To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:906

Relationship: 906

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Neuroinflammation leads to Degeneration of dopaminergic neurons of the nigrostriatal pathway

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits adjacent Moderate Moderate Cataia Ives (send email) Open for citation & comment WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Cells of the innate (microglia and astrocytes) and adaptive (infiltrating monocytes and lymphocytes) immune system of the brain have, like other immune cells (in peripheral tissues), various ways to kill neighboring cells. This is in part due to evolutionary-conserved mechanisms evolved to kill virus-infected cells or tumor cells; in part it is a bystander phenomenon due to the release of mediators that should activate other cells and contribute to the killing of invading microorganisms. An exaggerated or unbalanced activation of immune cells can thus lead to parenchymal (neuronal) cell death (Gehrmann et al., 1995). Mediators known to have such effects, and that are also known to be produced during inflammation in the brain comprise components of the complement system and cytokines/death receptor ligands triggering programmed cell death (Dong and Benveniste, 2001). Besides these specific signals, various secreted proteases (e.g. matrix metalloproteases), lipid mediators (e.g. ceramide or gangliosides) or reactive oxygen species can contribute to bystander death of neurons (Chao et al., 1995; Nakajima et al., 2002; Brown and Bal-Price, 2003; Kraft and Harry, 2011; Taetzsch and Block, 2013). Especially the equimolar production of superoxide and NO from glial cells can lead to high steady state levels of peroxynitrite, which is a very potent cytotoxicant (Yuste et al., 2015). Already damaged neurons, with an impaired anti-oxidant defence system, are more sensitive to such mediators. An important role of microglia in the brain is the removal of cell debris (Xu et al., 2015). Healthy cells continuously display anti-“eat me” signals, while damaged and stressed neurons/neurites display “eat-me” signals that may be recognbized by microglia as signal to start phagocytosis (Neher et al., 2012), thus accelerating the loss of DA neurites in the striatum. Activated microglia surrounding DAergic neurons in PD express the M1 neurodegenerative phenotype (Hunot et al., 1999), which promote proliferation and function of CD4+ T cells (for review Appel et al., 2010), which in turn induce DA neuron toxicity, as assessed by experiments with immunodeficient mice (Brochard et al., 2009). Possible infiltration of other myeloid cells, such as monocytes or macrophages through a compromised blood-brain barrier, may also be involved in phagocytosis and neurodegeneration (Depboylu et al., 2012 ; Pey et al., 2014).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Histopathological studies have shown that glial activation is a hallmark of every neurodegenerative disease, including Parkinson’s disease (Whitton, 2007 ; Tansey and Goldberg, 2009 ; Niranjan, 2014 ; Verkhratiky et al., 2014). PET studies in PD patients have revealed that microglial activation in the substantia nigra is an early event in the disease process (Iannaccone et al., 2012), and that it is extremely persistent. The role of astrocytes is less clear than the one of microglia, but reactive astrocytes are able to release neurotoxic molecules (Mena and Garcia de Ybenes, 2008 ; Niranjan, 2014). However, astrocytes may also be protective due to their capacity to quench free radicals and secrete neurotrophic factors. The activation of astrocytes reduces neurotrophic support to neurons, and the proportion of astrocytes surrounding dopaminergic neurons in the substantia nigra is the lowest for any brain area suggesting that dopaminergic neurons are more vulnerable in terms of glial support (for review, Mena and Garcia de Ybenes, 2008). In vitro co-culture experiments have demonstrated that reactive glial cells (microglia and astrocytes) can kill neurons (Chao et al., 1995 ; Brown and Bal-Price, 2003 ; Kraft and Harry, 2011 ; Taetzsch and Block, 2013), and that interventions with e.g. i-NOS inhibition can rescue the neurons (Yadav et al., 2012; Brzozowski et al., 2015). Direct activation of glial cells with the inflammogen LPS has also resulted in vivo in the death of DA neurons (Sharma and Nehru, 2015; Zhou et al., 2012; Li et al., 2009).

Circulating monocytes and lymphocytes: Neuroinflammation can disrupt blood-brain barrier integrity (Zhao et al., 2007), facilitating infiltration of circulating monocytes and lymphocytes (Machado et al., 2011; Quian et al., 2010). T cell infiltration has been found in CNS tissue of PD patients (Miklossy et al., 2006 ; Qian et al., 2010), and in animal models, in which depletion or inactivation of lymphocytes has been found to protect striatal DA terminals (for review, Appel et al., 2010).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

• Mice deficient in microglia (depletion by a ganciclovir-thymidine kinase system under the CD11b promoter) were still susceptible to MPTP toxicity, while mixed cell cultures prepared from these deficient mice showed partial protection (Kinugawa et al., 2013).

• Although some publications show strong protection by COX-2 inhibition/deletion, others showed that mice deficient for COX-2 were partly protected against MPTP-induced decrease of DAergic neurons in substantia nigra, but not against DA terminal loss in striatum (Feng et al., 2000).

• Mice deficient in IL6 (IL6-/-) showed an increased vulnerability of the nigrostriatal pathway following MPTP treatment associated to a normal astrogliosis but a transient microgliosis, suggesting that transient microgliosis and IL6 may have also protective effects (Cardenas and Bolin, 2003).

• MMTV integration site 1 (Wnt 1) is a key transcript involved in DAergic neurodevelopment, and is dynamically regulated during MPTP-induced DA degeneration and glial activation. MPTP-activated astrocytes of the ventral midbrain were identified as candidate source of Wnt 1 by in situ hybridization and RT-PCR in vitro, suggesting that reactive astrocytes may be rather involved in neuroprotective/neurorescue pathways, as further demonstrated by deletion of Wnt 1 or pharmacological activation of Wnt/-catenin signaling pathway (L’Episcopo et al, 2011).

• The role of microglia, NADPH-oxidase and oxidative stress in paraquat-induced neurodegeneration is well established. Nevertheless, the mechanism connecting these three elements remain poorly understood since direct evidence for extracellular and/or intracellular formation of radical paraquat and superoxide is controversial.

• Rotenone (1-3 nM) applied directly on BV2 microglial cells increased their phagocytosis and the release of pro-inflammatory cytokines (TNF-alpha, IL-1 beta), suggesting that microglial cell can also be a primary target of rotenone (Zhang et al., 2014). However, these results in a transformed microglial cell line contrast with the experiments performed on isolated primary microglial cells, where rotenone (10-50 nM) was not able to trigger a direct activation (Klintworth et al., 2009).

• The regulation of inducible nitric oxide synthase (for production of peroxynitrite) differs strongly between rodents and human, and thus, the role of NO in human remains unclear (Ganster et al., 2001).

• While in human long-term use of anti-inflammatory drugs (NSAIDs, aspirin, iboprufen) for preventing PD onset or for slowing the progression is still controversial, a new strategy is emerging aiming at targeting microglial cells by modulating their activity, rather than simply trying to counteract their inflammatory neurotoxicity. The advantage of this therapeutic approach could be to reduce neuroinflammation and neurotoxicity, while at the same time strengthening intrinsic neuroprotective properties (Pena-Altamira et al., 2015)

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Rodent models have been mainly used to study the impact of neuroinflammation on DAergic nigrostriatal pathway degeneration, without any sex restriction. Neuroinflammation preceding neuronal death was detected in monkeys exposed to MPTP (Barcia et al., 2011); and in human, neuroinflammation is considered as an early event in the disease process (Innaccone et al., 2012).

References

List of the literature that was cited for this KER description. More help

Appel SH, Beers DR, Henkel JS. 2010. T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31(1): 7-17.

Barcia C, Ros CM, Annese V, Gomez A, Ros-Bernal F, Aguado-Yera D, et al. 2011. IFN-gamma signaling, with the synergistic contribution of TNF-alpha, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease. Cell death & disease 2: e142.

Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. 2000. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3(12): 1301-1306.

Bobyn J, Mangano EN, Gandhi A, Nelson E, Moloney K, Clarke M, et al. 2012. Viral-toxin interactions and Parkinson's disease: poly I:C priming enhanced the neurodegenerative effects of paraquat. J Neuroinflammation 9: 86.

Bodea LG, Wang Y, Linnartz-Gerlach B, Kopatz J, Sinkkonen L, Musgrove R, et al. 2014. Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci 34(25): 8546-8556.

Bonneh-Barkay D, Reaney SH, Langston WJ, Di Monte DA. 2005. Redox cycling of the herbicide paraquat in microglial cultures. Brain Res Mol Brain Res 134(1): 52-56.

Borrajo A, Rodriguez-Perez AI, Villar-Cheda B, Guerra MJ, Labandeira-Garcia JL. 2014. Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death. Neuropharmacology 85: 1-8.

Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, et al. 2009. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119(1): 182-192.

Brown GC, Bal-Price A. 2003. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27(3): 325-355.

Brzozowski MJ, Jenner P, Rose S. 2015. Inhibition of i-NOS but not n-NOS protects rat primary cell cultures against MPP(+)-induced neuronal toxicity. J Neural Transm 122(6): 779-788.

Cardenas H, Bolin LM. 2003. Compromised reactive microgliosis in MPTP-lesioned IL-6 KO mice. Brain Res 985(1): 89-97.

Chang CY, Choi DK, Lee DK, Hong YJ, Park EJ. 2013. Resveratrol confers protection against rotenone-induced neurotoxicity by modulating myeloperoxidase levels in glial cells. PLoS One 8(4): e60654.

Chao CC, Hu S, Peterson PK. 1995. Glia, cytokines, and neurotoxicity. CritRevNeurobiol 9: 189-205.

Chao YX, He BP, Tay SS. 2009. Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease. J Neuroimmunol 216(1-2): 39-50.

Chung YC, Kim SR, Park JY, Chung ES, Park KW, Won SY, et al. 2011. Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. Neuropharmacology 60(6): 963-974.

Chung ES, Lee G, Lee C, Ye M, Chung HS, Kim H, et al. 2015. Bee Venom Phospholipase A2, a Novel Foxp3+ Regulatory T Cell Inducer, Protects Dopaminergic Neurons by Modulating Neuroinflammatory Responses in a Mouse Model of Parkinson's Disease. J Immunol.

Cicchetti F, Lapointe N, Roberge-Tremblay A, Saint-Pierre M, Jimenez L, Ficke BW, et al. 2005. Systemic exposure to paraquat and maneb models early Parkinson's disease in young adult rats. Neurobiol Dis 20(2): 360-371.

Dehmer T, Lindenau J, Haid S, Dichgans J, Schulz JB. 2000. Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J Neurochem 74(5): 2213-2216.

Depboylu C, Stricker S, Ghobril JP, Oertel WH, Priller J, Hoglinger GU. 2012. Brain-resident microglia predominate over infiltrating myeloid cells in activation, phagocytosis and interaction with T-lymphocytes in the MPTP mouse model of Parkinson disease. Exp Neurol 238(2): 183-191.

Dexter DT, Jenner P. 2013. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 62: 132-144.

Dong Y, Benveniste EN. 2001. Immune Function of Astrocytes. Glia 36: 180-190.

Emmrich JV, Hornik TC, Neher JJ, Brown GC. 2013. Rotenone induces neuronal death by microglial phagocytosis of neurons. The FEBS journal 280(20): 5030-5038.

Feng ZH, Wang TG, Li DD, Fung P, Wilson BC, Liu B, et al. 2002. Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neurosci Lett 329(3): 354-358.

Ferger B, Leng A, Mura A, Hengerer B, Feldon J. 2004. Genetic ablation of tumor necrosis factor-alpha (TNF-alpha) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum. J Neurochem 89(4): 822-833.

Ferris CF, Marella M, Smerkers B, Barchet TM, Gershman B, Matsuno-Yagi A, et al. 2013. A phenotypic model recapitulating the neuropathology of Parkinson's disease. Brain and behavior 3(4): 351-366.

Gao HM, Hong JS, Zhang W, Liu B. 2002. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 22(3): 782-790.

Gao HM, Liu B, Hong JS. 2003. Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 23(15): 6181-6187.

Gao L, Brenner D, Llorens-Bobadilla E, Saiz-Castro G, Frank T, Wieghofer P, et al. 2015. Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice. J Exp Med 212(4): 469-480.

Gehrmann J, Banati RB, Wiessnert C, Hossmann KA, Kreutzberg GW. 1995. Reactive microglia in cerebral ischaemia: An early mediator of tissue damage? NeuropatholApplNeurobiol 21: 277-289.

He Q, Yu W, Wu J, Chen C, Lou Z, Zhang Q, et al. 2013. Intranasal LPS-mediated Parkinson's model challenges the pathogenesis of nasal cavity and environmental toxins. PLoS One 8(11): e78418.

Hunot S, Dugas N, Faucheux B, Hartmann A, Tardieu M, Debre P, et al. 1999. FcepsilonRII/CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. J Neurosci 19(9): 3440-3447.

Iannaccone S, Cerami C, Alessio M, Garibotto V, Panzacchi A, Olivieri S, et al. 2013. In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson's disease. Parkinsonism & related disorders 19(1): 47-52.

Khan MM, Zaheer S, Nehman J, Zaheer A. 2014. Suppression of glia maturation factor expression prevents 1-methyl-4-phenylpyridinium (MPP(+))-induced loss of mesencephalic dopaminergic neurons. Neuroscience 277: 196-205.

Kinugawa K, Monnet Y, Bechade C, Alvarez-Fischer D, Hirsch EC, Bessis A, et al. 2013. DAP12 and CD11b contribute to the microglial-induced death of dopaminergic neurons in vitro but not in vivo in the MPTP mouse model of Parkinson's disease. J Neuroinflammation 10: 82.

Klintworth H, Garden G, Xia Z. 2009. Rotenone and paraquat do not directly activate microglia or induce inflammatory cytokine release. Neurosci Lett 462(1): 1-5.

Kokovay E, Cunningham LA. 2005. Bone marrow-derived microglia contribute to the neuroinflammatory response and express iNOS in the MPTP mouse model of Parkinson's disease. Neurobiol Dis 19(3): 471-478.

Kraft AD, Harry GJ. 2011. Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. International journal of environmental research and public health 8(7): 2980-3018.

L'Episcopo F, Tirolo C, Testa N, Caniglia S, Morale MC, Cossetti C, et al. 2011. Reactive astrocytes and Wnt/beta-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Neurobiol Dis 41(2): 508-527.

Li XZ, Bai LM, Yang YP, Luo WF, Hu WD, Chen JP, et al. 2009. Effects of IL-6 secreted from astrocytes on the survival of dopaminergic neurons in lipopolysaccharide-induced inflammation. Neuroscience research 65(3): 252-258.

Liu Y, Hu J, Wu J, Zhu C, Hui Y, Han Y, et al. 2012. alpha7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation. J Neuroinflammation 9: 98.

Liu Z, Chen HQ, Huang Y, Qiu YH, Peng YP. 2015. Transforming growth factor-beta1 acts via TbetaR-I on microglia to protect against MPP-induced dopaminergic neuronal loss. Brain, behavior, and immunity.

Liu Y, Zeng X, Hui Y, Zhu C, Wu J, Taylor DH, et al. 2015. Activation of alpha7 nicotinic acetylcholine receptors protects astrocytes against oxidative stress-induced apoptosis: implications for Parkinson's disease. Neuropharmacology 91: 87-96.

Machado A, Herrera AJ, Venero JL, Santiago M, De Pablos RM, Villaran RF, et al. 2011. Peripheral inflammation increases the damage in animal models of nigrostriatal dopaminergic neurodegeneration: possible implication in Parkinson's disease incidence. Parkinson's disease 2011: 393769.

Main BS, Zhang M, Brody KM, Ayton S, Frugier T, Steer D, Finklestein D, Crack PJ, Taylor JM. (2016) Type-1 Interferons contribute to the neuroinflammatory response and disease progression of the MPTP mouse model of Parkinson's disease. Glia: 64; 1590-1604.

Mangano EN, Peters S, Litteljohn D, So R, Bethune C, Bobyn J, et al. 2011. Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease. Neurobiol Dis 43(1): 99-112.

Mangano EN, Litteljohn D, So R, Nelson E, Peters S, Bethune C, et al. 2012. Interferon-gamma plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways. Neurobiol Aging 33(7): 1411-1426.

Mena MA, Garcia de Yebenes J. 2008. Glial cells as players in parkinsonism: the "good," the "bad," and the "mysterious" glia. Neuroscientist 14(6): 544-560.

Miklossy J, Doudet DD, Schwab C, Yu S, McGeer EG, McGeer PL. 2006. Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp Neurol 197(2): 275-283.

Miller RL, Sun GY, Sun AY. 2007. Cytotoxicity of paraquat in microglial cells: Involvement of PKCdelta- and ERK1/2-dependent NADPH oxidase. Brain Res 1167: 129-139.

Mitra S, Chakrabarti N, Bhattacharyya A. 2011. Differential regional expression patterns of alpha-synuclein, TNF-alpha, and IL-1beta; and variable status of dopaminergic neurotoxicity in mouse brain after Paraquat treatment. J Neuroinflammation 8: 163.

Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. 2002. Ceramide activates microglia to enhance the production/secretion of brain-derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro. J Neurochem 80: 697-705.

Neher JJ, Neniskyte U, Brown GC. 2012. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Frontiers in pharmacology 3: 27.

Niranjan R. 2014. The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson's disease: focus on astrocytes. Mol Neurobiol 49(1): 28-38.

Pena-Altamira E, Prati F, Massenzio F, Virgili M, Contestabile A, Bolognesi ML, et al. 2015. Changing paradigm to target microglia in neurodegenerative diseases: from anti-inflammatory strategy to active immunomodulation. Expert opinion on therapeutic targets: 1-14.

Pey P, Pearce RK, Kalaitzakis ME, Griffin WS, Gentleman SM. 2014. Phenotypic profile of alternative activation marker CD163 is different in Alzheimer's and Parkinson's disease. Acta neuropathologica communications 2: 21.

Phinney AL, Andringa G, Bol JG, Wolters E, van Muiswinkel FL, van Dam AM, et al. 2006. Enhanced sensitivity of dopaminergic neurons to rotenone-induced toxicity with aging. Parkinsonism & related disorders 12(4): 228-238.

Purisai MG, McCormack AL, Cumine S, Li J, Isla MZ, Di Monte DA. 2007. Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. Neurobiol Dis 25(2): 392-400.

Qian L, Flood PM, Hong JS. 2010. Neuroinflammation is a key player in Parkinson's disease and a prime target for therapy. J Neural Transm 117(8): 971-979.

Qian L, Wu HM, Chen SH, Zhang D, Ali SF, Peterson L, et al. 2011. beta2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway. J Immunol 186(7): 4443-4454.

Rappold PM, Cui M, Chesser AS, Tibbett J, Grima JC, Duan L, et al. 2011. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci U S A 108(51): 20766-20771.

Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. 2010. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol 184(5): 2261-2271.

Rojo AI, Innamorato NG, Martin-Moreno AM, De Ceballos ML, Yamamoto M, Cuadrado A. 2010. Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease. Glia 58(5): 588-598.

Ros-Bernal F, Hunot S, Herrero MT, Parnadeau S, Corvol JC, Lu L, et al. 2011. Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism. Proc Natl Acad Sci U S A 108(16): 6632-6637.

Saint-Pierre M, Tremblay ME, Sik A, Gross RE, Cicchetti F. 2006. Temporal effects of paraquat/maneb on microglial activation and dopamine neuronal loss in older rats. J Neurochem 98(3): 760-772.

Salama M, Helmy B, El-Gamal M, Reda A, Ellaithy A, Tantawy D, et al. 2013. Role of L-thyroxin in counteracting rotenone induced neurotoxicity in rats. Environmental toxicology and pharmacology 35(2): 270-277.

Sathe K, Maetzler W, Lang JD, Mounsey RB, Fleckenstein C, Martin HL, et al. 2012. S100B is increased in Parkinson's disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain 135(Pt 11): 3336-3347.

Sharma N, Nehru B. 2015. Characterization of the lipopolysaccharide induced model of Parkinson's disease: Role of oxidative stress and neuroinflammation. Neurochem Int 87: 92-105.

Sherer TB, Betarbet R, Kim JH, Greenamyre JT. 2003. Selective microglial activation in the rat rotenone model of Parkinson's disease. Neurosci Lett 341(2): 87-90.

Sriram K, Matheson JM, Benkovic SA, Miller DB, Luster MI, O'Callaghan JP. 2002. Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease. Faseb J 16(11): 1474-1476.

Taetzsch T, Block ML. 2013. Pesticides, microglial NOX2, and Parkinson's disease. J Biochem Mol Toxicol 27(2): 137-149.

Tanaka S, Ishii A, Ohtaki H, Shioda S, Yoshida T, Numazawa S. 2013. Activation of microglia induces symptoms of Parkinson's disease in wild-type, but not in IL-1 knockout mice. J Neuroinflammation 10: 143.

Tansey MG, Goldberg MS. 2009. Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis.

Verkhratsky A, Parpura V, Pekna M, Pekny M, Sofroniew M. 2014. Glia in the pathogenesis of neurodegenerative diseases. Biochemical Society transactions 42(5): 1291-1301.

Wang T, Zhang W, Pei Z, Block M, Wilson B, Reece JM, et al. 2006. Reactive microgliosis participates in MPP+-induced dopaminergic neurodegeneration: role of 67 kDa laminin receptor. Faseb J 20(7): 906-915.

Wang Q, Chu CH, Qian L, Chen SH, Wilson B, Oyarzabal E, et al. 2014. Substance P exacerbates dopaminergic neurodegeneration through neurokinin-1 receptor-independent activation of microglial NADPH oxidase. J Neurosci 34(37): 12490-12503.

Wang Q, Chu CH, Oyarzabal E, Jiang L, Chen SH, Wilson B, et al. 2014. Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases. Glia 62(12): 2034-2043.

Whitton PS. 2007. Inflammation as a causative factor in the aetiology of Parkinson's disease. Br J Pharmacol 150(8): 963-976.

Wu XF, Block ML, Zhang W, Qin L, Wilson B, Zhang WQ, et al. 2005. The role of microglia in paraquat-induced dopaminergic neurotoxicity. Antioxidants & redox signaling 7(5-6): 654-661. Xu L, He D, Bai Y. 2015. Microglia-Mediated Inflammation and Neurodegenerative Disease. Mol Neurobiol. Yadav S, Gupta SP, Srivastava G, Srivastava PK, Singh MP. 2012. Role of secondary mediators in caffeine-mediated neuroprotection in maneb- and paraquat-induced Parkinson's disease phenotype in the mouse. Neurochem Res 37(4): 875-884. Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F. 2015. Implications of glial nitric oxide in neurodegenerative diseases. Frontiers in cellular neuroscience 9: 322.

Zhao C, Ling Z, Newman MB, Bhatia A, Carvey PM. 2007. TNF-alpha knockout and minocycline treatment attenuates blood-brain barrier leakage in MPTP-treated mice. Neurobiol Dis 26(1): 36-46.

Zhang XY, Chen L, Yang Y, Xu DM, Zhang SR, Li CT, et al. 2014. Regulation of rotenone-induced microglial activation by 5-lipoxygenase and cysteinyl leukotriene receptor 1. Brain Res 1572: 59-71. Zhou Y, Wang Y, Kovacs M, Jin J, Zhang J. 2005. Microglial activation induced by neurodegeneration: a proteomic analysis. Molecular & cellular proteomics : MCP 4(10): 1471-1479.

Zhou F, Wu JY, Sun XL, Yao HH, Ding JH, Hu G. 2007. Iptakalim alleviates rotenone-induced degeneration of dopaminergic neurons through inhibiting microglia-mediated neuroinflammation. Neuropsychopharmacology 32(12): 2570-2580.

Zhou Y, Zhang Y, Li J, Lv F, Zhao Y, Duan D, et al. 2012. A comprehensive study on long-term injury to nigral dopaminergic neurons following intracerebroventricular injection of lipopolysaccharide in rats. J Neurochem 123(5): 771-780.