CoChat
Sign Up
Cited by 355Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsNuclear Receptors and Signaling

The DOI matches its Crossref record; 85 of the 86 references it cites were found in a registry or an index.

Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease

Open access
Koprich, James B, Reske-Nielsen, Casper, Mithal, Prabhakar, Isacson, Ole·2008·Journal of Neuroinflammation
DOI 10.1186/1742-2094-5-8PMC PMC2292163
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: The etiology of Parkinson's disease (PD) remains elusive despite identification of several genetic mutations. It is more likely that multiple factors converge to give rise to PD than any single cause. Here we report that inflammation can trigger degeneration of dopamine (DA) neurons in an animal model of Parkinson's disease. Methods: We examined the effects of inflammation on the progressive 6-OHDA rat model of Parkinson's disease using immunohistochemistry, multiplex ELISA, and cell counting stereology. Results: We show that a non-toxic dose of lipopolysaccharide (LPS) induced secretion of cytokines and predisposed DA neurons to be more vulnerable to a subsequent low dose of 6-hydroxydopamine. Alterations in cytokines, prominently an increase in interleukin-1beta (IL-1β), were identified as being potential mediators of this effect that was associated with activation of microglia. Administration of an interleukin-1 receptor antagonist resulted in significant reductions in tumor necrosis factor-α and interferon-γ and attenuated the augmented loss of DA neurons caused by the LPS-induced sensitization to dopaminergic degeneration. Conclusion: These data provide insight into the etiology of PD and support a role for inflammation as a risk factor for the development of neurodegenerative disease.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/1742-2094-5-8

Cites

85 of 85 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Experimental timelines. Each timeline represents in vivo experimental procedures and postmortem analyses conducted. Number of animals in each group: (A) n = 6, (B) n = 6, (C) n = 7, (D) n = 7, (E) n = 5, (F) n = 8. LPS, lipopolysaccharide; 6-OHDA, 6-hydroxydopamine, SAL, saline; IL-1ra, interluekin-1 receptor antagonist; veh, vehicle; SN, substantia nigra, Str, striatum.
Figure 1 Experimental timelines. Each timeline represents in vivo experimental procedures and postmortem analyses conducted. Number of animals in each group: (A) n = 6, (B) n = 6, (C) n = 7, (D) n = 7, (E) n = 5, (F) n = 8. LPS, lipopolysaccharide; 6-OHDA, 6-hydroxydopamine, SAL, saline; IL-1ra, interluekin-1 receptor antagonist; veh, vehicle; SN, substantia nigra, Str, striatum.CC BY · PubMed Central
Figure 2 (A) Tyrosine hydroxylase positive (TH+) cell counts in the substantia nigra (SN). (B) Animals received, into the SN, saline (SAL) and 12 days later received an intra-striatal injection of SAL. (C) Animals received lipopolysaccharide (LPS) into the SN and 12 days later received an intra-striatal injection of SAL. (D) Animals received SAL into the SN and 12 days later received an intra-striatal injection of 6-OHDA (5.0 μg). (E) Animals received LPS into the SN and 12 days later received an intra-striatal injection of 6-OHDA (5.0 μg). (F) Animals received an intra-striatal injection of 6-OHDA (5.0 μg) and 12 days later received LPS into the SN. (G) Animals received an intra-striatal injection of 6-OHDA-h (high) (22.5 μg). Letters inside bars of panel A represent respective images in panels below. 21 days was allowed following 6-OHDA injection in all conditions. There was an overall main effect across groups (ANOVA, p < 0.001). LPS injection into the SN was non-toxic to TH+ neurons (B vs. C, NS). LPS injection prior to 6-OHDA administration increased the amount of TH+ cell loss compared to SAL prior to 6-OHDA (D vs. E, *p < 0.05, post-hoc Holm-Sidak). Intra-striatal injection of 6-OHDA followed by injection of LPS in the SN produced no greater cell loss (D vs. F, NS). The high dose of 6-OHDA produced cell loss that was not significantly different from a low dose of 6-OHDA with prior exposure to LPS (E vs. G, NS), however the high dose of 6-OHDA was significantly greater than other conditions receiving the lower dose of 6-OHDA (G vs. D and F, # p < 0.05, post-hoc Holm-Sidak). 1st, first injection; 2nd, second injection; SNpc, pars compacta; SNpr, pars reticulata; VTA, ventral tegmental area; CP, cerebral peduncle; scale bar, 1.0 mm; magnification, 2.5×. Error bars, ± SEM; n = 6 per condition.
Figure 2 (A) Tyrosine hydroxylase positive (TH+) cell counts in the substantia nigra (SN). (B) Animals received, into the SN, saline (SAL) and 12 days later received an intra-striatal injection of SAL. (C) Animals received lipopolysaccharide (LPS) into the SN and 12 days later received an intra-striatal injection of SAL. (D) Animals received SAL into the SN and 12 days later received an intra-striatal injection of 6-OHDA (5.0 μg). (E) Animals received LPS into the SN and 12 days later received an intra-striatal injection of 6-OHDA (5.0 μg). (F) Animals received an intra-striatal injection of 6-OHDA (5.0 μg) and 12 days later received LPS into the SN. (G) Animals received an intra-striatal injection of 6-OHDA-h (high) (22.5 μg). Letters inside bars of panel A represent respective images in panels below. 21 days was allowed following 6-OHDA injection in all conditions. There was an overall main effect across groups (ANOVA, p < 0.001). LPS injection into the SN was non-toxic to TH+ neurons (B vs. C, NS). LPS injection prior to 6-OHDA administration increased the amount of TH+ cell loss compared to SAL prior to 6-OHDA (D vs. E, *p < 0.05, post-hoc Holm-Sidak). Intra-striatal injection of 6-OHDA followed by injection of LPS in the SN produced no greater cell loss (D vs. F, NS). The high dose of 6-OHDA produced cell loss that was not significantly different from a low dose of 6-OHDA with prior exposure to LPS (E vs. G, NS), however the high dose of 6-OHDA was significantly greater than other conditions receiving the lower dose of 6-OHDA (G vs. D and F, # p < 0.05, post-hoc Holm-Sidak). 1st, first injection; 2nd, second injection; SNpc, pars compacta; SNpr, pars reticulata; VTA, ventral tegmental area; CP, cerebral peduncle; scale bar, 1.0 mm; magnification, 2.5×. Error bars, ± SEM; n = 6 per condition.CC BY · PubMed Central
Figure 3 Representative coronal sections of microglia in the ventral midbrain at the level of the substantia nigra (SN) visualized by CD11b-immunoreactivity (-ir). (A) activated microglia in the SN of a rat injected in the SN with LPS 12 days prior and (B) the contralateral side. (C) low level of microglia activation 12 days following an intra-striatal injection of 6-OHDA (5.0 μg) and (D) the contralateral side showing resting microglia. Insets are 20× images taken from the area outlined in lower magnification pictures. Scale bar of inset, 100 μm; scale bar of low magnification images (2.5×), 1.0 mm).
Figure 3 Representative coronal sections of microglia in the ventral midbrain at the level of the substantia nigra (SN) visualized by CD11b-immunoreactivity (-ir). (A) activated microglia in the SN of a rat injected in the SN with LPS 12 days prior and (B) the contralateral side. (C) low level of microglia activation 12 days following an intra-striatal injection of 6-OHDA (5.0 μg) and (D) the contralateral side showing resting microglia. Insets are 20× images taken from the area outlined in lower magnification pictures. Scale bar of inset, 100 μm; scale bar of low magnification images (2.5×), 1.0 mm).CC BY · PubMed Central
Figure 4 Interleukin-1 receptor antagonist (IL-1ra) reduces the amount of tyrosine hydroxylase-immunoreactive (TH-ir) cell loss associated with LPS and 6-OHDA (t-test, *p < 0.05). Each animal received LPS into the substantia nigra (SN), 9 days later started on either IL-1ra or vehicle (Veh) which continued through the experiment, and all animals then received an intra-striatal injection of 6-OHDA (5.0 μg) and were allowed 21 days until post-mortem analyses. Magnification, 2.5×; scale bar, 1.0 mm. Error bars, ± SEM; n = 8 per condition.
Figure 4 Interleukin-1 receptor antagonist (IL-1ra) reduces the amount of tyrosine hydroxylase-immunoreactive (TH-ir) cell loss associated with LPS and 6-OHDA (t-test, *p < 0.05). Each animal received LPS into the substantia nigra (SN), 9 days later started on either IL-1ra or vehicle (Veh) which continued through the experiment, and all animals then received an intra-striatal injection of 6-OHDA (5.0 μg) and were allowed 21 days until post-mortem analyses. Magnification, 2.5×; scale bar, 1.0 mm. Error bars, ± SEM; n = 8 per condition.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 86 references

Cited by

Sorted by citations

See all 355

Related

Metadata

Authors
Koprich, J. B., Reske-Nielsen, C., Mithal, P., & Isacson, O.
Affiliations
Harvard University (US)
ORCID
Koprich, James B
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2008-02-27
Volume
5
Issue
1
Pages
8-8
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/1742-2094-5-8
PMC
PMC2292163
OpenAlex
W1990872391
Cited by
355
References
86
Citations by year
2026: 14 · 2025: 15 · 2024: 27 · 2023: 18 · 2022: 30 · 2021: 24 · 2020: 22 · 2019: 15 · 2018: 21 · 2017: 15 · 2016: 21 · 2015: 22 · 2014: 16 · 2013: 19 · 2012: 14
FWCI
13.05
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Institute of Neurological Disorders and Stroke (P50NS039793, NS-39793)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, neuroinflammation, IL-1β, dopaminergic neurons, dopaminergic neuron loss, lipopolysaccharide, 6-hydroxydopamine, microglial activation, interleukin-1 receptor antagonist, TNF-α, interferon-gamma, neurodegeneration, Parkinson's disease model
MeSH terms
Animals, Disease Models, Animal, Disease Susceptibility, Dopamine, Female, Lipopolysaccharides, Nerve Degeneration, Neuritis, Risk Factors, Substantia Nigra, Sympatholytics, Neuroimmunomodulation, Oxidopamine, Rats, Sprague-Dawley, Microglia, Antirheumatic Agents, Parkinsonian Disorders, Rats, Interleukin-1beta, Interleukin 1 Receptor Antagonist Protein

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review