Effects of peroxisome proliferator‐activated receptor γ ligands ciglitazone and 15‐deoxy‐Δ^12,14‐prostaglandin J₂ on rat cultured cerebellar granule neuronal viability

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been the focus of studies assessing its potential neuroprotective role. These studies have shown either neuroprotection or neurotoxicity by PPARgamma ligands. Comparison of these studies is complicated by the use of different PPARgamma ligands, mechanisms of neurotoxicity induction, and neuronal cell type. In this study, we compared the effects of the synthetic PPARgamma ligand ciglitazone with an endogenous PPARgamma ligand, 15-deoxy-delta(12,14)-prostaglandin J(2) (15-deoxy PGJ(2)), on inherent neurotoxicity and neuroprotection using a reduction in extracellular KCl in rat cultured cerebellar granule neurons (CGN). We also assessed the effects of these ligands on c-Jun protein expression, which is up-regulated on induction of low-KCl-mediated neuronal apoptosis as well as being associated with PPAR in other cell types. We showed that PPARgamma mRNA is expressed in CGN cultures and observed ciglitazone- and 15-deoxy PGJ(2)-mediated inherent neurotoxicity that was concentration and time dependent. c-Jun was only modestly increased in the presence of ciglitazone but was markedly up-regulated by 15-deoxy PGJ(2) after 12 hr. Treatment of CGN cultures with ciglitazone simultaneous with KCl withdrawal resulted in a modest, time-dependent neuroprotection. Such neuroprotection after KCl withdrawal was not observed with 15-deoxy PGJ(2). Despite the absence of neuroprotection, 15-deoxy PGJ(2) markedly inhibited the early up-regulation of c-Jun during KCl withdrawal. These studies suggest that ciglitazone and 15-deoxy PGJ(2) have markedly different effects on inherent and low-KCl-induced toxicity and c-Jun expression in CGN, indicating potential non-PPARgamma mechanisms.

Antisense-mediated Inhibition of the Plasma Membrane Calcium-ATPase Suppresses Proliferation of MCF-7 Cells

“…On days 3, 7, and 13, the cells were trypsinized and stored as cell pellets at Ϫ80°C until further processing for total protein isolates. Total protein was analyzed by immunoblotting, as described previously (26). For each sample, 40 g of total protein was loaded onto 7.5% gels.…”

PPARs in Diseases: Control Mechanisms of Inflammation

“…PPARγ ligands, in addition to reducing neuron apoptosis by decreasing the expression of neurotoxic molecules released from the microglia and astrocytes [134], have a direct effect on neuron survival by preventing LPS-or low potassium concentration-induced neuronal apoptosis [135,136]. In contrast, other findings suggest a possible role of PPARγ ligands in augmentation of neuronal death, for instance after toxic stimuli [137]. Finally, an in vivo study in mouse suggests that PPARα activation by chronic fenofibrate pretreatment before cerebral injury has a preventive neuroprotection effect via anti-oxidant and antiinflammatory mechanisms [138].…”

Cyclopentenone Eicosanoids as Mediators of Neurodegeneration: A Pathogenic Mechanism of Oxidative Stress-Mediated and Cyclooxygenase-Mediated Neurotoxicity

“…Cyclopentenone PGs potently induce apoptosis in several cancer cell lines (22,51,68,138), as well as in non-cancerous cells, including neurons (120,125), endothelial cells (63), macrophages (15,42), hepatic myofibroblasts (65), and dendritic cells (101). Cyclopentenone PGs can induce in-tracellular oxidative stress in a variety of cell types (4,55,62,65).…”

“…While cyclopentenone PGs have never been shown to be formed in brain, PGE 2 and PGD 2 , the precursors to cyclopentenone PGs, are produced abundantly in the CNS and are elevated in several neurodegenerative diseases (47,78,86 (120) and cerebellar granule cells (125) in culture, as well as in SH-SY5Y neuroblastoma cells. In SH-SY5Y cells, 15-deoxy-Δ 12,14 PGJ 2 -induced apoptosis is mediated by increased p53 expression and activation of the Fas-Fas ligand pathway (56).…”