Journal
NEUROSCIENCE LETTERS
Volume 426, Issue 2, Pages 117-122Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2007.08.053
Keywords
peripheral benzodiazepine receptor; macrophages; PK11195; PI3-kinase; HIV encephalitis; SIV encephalitis
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Funding
- NIMH NIH HHS [K24 MH001717, R01 MH071151, R01 MH071151-03, K24 MH01717, R01 MH064921, R01 MH064921-03, R01 MH64921, K24 MH001717-08] Funding Source: Medline
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HIV encephalitis (HIVE) is a neurodegenerative disease seen in approximately one in four terminally infected patients. Macaques infected with the simian immunodeficiency virus develop encephalitis (SIVE) very similar to the human disease. Neurodegeneration in both these conditions occurs from the effects of toxic viral proteins and neurotoxins derived from activated brain macrophages. Activated macrophages in the brain of macaques with SIVE can be labeled in vivo using positron emission tomography (PET) using PK11195, a ligand that binds the peripheral benzodiazepine receptor (PBR). However, the functional significance and mechanisms mediating increased PK11195 binding in activated brain macrophages are not known. Using post mortem tissues from macaques with SIVE and macrophages cell cultures activated with lipopolysaccharide (LPS), we show that [H-3](R)-PK11195 binding is increased in activated macrophages. Increased [H-3](R)-PK11195 binding in LPS-activated macrophages was reversed by pharmacologically inhibiting class III phosphatidylinositol-3 kinase (PI3-kinase), but was not altered by inhibiting the mitogen-activated protein kinase (MAP-kinase) pathway. Our results suggest that activated macrophages in lentiviral encephalitis show increased [H-3](R)-PK11195 binding in a PI3-kinase-dependent fashion which may help elucidate the function of PBR in activated brain macrophages in HIVE and other neuroinflammatory diseases. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
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