and cytoplasmic caspase-1 and caspase-3 expression (Chenet al., 2000). In animal models of PD, minocycline has been shown 5. Conclusionto be effective in preventing MPTP-, 6-OHDA- and LPS-induceddopaminergic neurodegeneration (Du et al., 2001; He et al., 2001; The death of dopaminergic neurons in the SNpc is the keyQuintero et al., 2006; Tomas-Camardiel et al., 2004). However, pathology of PD. Therefore, it is imperative that research isthere have also been contradictory reports regarding its efficacy in undertaken, not only in areas which could provide protectiveprotecting striatal dopaminergic fibres (Diguet et al., 2004; Yang strategies for the remaining neurons, or which involve dopami-et al., 2003). Recent results from a Phase II clinical trial did not nergic neuronal cell replacement therapies, but also into under-show any adverse events in early PD patients and suggest that standing the fundamental mechanisms by which these cells die.minocycline should be considered for Phase III trials (NINDS NET- Although the precise role of inflammation in the pathogenesis ofPD Investigators, 2008). PD remains unclear, an array of evidence from the clinic and from The anti-inflammatory cytokine IL-10 has been shown to hold animal models now points to its substantial involvement in thistherapeutic potential; pre-treatment of cultures of mesencephalic debilitating disease. In addition, rapid advances in diagnostic toolsneuroglia with IL-10 inhibited LPS-stimulated microglial activation are being made to detect dopaminergic neuronal degeneration, theand degeneration of dopaminergic neurons (Qian et al., 2006). vast majority of which has already occurred before patients areSimilar neuroprotective effects were observed in vivo after chronic currently diagnosed with PD. Thus, it is likely that a deeperinfusion of IL-10 into the SNpc of rats that were challenged with LPS understanding of microglial activation and the consequent(Arimoto et al., 2006). More recently, gene therapy approaches have inflammatory response, will contribute to the advancement ofbeen developed to deliver IL-10 or a dominant negative TNF protein therapeutics aimed at halting the demise of dopaminergic neuronsinto the rat SNpc, and both of these methods have proved effective in before substantial clinical manifestations appear.attenuating the neuronal loss and behavioural deficits in the 6-OHDA-rat model of PD (Johnston et al., 2008; McCoy et al., 2008). References Other agents with a variety of mechanisms of actions have also Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W., Rossi, F.M., 2007. Local self-renewalbeen shown to have both anti-inflammatory and neuroprotective can sustain CNS microglia maintenance and function throughout adult life. Nat.activities in models of PD. LPS-stimulated microglial activation and Neurosci. 10, 1538–1543.degeneration of nigral dopaminergic neurons in vitro (Liu et al., Akiyama, H., McGeer, P.L., 1989. 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