Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro.
Increased binding of a ligand for the peripheral benzodiazepine binding receptor is currently used in PET studies as an in vivo measurement of inflammation in diseases like multiple sclerosis and Alzheimer's disease. Although peripheral-type benzodiazepin receptors (PBRs) are abundant in many cell types and expressed in the CNS physiologically only at low levels, previous reports suggest that after experimental lesions in animal models and in human neurodegenerative/-inflammatory diseases upregulated PBR expression with increased binding of its ligand PK11195 is confined mainly to activated microglia in vivo/in situ. Because the functional role of the PBR is unknown, we confirm by immunohistochemistry and PCR (I) that this receptor is expressed on microglia in vitro and (II) that benzodiazepines modulate proliferation of microglial cells and the release of the inflammatory molecules nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in cell culture supernatants of primary rat microglia. Compared to lipopolysaccharide-activated controls the release of NO was markedly decreased in cultures treated with benzodiazepines (clonazepam, midazolam, diazepam) and the PBR ligand PK11195. Moreover, release of TNF-alpha and proliferation was significantly inhibited in the benzodiazepine-treated groups. These findings link the in vivo data of elevated PBR levels in neurodegenerative/-inflammatory diseases to a functional role and opens up possible therapeutic intervention targeting the PBR in microglia.
Wilms
H
H
Klinik für Neurologie, Christian-Albrechts-Universität zu Kiel, Niemannsweg 147, 24105 Kiel, Germany. h.wilms@neurologie.uni-kiel.de
Claasen
J
J
Röhl
C
C
Sievers
J
J
Deuschl
G
G
Lucius
R
R
D000818:Animals; D000831:Animals, Newborn; D001569:Benzodiazepines / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D005911:Gliosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009187:Myelitis / Q000378:metabolism / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018836:Inflammation Mediators; D007546:Isoquinolines; D008024:Ligands; D011963:Receptors, GABA-A; D014409:Tumor Necrosis Factor-alpha; D001569:Benzodiazepines; D009569:Nitric Oxide; C037850:PK 11195