Neuroprotective Properties of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) and its Lipid Ligands

Signalling lipids are known to control a wide array of cellular processes, including cell proliferation, apoptosis, migration, and energy metabolism. Fatty acids and their derivatives, eicosanoids, phosphoinositides, sphingolipids, some cannabinoid-like molecules bind and activate nuclear receptors, including peroxisome proliferator-activated receptors (PPARs). This subfamily of transcription factors comprises three isotypes - PPAR alpha (NR1C1), PPAR beta/delta (NR1C2), PPAR gamma (NR1C3) - which bind to specific DNA response elements, as heterodimers with retinoid X receptors. PPAR activity is modulated by post-translational modifications and cofactors, towards which they show differential affinity. The three PPARs mutually interact, being integrated in a complex system, leading to the concept of a "PPAR triad". Nevertheless, the isotypes also show distinct actions on cellular physiology and partially different tissue, ligand and target gene specificities. In the brain, while the functions of PPAR gamma and its ligands are being thoroughly investigated, the actual and potential roles of PPAR alpha and beta/delta are far from being clarified. PPAR appears especially intriguing, since it is selectively expressed in certain brain areas and neuronal/glial populations, and modulates antioxidant responses, neurotransmission, neuroinflammation, neurogenesis, and glial cell proliferation/differentiation. This receptor and its endogenous ligands, including oleoylethanoloamide (OEA) and palmitoylethanolamide (PEA), are involved in physiological and pathological responses, such as satiety, memory consolidation, and modulation of pain perception. The protective role of PPAR alpha agonists in neurodegenerative diseases and in neuropsychiatric disorders makes manipulation of this pathway highly attractive as therapeutic strategy for neuropathological conditions. In this review, we focus on the pleiotropic functions of PPAR alpha and its lipid ligands in the nervous tissue, devoting special attention to neuroprotection.