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Cited by 241Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

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CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease

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Pabon, Mibel M, Bachstetter, Adam D, Hudson, Charles E, Gemma, Carmelina, Bickford, Paula C·2011·Journal of Neuroinflammation
DOI 10.1186/1742-2094-8-9PMC PMC3039584
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Abstract

BACKGROUND: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of the neurodegeneration is unknown. Neuroinflammation has been clearly shown in Parkinson's disease and may be involved in the progressive nature of the disease. Microglia are capable of producing neuronal damage through the production of bioactive molecules such as cytokines, as well as reactive oxygen species (ROS), and nitric oxide (NO). The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1), produced by neurons, suppresses the activation of microglia. CX3CL1 is constitutively expressed. It is not known if addition of exogenous CX3CL1 beyond otherwise physiologically normal levels could decrease microglia activation and thereby minimize the secondary neurodegeneration following a neurotoxic insult. METHODS: The intrastriatal 6-hydroxydopamine (6-OHDA) rat model of Parkinson disease, was used to test the hypothesis that exogenous CX3CL1 could be neuroprotective. Treatment with recombinant CX3CL1 was delivered to the striatum by an osmotic minipump for 28 days beginning 7 days after the initial insult. Unbiased stereological methods were used to quantify the lesion size in the striatum, the amount of neuronal loss in the substantia nigra, and the amount of microglia activation. RESULTS: As hypothesized, CX3CL1 was able to suppress this microglia activation. The reduced microglia activation was found to be neuroprotective as the CX3CL1 treated rats had a smaller lesion volume in the striatum and importantly significantly fewer neurons were lost in the CX3CL1 treated rats. CONCLUSION: These findings demonstrated that CX3CL1 plays a neuroprotective role in 6-OHDA-induced dopaminergic lesion and it might be an effective therapeutic target for many neurodegenerative diseases, including Parkinson disease and Alzheimer disease, where inflammation plays an important role.

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Figure 1 CX3CL1 reduces 6-OHDA induced lesion volume in striatum: photomicrographs representing TH immunohistochemistry following a 6-OHDA lesion. In the dorsal striatum a noticeable decrease of TH immunoreactivity is seen in the control group (HI CX3CL1; A) as compared to the groups who received exogenous CX3CL1 for 28 days; 3 ng (B), 30 ng (C) CX3CL1 90 ng (D). Bar denotes 0.5 mm. Quantification of the TH negative zone in the striatum of 3-month-old rats as determined by the Cavalieri method of unbiased stereology, demonstrates significant decrease in the TH negative immunoreactivity when CX3CL1 was administered at the different concentrations (3, 30, and 90 ng) for 28 days (E). The group that received HI-CX3CL1 had a significant larger lesion size. These findings indicate that CX3CL1 plays a neuroprotective role in the 6-OHDA model of Parkinson disease. One way ANOVA testing [F(3,19) = 7.149, p = 0.0029]. Asterisk denotes significance (* P < 0.05) of Tukey post-hoc analysis compare to HI-CX3CL1 group.
Figure 1 CX3CL1 reduces 6-OHDA induced lesion volume in striatum: photomicrographs representing TH immunohistochemistry following a 6-OHDA lesion. In the dorsal striatum a noticeable decrease of TH immunoreactivity is seen in the control group (HI CX3CL1; A) as compared to the groups who received exogenous CX3CL1 for 28 days; 3 ng (B), 30 ng (C) CX3CL1 90 ng (D). Bar denotes 0.5 mm. Quantification of the TH negative zone in the striatum of 3-month-old rats as determined by the Cavalieri method of unbiased stereology, demonstrates significant decrease in the TH negative immunoreactivity when CX3CL1 was administered at the different concentrations (3, 30, and 90 ng) for 28 days (E). The group that received HI-CX3CL1 had a significant larger lesion size. These findings indicate that CX3CL1 plays a neuroprotective role in the 6-OHDA model of Parkinson disease. One way ANOVA testing [F(3,19) = 7.149, p = 0.0029]. Asterisk denotes significance (* P < 0.05) of Tukey post-hoc analysis compare to HI-CX3CL1 group.CC BY · PubMed Central
Figure 2 CX3CL1 suppresses microglia activation: Micrographs of OX-6 positive cells (MHCII; a marker for actived microglia) show a large increase in OX-6 staining in the control treated animals 5 weeks after a 6-OHDA in to striatum (A). Twenty-eight days infusion of CX3CL1 3 ng (B), CX3CL1 30 ng (C), or CX3CL1 90 ng (D), beginning 7 days after the insult with 6-OHDA show a clear reduction in OX-6 staining. Bar denotes 0.5 mm. Arrow denotes ameboid microglial cell (Panel A). Quantification of OX-6 immunoreactivity, by the Cavalieri method, found a significant decrease in OX-6 expression when exogenous CX3CL1 was administered (30 ng and 90 ng) as compared to the heat inactivated control (E). One way ANOVA testing [F(3,19) = 4.172, p = 0.0232]. Asterisk denotes significance (* P < 0.05) of Tukey post-hoc analysis compare to HI-CX3CL1 group.
Figure 2 CX3CL1 suppresses microglia activation: Micrographs of OX-6 positive cells (MHCII; a marker for actived microglia) show a large increase in OX-6 staining in the control treated animals 5 weeks after a 6-OHDA in to striatum (A). Twenty-eight days infusion of CX3CL1 3 ng (B), CX3CL1 30 ng (C), or CX3CL1 90 ng (D), beginning 7 days after the insult with 6-OHDA show a clear reduction in OX-6 staining. Bar denotes 0.5 mm. Arrow denotes ameboid microglial cell (Panel A). Quantification of OX-6 immunoreactivity, by the Cavalieri method, found a significant decrease in OX-6 expression when exogenous CX3CL1 was administered (30 ng and 90 ng) as compared to the heat inactivated control (E). One way ANOVA testing [F(3,19) = 4.172, p = 0.0232]. Asterisk denotes significance (* P < 0.05) of Tukey post-hoc analysis compare to HI-CX3CL1 group.CC BY · PubMed Central
Figure 3 Neurodegeneration is prevented in the substantia nigra. Photomicrographs of TH immunoreactivity in substantia nigra demonstrate a noticeable decrease in TH immunoreactivity in the control groups (A) as compared to the groups that received 3 ng (B), 30 ng (C) and 90 ng of CX3CL1 (D). Bar denotes 0.2 mm. (E) Quantification of the number of TH+ cells in the substantia nigra shows a significant decrease of TH immunoreactivity in the substantia nigra of animals who receive HI CX3CL1 (control treatment) but this affect was reversed when animals received 3, and 90 ng exogenous soluble CX3CL1 through and osmotic minipump for 28 days one week after a lesion with 6-OHDA. One-way ANOVA, [F(3,19) = 9.498, p = 0.0008]. Asterisk denotes significance (* P < 0.05) compare to HI-CX3CL1 group; † denotes significance († P < 0.05) compare to 90 ng CX3CL1 group as determined by Tukey post-hoc analysis. (F) Quantification of NeuN (neuronal nuclei marker) immunohistochemistry in substantia nigra shows a significant decrease in the HI-CX3CL1 control group as compared to the groups of animals treated with 3ng and 90 ng of CX3CL1. One-way ANOVA, [F(3,19) = 7.359, p = 0.0026]. Asterisk denotes significance (* P < 0.05) of Tukey post-hoc analysis compare to HI-CX3CL1 group. (G) An increase in the number of OX-6+ cells in substantia nigra was found in the HI-CX3CL1 control group. CX3CL1This was significantly decreased by all three doses of CX3CL1. One-way ANOVA, [F(3,19) = 19.04, P < 0.0001]. Asterisk denotes significance (* P < 0.05) compare to HI-CX3CL1 group by Tukey post-hoc analysis.
Figure 3 Neurodegeneration is prevented in the substantia nigra. Photomicrographs of TH immunoreactivity in substantia nigra demonstrate a noticeable decrease in TH immunoreactivity in the control groups (A) as compared to the groups that received 3 ng (B), 30 ng (C) and 90 ng of CX3CL1 (D). Bar denotes 0.2 mm. (E) Quantification of the number of TH+ cells in the substantia nigra shows a significant decrease of TH immunoreactivity in the substantia nigra of animals who receive HI CX3CL1 (control treatment) but this affect was reversed when animals received 3, and 90 ng exogenous soluble CX3CL1 through and osmotic minipump for 28 days one week after a lesion with 6-OHDA. One-way ANOVA, [F(3,19) = 9.498, p = 0.0008]. Asterisk denotes significance (* P < 0.05) compare to HI-CX3CL1 group; † denotes significance († P < 0.05) compare to 90 ng CX3CL1 group as determined by Tukey post-hoc analysis. (F) Quantification of NeuN (neuronal nuclei marker) immunohistochemistry in substantia nigra shows a significant decrease in the HI-CX3CL1 control group as compared to the groups of animals treated with 3ng and 90 ng of CX3CL1. One-way ANOVA, [F(3,19) = 7.359, p = 0.0026]. Asterisk denotes significance (* P < 0.05) of Tukey post-hoc analysis compare to HI-CX3CL1 group. (G) An increase in the number of OX-6+ cells in substantia nigra was found in the HI-CX3CL1 control group. CX3CL1This was significantly decreased by all three doses of CX3CL1. One-way ANOVA, [F(3,19) = 19.04, P < 0.0001]. Asterisk denotes significance (* P < 0.05) compare to HI-CX3CL1 group by Tukey post-hoc analysis.CC BY · PubMed Central

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Metadata

Authors
Pabon, M. M., Bachstetter, A. D., Hudson, C. E., Gemma, C., & Bickford, P. C.
Affiliations
  • University of South Florida (US)
  • University of Kentucky (US)
  • James A. Haley Veterans' Hospital (US)
Corresponding author
  • Gemma, Carmelina
  • Bickford, Paula C
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2011-01-25
Volume
8
Issue
1
Pages
9-9
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/1742-2094-8-9
PMC
PMC3039584
OpenAlex
W2163743819
Cited by
241
References
21
Citations by year
2026: 9 · 2025: 13 · 2024: 24 · 2023: 13 · 2022: 17 · 2021: 14 · 2020: 13 · 2019: 21 · 2018: 14 · 2017: 11 · 2016: 20 · 2015: 16 · 2014: 20 · 2013: 17 · 2012: 13
FWCI
9.89
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R21AG024165, P01 AG04418, F32AG037280, P01AG004418)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords
fractalkine, Parkinson's disease, microglial activation, neuroinflammation, neuroprotection, 6-hydroxydopamine, dopaminergic neuron loss, substantia nigra, striatum, neurodegeneration, recombinant protein therapy
MeSH terms
Animals, Corpus Striatum, Disease Models, Animal, Humans, Male, Nerve Degeneration, Neurons, Parkinson Disease, Rats, Inbred F344, Substantia Nigra, Oxidopamine, Microglia, Rats, Chemokine CX3CL1

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