Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression

Hans, Grégory; Wislet, Sabine; Lallemend, François; Robe, Pierre A.; Rogister, Bernard; Belachew, Shibeshih; Nguyen, Laurent; Malgrange, Brigitte; Moonen, Gustave; Rigo, Jean-Michel

doi:10.1016/j.bcp.2004.11.029

Cited by 41 publications

(27 citation statements)

References 52 publications

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“…By using RT-PCR, no PBR transcript was shown previously by Canat et al (1993) and Hans et al (2005). On the contrary, some evidences have demonstrated that PBR mRNA is expressed in human Fas-resistant T-cell line Jurkat (Decaudin et al, 2002).…”

Section: Discussionmentioning

confidence: 93%

“…The PBR amino acidic substitution H162R may explain why some authors have not detected protein in Jurkat cells by using the monoclonal anti-PBR 8D7 antibody (Carayon et al, 1996;Hans et al, 2005), which recognized the human PBR C-terminal region that contains His162 instead of arginine.…”

Section: Discussionmentioning

confidence: 99%

“…A peculiar condition is represented by the cell line Jurkat, deriving from a patient affected by acute lymphoblastic leukemia, in which the presence of PBR mRNA and protein is still debated. Indeed, several authors have failed to detect PBR expression (Canat et al, 1993;Carayon et al, 1996;Hans et al, 2005). Nevertheless, in the Jurkat cell line, PBR-selective ligands have been demonstrated to induce the same effects observed in other PBR-expressing cells (Zisterer et al, 2000).…”

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confidence: 99%

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Peripheral Benzodiazepine Receptor: Characterization in Human T-Lymphoma Jurkat Cells

Costa

Salvetti²,

Rossi³

et al. 2005

Mol Pharmacol

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Peripheral benzodiazepine receptor (PBR) has been considered a promising drug target for cancer therapy, and several ligands have been developed for this purpose. Human T-lymphoma Jurkat cells have been considered as lacking PBR and are often used as negative control to prove the specificity of PBR ligands effects. It is surprising that we evidenced PBR protein expression in this cell line by means of Western blotting and immunocytochemistry assays using specific anti-PBR antibodies. The pharmacological profile of the classic ligands showed that PK11195 was the most potent inhibitor in the radioligand binding assays followed by Ro5-4864 and diazepam, whereas clonazepam, a specific ligand for the central-type receptor, showed a K i Ͼ1.0 ϫ 10 Ϫ4 M. By a combined strategy of reverse transcriptase-polymerase chain reaction and Southern blot experiments, we succeeded in isolating and cloning the full-length

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Peripheral Benzodiazepine Receptor: Characterization in Human T-Lymphoma Jurkat Cells

Costa

Salvetti²,

Rossi³

et al. 2005

Mol Pharmacol

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“…Of greater concern is that ligands have been shown to participate in cellular functions independently of the TSPO (Gonzalez-Polo et al, 2005;Hans et al, 2005;Walter et al, 2005). Also perplexing is the fact that the so-called agonists and antagonists of the TSPO often exert the same effects (Chelli et al, 2001).…”

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confidence: 98%

Downregulation of the 18‐kDa translocator protein: Effects on the ammonia‐induced mitochondrial permeability transition and cell swelling in cultured astrocytes

Panickar

Jayakumar

Rao

et al. 2007

Glia

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Hepatic encephalopathy (HE) is a major neurological complication in patients with severe liver disease. While the pathogenesis of HE is unclear, elevated blood and brain ammonia levels are believed to be major etiological factors, and astrocytes appear to be the primary target of its toxicity. A notable feature of ammonia neurotoxicity is an upregulation of the 18-kDa translocator protein (TSPO) (formerly referred to as the peripheral benzodiazepine receptor or PBR), which is found on the outer mitochondrial membrane. However, the precise significance of this upregulation is unclear. To examine its potential role in ammonia-induced astrocyte dysfunction, we downregulated the TSPO using antisense oligonucleotides, and examined whether such downregulation could alter two prominent features of ammonia gliotoxicity, namely, the mitochondrial permeability transition (MPT) and astrocyte swelling. Nontransfected cultures treated with NH4Cl (5 mM; 48 h) showed a significant increase in astrocyte cell volume (37.5%). In cultured astrocytes transfected with TSPO antisense oligonucleotides, such cell swelling was reduced to 17%, but this change was not significantly different from control cell volume. Similarly, nontransfected cultures treated with NH4Cl (5 mM; 24 h) exhibited a 40% decline in the cyclosporin A-sensitive mitochondrial inner membrane potential (DeltaPsi(m)) (P < 0.01) (a measure of the MPT). By contrast, cells transfected with TSPO antisense oligonucleotides did not display a significant loss of the DeltaPsi(m) following ammonia exposure. Our findings highlight the important role of the TSPO in the mechanism of ammonia neurotoxicity.

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“…Interestingly, PK11195, but not Ro5-4864, exerts anti-inflammatory actions on mononuclear phagocytes, regulating the release of IL-1b (Klegeris et al, 2000). In addition, it is important to consider that both PK11195 and Ro5-4864 may have additional cellular actions that are independent of TSPO (Gonzalez-Polo et al, 2005;Hans et al, 2005;Papadopoulos et al, 2006;Walter et al, 2005). Therefore, PK11195 and Ro5-4864 may have different and complementary mechanisms of action on different cell populations.…”

Section: Discussionmentioning

confidence: 95%

Translocator protein (18 kDa) is involved in the regulation of reactive gliosis

Veiga

Carrero

Pernía

et al. 2007

Glia

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Translocator protein (18 kDa) (TSPO), previously known as peripheral‐type benzodiazepine receptor, is a critical component of the mitochondrial permeability transition pore. Brain inflammation results in the induction of the expression of TSPO in glial cells and some TSPO ligands decrease reactive gliosis after brain injury. However, since some TSPO ligands are neuroprotective, their effects on reactive gliosis may be the consequence of a reduced neurodegeneration. To assess whether TSPO ligands can modulate reactive gliosis in absence of neuronal death, we have tested their effects on the inflammatory response induced in the hippocampus of male rats by the intracerebroventricular infusion of lipopolysaccharide (LPS). LPS treatment did not induce neuronal death, assessed by Fluoro jade‐B staining, but increased the number of cells immunoreactive for vimentin and MHC‐II, used as markers of reactive astrocytes and reactive microglia, respectively. Furthermore, LPS produced an increase in the number of proliferating microglia. The TSPO ligand PK11195 reduced the number of MHC‐II immunoreactive cells and the proliferation of microglia in LPS treated rats. In contrast, another TSPO ligand, Ro5‐4864, did not significantly affect the response of microglia to LPS. Neither PK11195 nor Ro5‐4864 affected the LPS‐mediated increase in the number of vimentin‐immunoreactive astrocytes at the time point studied, although PK11195 reduced vimentin immunoreactivity. These findings identify TSPO as a potential target for controlling neural inflammation, showing that the TSPO ligand PK11195 may reduce microglia activation by a mechanism that is independent of the regulation of neuronal survival. © 2007 Wiley‐Liss, Inc.

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Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression

Abstract: Category

Cited by 41 publications

References 52 publications

Peripheral Benzodiazepine Receptor: Characterization in Human T-Lymphoma Jurkat Cells

Peripheral Benzodiazepine Receptor: Characterization in Human T-Lymphoma Jurkat Cells

Downregulation of the 18‐kDa translocator protein: Effects on the ammonia‐induced mitochondrial permeability transition and cell swelling in cultured astrocytes

Translocator protein (18 kDa) is involved in the regulation of reactive gliosis

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