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Cited by 411Cannabis and Cannabinoid ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement

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Esposito, Giuseppe, Scuderi, Caterina, Valenza, Marta, Togna, Giuseppina Ines, Latina, Valentina, De Filippis, Daniele, Cipriano, Mariateresa, Carratù, Maria Rosaria, Iuvone, Teresa, Steardo, Luca·2011·PLoS ONE
DOI 10.1371/journal.pone.0028668PMC PMC3230631
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Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported.

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Figure 1 Effect of CBD on the release of inflammatory mediators by in vitro cultured astrocytes. Aβ-challenged astrocytes (1 µg/ml) were treated with CBD (10−9–10−7 M) in the presence of PPARα (MK886, 3 µM) or PPARγ (GW9662, 9 nM) antagonist. 24 h later, NO production was determined by measuring nitrite (NO2 −) accumulation in the culture medium (A), whereas IL-1β, TNFα, and S100B release was determined by ELISA experiments (B,C,D). Each bar shows the mean ± S.E.M. of five separate experiments. ***p<0.001 vs. control; °p<0.05, °°p<0.01, and °°°p<0.001 vs. Aβ-challenged cells.
Figure 1 Effect of CBD on the release of inflammatory mediators by in vitro cultured astrocytes. Aβ-challenged astrocytes (1 µg/ml) were treated with CBD (10−9–10−7 M) in the presence of PPARα (MK886, 3 µM) or PPARγ (GW9662, 9 nM) antagonist. 24 h later, NO production was determined by measuring nitrite (NO2 −) accumulation in the culture medium (A), whereas IL-1β, TNFα, and S100B release was determined by ELISA experiments (B,C,D). Each bar shows the mean ± S.E.M. of five separate experiments. ***p<0.001 vs. control; °p<0.05, °°p<0.01, and °°°p<0.001 vs. Aβ-challenged cells.CC BY · PubMed Central
Figure 2 Effects of CBD on Aβ-induced iNOS, GFAP, S100B, and p50/p65 expression in rat astrocytes. Aβ-challenged cells (1 µg/ml) were treated with CBD (10−9–10−7 M) in the presence of PPARα (MK886, 3 µM) or PPARγ (GW9662, 9 nM) antagonist. iNOS, GFAP, and S100B expression was evaluated by Western blot 24 h after treatments. NF-κB activation was evaluated 3 h following treatments by Western blot analysis of its component p50 and p65. Figure shows results of Western blot analysis of proteins (A) and densitometric analysis of corresponding bands (B). Results are the mean ± S.E.M. of four separate experiments. ***p<0.001 vs. control; °p<0.5, °° p<0.01, and °°°p<0.001 vs. Aβ-challenged cells.
Figure 2 Effects of CBD on Aβ-induced iNOS, GFAP, S100B, and p50/p65 expression in rat astrocytes. Aβ-challenged cells (1 µg/ml) were treated with CBD (10−9–10−7 M) in the presence of PPARα (MK886, 3 µM) or PPARγ (GW9662, 9 nM) antagonist. iNOS, GFAP, and S100B expression was evaluated by Western blot 24 h after treatments. NF-κB activation was evaluated 3 h following treatments by Western blot analysis of its component p50 and p65. Figure shows results of Western blot analysis of proteins (A) and densitometric analysis of corresponding bands (B). Results are the mean ± S.E.M. of four separate experiments. ***p<0.001 vs. control; °p<0.5, °° p<0.01, and °°°p<0.001 vs. Aβ-challenged cells.CC BY · PubMed Central
Figure 3 Effects of CBD on Aβ-induced iNOS, GFAP, S100B, calbindin, and p50/p65 expression in rat hippocampi. Results of Western blot analyses of iNOS, GFAP, S100B, calbindin, and p50/p65 performed on rat hippocampus homogenates (A) and densitometric analysis of corresponding bands (B). Results are the mean ± S.E.M. of three separate experiments. *** p<0.001 vs. vehicle inoculated rats; °°p<0.01 and °°° p<0.001 vs. Aβ-inoculated rats.
Figure 3 Effects of CBD on Aβ-induced iNOS, GFAP, S100B, calbindin, and p50/p65 expression in rat hippocampi. Results of Western blot analyses of iNOS, GFAP, S100B, calbindin, and p50/p65 performed on rat hippocampus homogenates (A) and densitometric analysis of corresponding bands (B). Results are the mean ± S.E.M. of three separate experiments. *** p<0.001 vs. vehicle inoculated rats; °°p<0.01 and °°° p<0.001 vs. Aβ-inoculated rats.CC BY · PubMed Central
Figure 4 Effects of CBD on reactive gliosis, neuronal survival, and neurogenesis in rat hippocampi. A: representative photomicrographs of the CA1 area of rat hippocampus showing the results of immunohistochemical evaluation of GFAP. B: representative photomicrographs showing the results of Nissl staining of the whole rat hippocampus (2X magnification) and the corresponding CA1 region (10X magnification). C: immunofluorescence photomicrographs showing a particular (10X magnification) of DCX-labeled cells in the dentate gyrus (DG) of rat hippocampi.
Figure 4 Effects of CBD on reactive gliosis, neuronal survival, and neurogenesis in rat hippocampi. A: representative photomicrographs of the CA1 area of rat hippocampus showing the results of immunohistochemical evaluation of GFAP. B: representative photomicrographs showing the results of Nissl staining of the whole rat hippocampus (2X magnification) and the corresponding CA1 region (10X magnification). C: immunofluorescence photomicrographs showing a particular (10X magnification) of DCX-labeled cells in the dentate gyrus (DG) of rat hippocampi.CC BY · PubMed Central

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Metadata

Authors
Esposito, G., Scuderi, C., Valenza, M., Togna, G. I., Latina, V., De Filippis, D., Cipriano, M., Carratù, M. R., Iuvone, T., & Steardo, L.
Affiliations
  • Sapienza University of Rome (IT)
  • University of Bari Aldo Moro (IT)
  • University of Naples Federico II (IT)
Corresponding author
Steardo, Luca
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-12-05
Volume
6
Issue
12
Pages
e28668
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0028668
PMC
PMC3230631
OpenAlex
W2107076749
Cited by
410
References
41
Citations by year
2026: 23 · 2025: 24 · 2024: 53 · 2023: 41 · 2022: 49 · 2021: 48 · 2020: 45 · 2019: 22 · 2018: 18 · 2017: 26 · 2016: 16 · 2015: 13 · 2014: 8 · 2013: 13 · 2012: 10
FWCI
7.26
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
Funders
Ministero dell’Istruzione, dell’Università e della Ricerca
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
cannabidiol, PPARγ, Alzheimer's disease, amyloid-beta, neuroinflammation, hippocampal neurogenesis, reactive gliosis, neuroprotection, PPARγ antagonist, neurotoxicity
MeSH terms
Animals, Astrocytes, Binding Sites, Brain, Cannabidiol, Hippocampus, Inflammation, Male, Neurons, Nitric Oxide, Protein Binding, Time Factors, Amyloid beta-Peptides, Rats, Sprague-Dawley, Protein Structure, Tertiary, PPAR gamma, Rats, Neurogenesis

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