prostaglandin-d2 and benzyloxycarbonylleucyl-leucyl-leucine-aldehyde

Epidemiologic studies indicated that non-steroidal anti-inflammatory drugs (NSAIDs) might prevent or delay the clinical features of Alzheimer disease (AD). The pharmacological activity of NSAIDs is generally attributed to inhibition of cyclooxygenase and peroxisome proliferator-activated receptor gamma (PPARgamma) activation. Based on the antineoplastic and apoptotic effects of PPARgamma activation in a number of cell types, we hypothesized that NSAIDs could protect neurons by controlling the regulation of cell cycle. Recent work suggests that uncoordinated expression of cell cycle molecules and perturbation of cell cycle checkpoints may be one of the mechanisms by which post-mitotic neurons die. Since cell cycle dysfunction is not restricted to neurons in AD, we found it interesting to study the role of PPARgamma activation on cell proliferation in immortalized lymphocytes from AD patients. We report here that 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2), but not NSAIDs or thiazolidinediones inhibited the serum-mediated enhancement of cell proliferation in AD by blocking the events critical for G1/S transition. The cyclopentenone induced a partial inhibition of retinoblastoma protein phosphorylation and increased levels of the CDK inhibitor p27kip1.

Topics: Aged; Alzheimer Disease; Analysis of Variance; Apoptosis; Case-Control Studies; Cell Cycle; Cell Line; Cell Proliferation; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Electrophoretic Mobility Shift Assay; Female; Gene Expression Regulation; Humans; Leupeptins; Lymphocytes; Male; Peroxisome Proliferator-Activated Receptors; Phosphorylation; PPAR gamma; Prostaglandin D2; Retinoblastoma Protein; Time Factors

We have previously shown that nuclear factor-kappaB inhibition by adenovirus expressing mutated IkappaB-alpha or by proteasome inhibitor increases human articular chondrocytes sensibility to apoptosis. Moreover, the nuclear factor-kappaB inhibitor BAY11-7085, a potent anti-inflammatory drug in rat adjuvant arthritis, is itself a proapoptotic agent for chondrocytes. In this work, we show that BAY 11-7085 but not the proteasome inhibitor MG-132 induced a rapid and sustained phosphorylation of extracellular signal-regulated kinases (ERK1/2) in human articular chondrocytes. The level of ERK1/2 phosphorylation correlated with BAY 11-7085 concentration and chondrocyte apoptosis. 15-Deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and its precursor prostaglandin (PG) D2 but not PGE2 and PGF2alpha rescued chondrocytes from BAY 11-7085-induced apoptosis. 15d-PGJ2 markedly inhibited BAY 11-7085-induced phosphorylation of ERK1/2. BAY 11-7085 also induced ERK1/2 phosphorylation and apoptosis in human synovial fibroblasts, and these reactions were down-regulated by 15d-PGJ2. Further analysis in synovial fibroblasts showed that only molecules that suppressed BAY 11-7085-induced phosphorylation of ERK1/2 (i.e. 15d-PGJ2, PGD2, and to a lesser extent, MEK1/2 inhibitor UO126, but not prostaglandins E2 and F2alpha or peroxisome proliferator-activated receptor-gamma agonist ciglitazone) were able protect cells from apoptosis. These results suggested that the antiapoptotic effect of 15d-PGJ2 on chondrocytes and synovial fibroblasts might involve inhibition of ERK1/2 phosphorylation.

Topics: Annexin A5; Anti-Infective Agents; Apoptosis; Blotting, Western; Cartilage; Cartilage, Articular; Cell Survival; Cells, Cultured; Chondrocytes; Coloring Agents; Cysteine Endopeptidases; Dinoprost; Dinoprostone; Down-Regulation; Fibroblasts; Humans; I-kappa B Proteins; Immunologic Factors; Leupeptins; Mitogen-Activated Protein Kinases; Multienzyme Complexes; Mutation; NF-kappa B; NF-KappaB Inhibitor alpha; Nitriles; Phosphorylation; Prostaglandin D2; Proteasome Endopeptidase Complex; Receptors, Cytoplasmic and Nuclear; Sulfones; Synovial Membrane; Thiazolidinediones; Transcription Factors