Relationship: 906



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


KE downstream

Neurodegeneration of dopaminergic nigrostriatal pathway


Type of study


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


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


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



(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


MPP+ 5 microM


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


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


0.1-0.5 microM


Inhibition of glial activation-mediated oxidative stress


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


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


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


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


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



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


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


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




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).



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