The biology and role of peroxisome proliferator-activated receptors (PPARs) for physiological and pathophysiological processes has been primarily studied in peripherial organs and tissues. Little is known about the physiological role of PPARs for brain development, maintainance and function. Lessions from transgenic mouse models, however, provide evidence that PPARs may play pivotal roles for CNS development and performance. Thus, knock-out of the PPARβ/δ isoform results in disconnection of the two brain hemispheres and the expression pattern of PPARγ in late fetal development points to an important role for CNS development.

Recently it became clear, that PPARs play an important role for the pathogenesis of various disorders of the CNS. The finding that activation of PPARs, and in particular of the PPARγ isoform, suppresses inflammation in peripherial macrophages and in models of human autoimmune disease, instigated the experimental evaluation of these salutary actions for several CNS disorders that harbor an inflammatory component. Activation of all PPAR isoforms, but especially of PPARγ, has been found to be protective in murine in vitro and in vivo models of Multiple Sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARγ activation in Multiple Sclerosis patients. Likewise, Alzheimer's disease (AD) has a prominent inflammatory component that arises in response to neurodegeneration and in particular to extracellular deposition of β-amyloid peptides. The fact that non-steroidal anti-inflammatory drugs (NSAIDs) delay the onset and reduce the risk to develop AD, while they also bind to and activate PPARγ, led to the hypothesis that one dimension of NSAID protection in AD may be mediated by PPARγ. Several lines of evidence from in vitro and in vivo studies have supported this hypothesis, using AD-related transgenic cellular and animal models. Principally, anti-amyloidogenic, anti-inflammatory and insulin-sensitizing effects may account for the observed effects. A number of clinical trials have been communicated with promising results and further trials are in preparation, which aim to delineate the exact mechanism of interaction. Animal models of other neurodegenerative disease such as Parkinson's and Amyotrophic Lateral Sclerosis, both associated with a considerable degree of CNS inflammation, have been studied with a positive outcome. Yet, it is not clear whether reduction of inflammation or other, to date unknown mechanisms, account for the observed neuroprotection.