Regulation of Inflammatory Response in Neural Cells in Vitro by Thiadiazolidinones Derivatives through Peroxisome Proliferator-activated Receptor γ Activation

Abstract

In most neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and Alzheimer disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated astrocytes and microglia and their cytotoxic agents play a crucial pathological role. Current treatments for these diseases are not effective. In the present study we investigate the effect of thiadiazolidinone derivatives, which have been recently suggested to play a role in neurodegenerative disorders. We have found that thiadiazolidinones are potent neuroprotector compounds. Thiadiazolidinones inhibited inflammatory activation of cultured brain astrocytes and microglia by diminishing lipopolysaccharide-induced interleukin 6, tumor necrosis factor ␣, inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor-␣ and nitric oxide production and, concomitantly, protected cortical neurons from cell death induced by the cell-free supernatant from activated microglia. The neuroprotective effects of thiadiazolidinones are completely inhibited by the peroxisome proliferator-activated receptor ␥ antagonist GW9662. In contrast the glycogen synthase kinase 3␤ inhibitor LiCl did not show any effect. These findings suggest that thiadiazolidinones potently attenuate lipopolysaccharide-induced neuroinflammation and reduces neuronal death by a mechanism dependent of peroxisome proliferator-activated receptor ␥ activation.

Pioglitazone Attenuates Tactile Allodynia and Thermal Hyperalgesia in Mice Subjected to Peripheral Nerve Injury

“…Both types of activated glia express PPARγ in cultures and in injured brain (9). In addition, thiazolidinedione derivatives, including pioglitazone, were reported to inhibit induction of inflammatory mediators in lipopolysaccharide-stimulated astrocyte cultures and microglia cultures (10). We therefore, propose a hypothesis that pioglitazone may control neuropathic pain through activation of PPARγ in glial cells activated at different phases.…”

Stress-induced neuroinflammation: mechanisms and new pharmacological targets

“…Later, other more detailed studies have demonstrated that PPARγ presents a high degree of expression in the rat cerebral frontal cortex, in all layers and mainly in the neurons of layer II, showing immunostaining in the nuclear and cytoplasmic compartments (44). Also, PPARγ expression has been detected in microglial cells and in astrocytes, making these cells potential targets for the PPARγ ligand anti-inflammatory activity in neurological diseases having an associated inflammatory component (45).…”

CCAAT/enhancer binding protein β deficiency provides cerebral protection following excitotoxic injury

“…At the end of the treatment period cultures, grown on glass coverslips in 24-well cell culture plates, were washed with phosphate-buffered-saline (PBS) and processed for immunocytochemistry as previously described (Luna-Medina et al, 2005). Briefly, cells were fixed for 30 minutes with 4% paraformaldehyde at 25°C, and permeabilized with 0.5% Triton X-100 for 30 minutes at 37°C.…”

“…Rat primary astrocyte and microglial cultures were prepared as previously described (Luna-Medina et al, 2005). Mouse primary C/EBPβ +/+ and C/EBPβ -/-astrocyte and microglial cultures were prepared as rat primary cells with some minor modifications.…”