Modulation of the Purinergic P2X7Receptor Attenuates Lipopolysaccharide-Mediated Microglial Activation and Neuronal Damage in Inflamed Brain
Open accessAbstract
We investigated the involvement and roles of the ionotropic purinergic receptor P2X 7 R in microglia in mediating lipopolysaccharide (LPS)-induced inflammatory responses and neuronal damage in rat striatum. A detailed in vivo study showed that LPS injection into striatum markedly increased the expression of P2X 7 R in microglia compared with control (saline)-injected animals. Additionally, LPS injection upregulated a broad spectrum of proinflammatory mediators, including inducible nitric oxide synthase (nitric oxide production marker), 3-nitrotyrosine (peroxynitrite-mediated nitration marker), 4-hydroxynonenal (lipid peroxidation marker), and 8-hydroxy-2′-deoxyguanosine (oxidative DNA damage marker), and reduced neuronal viability. The P2X 7 R antagonist oxidized ATP (oxATP) was effective in attenuating expressions of all inflammatory mediators and in addition inhibited LPS-induced activation of the cellular signaling factors p38 mitogen-activated protein kinase and transcriptional factor nuclear factor κB. Most importantly,in vivo, oxATP blockade of P2X 7 R also reduced numbers of caspase-3-positive neurons and increased neuronal survival in LPS-injected brain.In vitro, LPS stimulation of cultured human microglia enhanced cellular expressions of a host of proinflammatory factors, including cyclooxygenase-2, interleukin-1β (IL-1β), IL-6, IL-12, and tumor necrosis factor-α; all factors were inhibited by oxATP. A novel finding was that LPS potentiated intracellular [Ca 2+]i mobilization induced by the P2X 7 R ligand 2′,3′-O-(4-benzoyl-benzoyl) ATP, which could serve as a mechanistic link for P2X 7 R amplification of inflammatory responses. Our results suggest critical roles for P2X 7 R in mediating inflammation and inhibition of this subtype purinergic receptor as a novel therapeutic approach to reduce microglial activation and confer neuroprotection in inflamed and diseased brain.
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In previous studies, LPS caused neuronal death when injected in the striatum of rats and gerbils but not mice.
“In previous studies, LPS caused neuronal death when injected in the striatum of rats and gerbils but not mice, as indicated by silver or cresyl violet staining (Zito et al., 2001;Choi et al., 2007).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Choi et al., 2007
The Discussion reports fewer striatal neurons three days after LPS injection in rats, supporting the rat neuronal-loss finding. The paper does not establish the claimed results for gerbils or mice, and its Methods describe NeuN and caspase-3 immunostaining rather than silver or cresyl violet staining. (LLM, conf=0.88)
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- Authors
- Choi, H. B., Ryu, J. K., Kim, S. U., & McLarnon, J. G.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- McLarnon, James G.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-05-02
- Volume
- 27
- Issue
- 18
- Pages
- 4957-4968
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672082
- OpenAlex
- W2072598425
- Cited by
- 173
- References
- 5
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 10 · 2020: 7 · 2019: 7 · 2018: 7 · 2017: 11 · 2016: 3 · 2015: 16 · 2014: 12 · 2013: 14 · 2012: 12
- FWCI
- 6.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- Heart and Stroke Foundation of Canada
- Korea Science and Engineering Foundation
- Fondation pour la Recherche sur Alzheimer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- P2X7 receptor, microglial activation, lipopolysaccharide, neuroinflammation, neuronal injury, striatum, oxidized ATP, neuroprotection, p38 MAPK, NF-κB, caspase-3, calcium mobilization, oxidative stress, nitric oxide, purinergic signaling
- MeSH terms
- Animals, Brain, Cells, Cultured, Humans, Inflammation, Lipopolysaccharides, Male, Neurons, Rats, Sprague-Dawley, Microglia, Receptors, Purinergic P2, Rats, Receptors, Purinergic P2X7
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