Nuclear peroxisome proliferator activated receptor-gamma (PPARγ) as a therapeutic target to treat neurodegeneration and dependence elicited by drugs of abuse

Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that are located in the cytoplasm. After activation by specific ligands, PPARs enter the nucleus and heterodimerize with the retinoid x receptor. This heterodimer binds to PPAR response element in DNA to regulate the transcription of genes that are involved in different physiological processes, including insulin sensitization inflammatory response, and neuroprotection (Kapadia et al., 2008). The PPAR receptor family is composed of three isoforms—PPARalpha, PPARgamma and PPARdelta—that are expressed in both peripheral tissues and the brain. Endogeneous ligands of PPAR include polyunsatured fatty acids (e.g., oleic acid and arachidonic acid), prostaglandins, and low-density lipoproteins. PPAR can also be targeted by specific synthetic agonists that belong to the class of thiazolidinediones (TZDs), including pioglitazone and rosiglitazone. Because of their ability to bind PPARgamma, TZDs are approved for the treatment of type 2 diabetes and insulin resistance, improving insulin sensitivity in muscle, liver, and adipose tissue.