Peripheral benzodiazepine receptor ligand PK11195 reduces microglial activation and neuronal death in quinolinic acid-injected rat striatum
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The effects of the peripheral benzodiazepine receptor (PBR) ligand, PK11195, were investigated in the rat striatum following the administration of quinolinic acid (QUIN). Intrastriatal QUIN injection caused an increase of PBR expression in the lesioned striatum as demonstrated by immunohistochemical analysis. Double immunofluorescent staining indicated PBR was primarily expressed in ED1-immunoreactive microglia but not in GFAP-immunoreactive astrocytes or NeuN-immunoreactive neurons. PK11195 treatment significantly reduced the level of microglial activation and the expression of pro-inflammatory cytokines and iNOS in QUIN-injected striatum. Oxidative-mediated striatal QUIN damage, characterized by increased expression of markers for lipid peroxidation (4-HNE) and oxidative DNA damage (8-OHdG), was significantly diminished by PK11195 administration. Furthermore, intrastriatal injection of PK11195 with QUIN significantly reduced striatal lesions induced by the excitatory amino acid and diminished QUIN-mediated caspase-3 activation in striatal neurons. These results suggest that inflammatory responses from activated microglia are damaging to striatal neurons and pharmacological targeting of PBR in microglia may be an effective strategy in protecting neurons in neurological disorders such as Huntington's disease.
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TSPO ligands have anti-inflammatory properties, suggesting a role for TSPO in neuroinflammation.
“Additionally, since TSPO ligands have anti-inflammatory properties, suggesting a role for TSPO in neuroinflammation [12;13;22], an understanding of its cell type expression in various disease states may be a key resource in how to target the TSPO in these diseases.”
From Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain (2009) · cites this paper as [22]
The apparent effects of TSPO ligands to reduce pathology in animal disease models could be mediated through effects on astrocytes.
“The apparent effects of TSPO ligands to reduce pathology in animal disease models could be mediated through effects on astrocytes (Ryu et al., 2005; Veiga et al., 2005).”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Ryu et al., 2005
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References 60 · Cited by 93
- Authors
- Ryu, J. K., Choi, H. B., & McLarnon, J. G.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- McLarnon, James G.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2005-11
- Volume
- 20
- Issue
- 2
- Pages
- 550-561
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W1996408796
- Cited by
- 93
- References
- 60
- Citations by year
- 2024: 1 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 6 · 2018: 3 · 2017: 2 · 2016: 9 · 2015: 3 · 2014: 11 · 2013: 5 · 2012: 2
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- green
- doaj.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alzheimer's Association
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- PK11195, translocator protein (TSPO), quinolinic acid, microglial activation, striatum, neuroinflammation, neuronal cell death, excitotoxicity, caspase-3, oxidative DNA damage, lipid peroxidation, inflammatory cytokines, inducible nitric oxide synthase, Huntington's disease, neuroprotection
- MeSH terms
- 8-Hydroxy-2'-Deoxyguanosine, Aldehydes, Animals, Antineoplastic Agents, Carrier Proteins, Corpus Striatum, Deoxyguanosine, Disease Models, Animal, Encephalitis, Gliosis, Huntington Disease, Isoquinolines, Ligands, Male, Membrane Proteins, Nerve Degeneration, Neurotoxins, Receptors, GABA-A, Cytokines, Rats, Sprague-Dawley, Quinolinic Acid, Microglia, Oxidative Stress, Caspases, Tumor Necrosis Factors, Rats, Nitric Oxide Synthase Type II, Ectodysplasins
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