PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation

Over 25 years have passed since peroxisome proliferators-activated receptors (PPARs), were first described. Like other members of the nuclear receptors superfamily, PPARs have been defined as critical sensors and master regulators of cellular metabolism. Recognized as ligand-activated transcription factors, they are involved in lipid, glucose and amino acid metabolism, taking part in different cellular processes, including cellular differentiation and apoptosis, inflammatory modulation and attenuation of acute and chronic neurological damage in vivo and in vitro. Interestingly, PPAR activation can simultaneously reprogram the immune response, stimulate metabolic and mitochondrial functions, promote axonal growth, induce progenitor cells to differentiate into myelinating oligodendrocytes, and improve brain clearance of toxic molecules such as β-amyloid peptide. Although the molecular mechanisms and cross-talk with different molecular pathways are still the focus of intense research, PPARs are considered potential therapeutic targets for several neuropathological conditions, including degenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. This review considers recent advances regarding PPARs, as well as new PPAR agonists. We focus on the mechanisms behind the neuroprotective effects exerted by PPARs and summarise the roles of PPARs in different pathologies of the central nervous system, especially those associated with degenerative and inflammatory mechanisms.