Implication for Thiazolidinediones (TZDs) as Novel Potential Anti- Inflammatory Drugs
PPAR-γ (peroxisome proliferator activated receptor gamma) mediates ligand-dependent transcriptional activation and repression. PPAR-γ was shown to be directly activated by naturally occurring fatty acids and several synthetic compounds such as thiazolidinediones (TZDs), agonists of PPAR-γ. TZDs are used in the first place as orally active antidiabetic agents in the treatment of type 2 diabetes. Lately, it has been implicated that TZDs might also serve as regulators of inflammatory diseases. TZDs inhibit the production of monocyte inflammatory cytokines such as RANTES, TNF-α, IL-6 and IL-1β in vitro and reduce plasma concentrations of TNF-α, sICAM-1, MCP-1, CRP and PAI-1 in vivo. TZDs can also stimulate the secretion of IL-6, IL-8 and CSF-1 in a cultured human endometrial cell line (EM42), which suggested a role of PPAR-γ in the pathogenesis of endometriosis. Although TZDs are not currently in clinical use as anti-inflammatory drugs, more recent observations were done to show that TZDs act as anti-inflammatory substances in several diseases. TZDs have anti-inflammatory, antiatherogenic and anti-oxidative stress effects reducing the incidence and severity of atherosclerosis and can reduce blood pressure. TZDs may be of therapeutic benefits in patients with Alzheimers disease (AD) based on convergent findings that insulin also plays a role in aspects of CNS function. It has been confirmed that TZDs can prevent progressive cavitation by limiting inflammation subsequent secondary damage after CNS trauma in vivo and in vitro. TZDs can also prevent experimental autoimmune encephalomyelitis. The beneficial effects of TZDs in some autoimmune or atopic diseases, such as multiple sclerosis (MS), psoriasis, atopic dermatitis and asthma, and a common chronic liver disease, nonalcoholic steatohepatitis (NASH) have been shown in several clinical trials. There are some recent data demonstrating that TZDs may have anti-inflammatory properties in animal models and in cellular systems of other diseases such as inflammatory bowel disease, arthritis, glomerulonephritis, sepsis, chronic obstructive pulmonary disease (COPD) and endometriosis. All of the above mentioned results reveal a novel potential anti-inflammatory pathway of TZDs in these diseases.
Keywords: peroxisome proliferator-activated receptor gamma (ppar-g), thiazolidinediones (tzds), inflammation
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