API

Relationship: 906

Title

?

N/A, Neuroinflammation leads to Degeneration of dopaminergic neurons of the nigrostriatal pathway

Upstream event

?

N/A, Neuroinflammation

Downstream event

?


Degeneration of dopaminergic neurons of the nigrostriatal pathway

Key Event Relationship Overview

?


AOPs Referencing Relationship

?

AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits adjacent Moderate Moderate

Taxonomic Applicability

?

Sex Applicability

?

Life Stage Applicability

?

Key Event Relationship Description

?


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 Supporting this KER

?


Biological Plausibility

?

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).

Empirical Evidence

?

LPS injections: Lipopolysaccharide (LPS, a known activator of microglia) injected into the substantia nigra successfully replicated the pathogenic features of Parkinson’s disease in rats. An increase in the mRNA expression of pro-inflammatory cytokines (TNF-alpha, IL-1 beta) was observed 7 days post-injection; alterations in oxidative stress markers (ROS, lipid peroxidation, NO formation, NADPH oxidase activity, GSH system, SOD and catalase) became significant 14 days post-injection, and this was followed by a significant decline in tyrosine hydroxylase (TH), as marker of dopaminergic neurons (Sharma and Nehru, 2015). LPS-induced downregulation of TH expression seemed to depend on the pro-inflammatory cytokine IL-1 beta, since it was not observed in LPS-injected IL-1 knockout mice (Tanaka et al., 2013). Progressive hypokinesia, selective loss of dopaminergic neurons in substantia nigra and reduction of striatal dopamine content, as well as alpha-synuclein aggregation in substantia nigra was also achieved by unilateral intranasal instilation of LPS every other day for 5 months, mimicking a progressive inflammation-mediated chronic pathogenesis of Parkinson’s disease (He et al., 2013). It is important to note that LPS administrated either directly in the brain, intraperitoneally or in utero results in a delayed and progressive loss of nigral DA neurons that persists well after the initial inflammatory stimulis (for review, Taetzsch and Block, 2013).

Rotenone: Chronic systemic rotenone exposure reproduces features of Parkinsons’ disease with loss of DA neurons and putative Lewis bodies in substantia nigra, accompanied by neuroinflammation and oxidative stress, and reduction of TH immunoreactivity in striatum together with an increase in reactive astrocytes (Betarbet et al., 2000; Ferris et al., 2013). In this chronic rotenone model (2-3 mg/kg per day up to 4 weeks), microglia activation precedes neuronal death (Sherer et al., 2003). Several interventions aiming at blocking several features of microglial activation (NADPH oxidase, myeloperoxidase, phagocytosis, opening of K ATP channels,…) protected DA neurons from death (Wang et al., 2014 ; Emmrich et al., 2013 ; Chang et al., 2013 ; Salama et al., 2013 ; Zhou et al., 2007 ; Gao et al., 2003). An enhanced sensitivity of dopaminergic neurons to rotenone-induced toxicity was observed with aging, in parallel with the increase of glial cell activation in older rats (Phiney et al., 2006). In vitro, little neurotoxicity was detected in primary DA neuron cultures (low glia-content) exposed to rotenone, whereas significant and selective dopaminergic neurodegeneration was observed in neuron/glia cultures (Gao et al., 2002).

MPTP/MPP+: Following MPTP treatment, microglial cells are activated by a mechanism secondary to dopaminergic neuron injury (Zhou et al., 2005). However, elevation of interferon-gamma and TNFalpha in substantia nigra was detected before the death of DAergic neurons (Barcia et al., 2011); and serum levels of IFN-gamma and TNFalpha remain elevated for years in monkeys exposed to MPTP (Barcia et al., 2011). The role of microglia in the progression of DA neurodegeneration is suggested by in vivo and in vitro experiments in which feature of microglial reactivity (TNF-alpha, i-NOS, NADPH-oxydase, ROS generation) were blocked (Brzozowski et al., 2015; Wang et al., 2006 ; Liu et al., 2015 ; Wang et al., 2014 ; Chung et al., 2011 ; Borrajo et al., 2014 ; Bodea et al., 2014 ; Sriram et al., 2002 ; Feng et al., 2002 ; Dehmer et al., 2000 ; Ferger et al., 2004). Some evidence from above studies also extends to astrocytes (Sathe et al., 2012; Khan et al., 2014). For instance, systemic adminstration of nicotine (stimulating the anti-inflammatory role of alpha 7 nicotinic acetylcholine receptors on astrocytes and microglia) reduced MPTP-induced motor symptoms, and protected against neurodegeneration in the substantia nigra by (Liu et al., 2012; 2015). Entrance into the brain of bone marrow-derived cells expressing i-NOS may also play a deleterious role in neurodegeneration (Kokovay and Cunningham, 2005). Indeed, pharmacological inhibition or deletion of CD95 in peripheral myeloid cells hampered brain infiltration and was protective for MPTP-induced DA loss in striatum (Gao et al., 2015 ; Chung et al., 2015). Similarly, therapies aiming at suppressing immune reactivity, such as administration of Treg cells (CD4+CD25+ regulatory T cells) lead in MPTP treated mice, to a robust nigrostriatal protection associated to an inhibition of microglial reactivity (Reynolds et al., 2010).

A deleterious role of type-1 interferons (key modulators of early neuroinflammation), was demonstrated in mice treated with MPTP. Mice lacking the type-1 IFN receptor showed an attenuated pro-inflammatory response and reduced loss of dopaminergic neurons and the neuroprotective potential was confirmed by treatment with a blocking monoclonal IFNAR1 antibody (Main et al. 2016).

 

Uncertainties and Inconsistencies

?

• 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)

Quantitative Understanding of the Linkage

?


As it is rather the features and the duration of the inflammatory response that determine the extent of the nigrostriatal pathway neurodegeneration, the best way to propose a quantitative or semi-quantitative evaluation of the links between KEup and KEdown is to use studies where any feature of neuroinflammation is inhibited and to quantify the protection of the Daergic neurons and terminals. Thus it will give an evaluation of how much neurodegeneration depends on the neuroinflammatory process. Below are some examples for illustration.

KE upstream

Neuroinflammation

KE downstream

Neurodegeneration of dopaminergic nigrostriatal pathway

Reference

Type of study


Comment

Inhibition of any feature of neuroinflammation (microglia/astrocyte)

How much nigrostriatal pathway degeneration depends on KEup

as assessed by protection when any KEup feature is inhibited

   

 

       

 

KATP channel opener (iptakalim) induced decrease of TNF-alpha and COX2 mRNA expression and TNF-alpha content, as well as microglial reactivity (OX42, ED1)

TH immunoreactivity :

Total recovery

Zhou et al., 2007

In vivo

Rotenone 2.5 mg/kg/d

+ in vitro

 

NADPH oxydase

Neuron enriched cultures

Neuron-Glia co-cultures +apocynin

DA uptake

TH immunoreactivity

About 50% more neuronal death in presence of glia

(80 % of protection with apocynin)

Gao et al., 2002

In vitro

Rotenone

5-20 nM

 

NADPH oxydase

Mice knockout for NADPH ox gp91-/-

Co-culture neuron-glia

DA uptake : 40% protection

TH immuno : 20% protection

Gao et al., 2003

In vitro

Rotenone

5-10 nM

 

Phagocytic signaling between neuron and microglia i.e. block of vitronectin and P2Y6 on microglia or annexin or phophatidylserine on neuron (eat-me signal)

About 20% neuronal protection

Emmrich et al., 2013

In vitro

Co-cultures of cerebellum

Rotenone 2.5 nM

 

Decrease in the number of activated microglia by  L-thyroxin

in substantia nigra, not in striatum

Protection of DA terminals in striatum, but no effect in substantia nigra

Salama et al., 2012

In vivo

Rotenone 3mg/kg/d

 

Myeloperoxidase

(HOCl from H2O2)

Resveratrol decreased NO, ROS, phagocytosis in microglia and astrocytes

Protection of neuron :

40% cell viability

50-60% TH immuno + number of dendrites

Chang et al., 2013

In vitro

Rotenone 30 nM

MPP+ 0.1 microM

 

NADPH oxydase : NOX2

Diphenyleneiodonium : long acting NOX2 inhibitor

DA uptake and TH immuno :

30-40 % of protection

Wang et al., 2014

In vitro

LPS 20 ng/ml

MPP+ 0.15 microM

 

Control of microglial and astrocyte reactivity by Alpha 7 nicotinic Ach receptor

present on microglia and astrocyte

Its activation decreased microglial and astrocyte reactivity

MPP+ cuased 40% decrease of TH+ neurons

Nicotine induced a 30% recovery

Liu et al., 2012, 2015

In vivo

MPTP 20mg/kg

Nicotine 5mg/kg

In vitro on isolated microglia and astrocytes

 

'TNF-alpha of microglial origin

By blocking angiotensin-1 receptors, NADPH-oxydase, Rho-kinase and NF.kB

20 % of recovery of TH immunoreactivity

Borrajo et al., 2013

In vitro + in vivo

MPP+ 0.25 microM

 

Infusion of the anti-inflammatory cytokine TGF beta

protects from MPP+-induced cell loss by decreasing CD11b, i-NOS, TNFalpha, IL+ beta, and increas ing IGF-1. Silencing of TGFbR1 gene abolished the protective effect

MPP+ caused 60% decrease of TH immuno, and TGFbeta induced a dose-dependent recovery (5-20 ng/ml)

Liu et al., 2015

In vitro

Co-cultures

MPP+ 5 microM

indirect

i-NOS inhibition

caused a decrease of astrocyte and microglial reactivity as assessed by GFAP and OX6, respectively

(n-NOS inhibition had no effect)

TH immunoreactivity

Dose-dependent recovery with 1400W (0.1-100 micoM)

Brzozowski et al., 2015

In vitro

MPP+

43 microM

 

Inhibition of laminin receptor on microglia

i.e. regulating cell-ECM interactions induced a decrease of microglia phagocytosis and of O2- production

Dose-dependent partial recovery (about 35% of TH immunoreactivity

Wang et al., 2006

In vitro

MPP+

0.1-0.5 microM

 

Inhibition of glial activation-mediated oxidative stress

by

Fluoxetine, anti-depressant)

30% of recovery of TH immunoreactivity in Substantia nigra and total recovery of DA terminals in striatum

Chung et al., 2011

In vivo

MPTP 20 mg/ kg ip

 

Mice lacking both TNFR

Induced a decrease of GFAP in striatum

Double KO, if only KO for TNFR1 or TNFR2, no protection

TH staining in striatum, DA content and GFAP staining , all returned to control level

Sriram et al., 2014

In vivo

MPTP

12.5 mg/kg sc

 

Mice-deficient for COX2

Microglial cells are the major cells expressing COX2

MPTP caused 

in substantia nigra

40% loss in wild type

45% loss in COX1-/-

20% loss in COX2-/-

in striatum

70% loss of DA in all 3 types of mice

Feng et al., 2002

In vivo

MPTP 20 mg/kg sc

 

S100B-/- in astrocytes

caused decreased microgliosis, TNF-alpha and RAGE

12% of protection for TH+ neuron

30% of protection for Nissl-labelled neurons

Sathe et al., 2012

In vivo

MPTP 30 mg/kg ip

 

Glia Maturation Factor (GMF) overexpression

or

GMF-/- showed decreased TNF-alpha, IL-1beta, ROS and NFkappaB downregulation

Overexpression of GMF exacerbate DA neuron degeneration

GMF-/- induced a protection of 40% of TH+ neurons

Khan et al., 2014

In vitro

Mesencephalic neuron/glia cultures

MPP+

5,10,20 microM

 

Pharmacological inhibition or deletion of CD95 in peripheral myeloid cells

(monocytes, macrophages, microglia, leucocytes) hampered infiltration in the brain of peripheral myeloid cells

Total preservation of DA level in striatum

Total protection of TH+ neurons in Snigra (25% affected in wild type mice)

Gao et al., 2015

In vivo

MPTP 30 mg/kg ip

 

Glucocorticoid receptor (GR) deletion in microglia

increased their reactivity and induced a persistant activation

 

2X aggravation of TH+ neuronal loss in Snigra

Ros-Bernal et al., 2011

In vivo

MPTP 20 mg/kg ip

 

TNF -/- mice

No protection in substantia nigra

TH density in striatum : return to control level

Ferger et al., 2004

In vivo

MPTP

20 mg/kg ip

 

Intra-venous transplantation of mesenchymal stem cells

Cell migration in substantianigra and release of TGFbeta (anti-inflammatory)

Reparation of BBB, decreased infilatration and microglial activation

About 15% protection of TH+ neurons in Snigra

Chao et al., 2009

In vivo

MPTP 20 mg/kg ip

 

Nrf2-/-

Increase in microgliosis and astrogliosis

Microglial M1 phenotype

Nrf2 involved in tuning microglial activation, switch M1/M2 phenotypes

40% more DA neurons loss in substantia nigra (TM immunostaining)

Rojo et al., 2010

In vivo

MPTP 20mg/kg ip

indirect

Beta2 adrenergic receptor activation decreased microglial activation

20% protection of TH+ neurons in Substantia nigra

Qian et al., 2011

In vivo

MPTP 15 mg/kg sc

 

Deficiency in i-NOS

blocks MPTP-induced increase of i-NOS, but not morphological microglial activation (IB4)

Rescue of TH+ neurons in substantia nigra to control level, but no protection for striatal DA content

Dehmer et al., 2000

In vivo

MPTP

30 mg/KG/d ip, 5d

 

C3-deficient mice

Inhibition of complement-phagossome pathway

Induced a decrease in several markers of microglial activation

Loss of DA neurons induced by repeated systemic LPS application is rescued to control level

Bodea et al., 2014

In vivo

4 dayly injection of LPS 1 microg/gbw LPS

 

         

 

Response-response Relationship

?

Time-scale

?

Known modulating factors

?

Known Feedforward/Feedback loops influencing this KER

?

Domain of Applicability

?


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

?



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.