Endotoxin induces a delayed loss of TH-IR neurons in substantia nigra and motor behavioral deficits

Liu, Yuxin; Qin, Liya; Wilson, Belinda; Wu, Xing; Li, Qian; Granholm, Ann Charlotte; Crews, Fulton T.; Hong, Jau–Shyong

doi:10.1016/j.neuro.2008.02.014

Cited by 70 publications

(87 citation statements)

References 33 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The elapsed time between these experiments could have favored the progression of dopaminergic neurodegeneration. In female mice receiving five monthly LPS injections, the loss of dopamine neurons reached 37 % 9 months after the first LPS injection and progressed to 55 % after 20 months of the first endotoxin administration [21]. In our studies, dopaminergic neurodegeneration may also have progressed between 9 and 15 months.…”

Section: Discussionsupporting

confidence: 48%

Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

et al. 2016

View full text Add to dashboard Cite

Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson’s disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1−/−)] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra−/−)] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra−/− mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1−/− mice. Casp1−/− mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra−/− mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1−/− mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.

show abstract

Section: Discussionsupporting

confidence: 48%

Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In our studies, females and males have been respectively used for mRNA and immunohistochemistry experiments. Indeed, in a LPS-induced neurodegeneration model, a higher sensitivity of males versus females has been observed [65]. …”

Section: Discussionmentioning

confidence: 99%

Tollip, an early regulator of the acute inflammatory response in the substantia nigra

Humbert-Claude

Duc

Dwir

et al. 2016

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundTollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson’s disease.MethodsWe first investigated Tollip distribution in the midbrain by immunohistochemistry. Then, we addressed TLR4-mediated response by intra-nigral injections of lipopolysaccharide (LPS), a TLR4 agonist, on inflammatory markers in Tollip knockout (KO) and wild-type (WT) mice.ResultsWe report an unexpectedly high Tollip immunostaining in dopaminergic neurons of the mice brain. Second, intra-nigral injection of LPS led to increased susceptibility to neuroinflammation in Tollip KO compared to Tollip WT mice. This was demonstrated by a significant increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and interferon gamma (IFN-γ) messenger RNA (mRNA) in the midbrain of Tollip KO mice upon LPS injection. Consistently, brain rAAV viral vector transduction with a nuclear factor kappa B (NF-κB)-inducible reporter gene confirmed increased NF-κB activation in Tollip KO mice. Lastly, Tollip KO mice displayed higher inducible NO synthase (iNOS) production, both at the messenger and protein level when compared to LPS-injected WT mice. Tollip deletion also aggravated LPS-induced oxidative and nitrosative damages, as indicated by an increase of 8-oxo-2′-deoxyguanosine and nitrotyrosine immunostaining, respectively.ConclusionsAltogether, these findings highlight a critical role of Tollip in the early phase of TLR4-mediated neuroinflammation. As brain inflammation is known to contribute to Parkinson’s disease, Tollip may be a potential target for neuroprotection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0766-5) contains supplementary material, which is available to authorized users.

show abstract

“…This treatment regimen causes progressive loss of neurons in the substantia nigra in male mice [47]. Under normal conditions peripheral LPS passage across the blood-brain barrier is low [48] and therefore does not induce brain inflammation directly.…”

Section: Discussionmentioning

confidence: 99%

Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo

Üllen

Fauler

Köfeler

et al. 2010

Free Radical Biology and Medicine

View full text Add to dashboard Cite

Plasmalogens, 1-O-alk-1′-enyl-2-acyl-sn-glycerophospholipids, are significant constituents of cellular membranes and are essential for normal brain development. Plasmalogens, which contain a vinyl ether bond at the sn-1 position, are preferential targets for hypochlorous acid (HOCl), generated by myeloperoxidase (MPO) from H 2 O 2 and chloride ions. Because MPO is implicated in neurodegeneration, this study pursued two aims: (i) to investigate the reactivity of mouse brain plasmalogens toward HOCl in vitro and (ii) to obtain in vivo evidence for MPO-mediated brain plasmalogen modification. Liquid chromatography coupled to hybrid linear ion trap-Fourier transform-ion cyclotron resonance mass spectrometry revealed plasmalogen modification in mouse brain lipid extracts at lower HOCl concentrations as observed for diacylphospholipids, resulting in the generation of 2-chloro fatty aldehydes and lysophospholipids. Lysophosphatidylethanolamine accumulation was transient, whereas lysophosphatidylcholine species containing saturated acyl residues remained stable. In vivo, a single, systemic endotoxin injection resulted in upregulation of cerebral MPO mRNA levels to a range comparable to that observed for tumor necrosis factor-α and cyclooxygenase-2. This inflammatory response was accompanied by a significant decrease in several brain plasmalogen species and concomitant in vivo generation of 2-chlorohexadecanal. The present findings demonstrate that activation of the MPO-H 2 O 2 -chloride system under neuroinflammatory conditions results in oxidative attack of the total cerebral plasmalogen pool. As this lipid class is indispensable for normal neuronal function, HOCl-mediated plasmalogen modification is likely to compromise normal synaptic transmission.© 2010 Elsevier Inc. All rights reserved. * Corresponding author. Fax: +43 316 380 9615. wolfgang.sattler@medunigraz.at. The mammalian brain is particularly sensitive toward oxidative damage, a result of the high oxygen demand and the high content of unsaturated lipids in the central nervous system (CNS) [1]. Potential sources of reactive species in the brain are mitochondria, amyloid-β peptides, redox-active iron, the NADPH-oxidase complex, and myeloperoxidase (MPO) [1][2][3]. MPO, a member of the heme peroxidase family, is present in the azurophilic granules of phagocytes, and H 2 O 2 -dependent oxidation of chloride ions to the powerful oxidant hypochlorous acid/hypochlorite (HOCl/OCl − ) is catalyzed by MPO. Under physiological conditions MPO-generated oxidants play an important role in killing invading pathogens, thereby contributing to host defense [3]. However, chronic activation of MPO results in elevated levels of reactive species, favoring chloramine formation, a modification potentially leading to tissue and/or organ injury [4][5][6][7][8]. Increasing evidence points toward MPO as a disease-amplifying enzyme in neurodegeneration [2]. In multiple sclerosis, MPO is present in microglia/macrophages at lesion sites [9,10] and cortical demyelination is associa...

show abstract

Endotoxin induces a delayed loss of TH-IR neurons in substantia nigra and motor behavioral deficits

Cited by 70 publications

References 33 publications

Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

Tollip, an early regulator of the acute inflammatory response in the substantia nigra

Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo

Contact Info

Product

Resources

About