Role of the peroxisome proliferator-activated receptors (PPAR)-α, β/δ and γ triad in regulation of reactive oxygen species signaling in brain

Abstract

Overwhelming evidence shows that oxidative stress is a major cause in development of brain disorders. Low activity of the reactive oxygen species (ROS)-degrading system as well as high levels of oxidative damage markers have been observed in brain tissue of patients with neurodegenerative and other brain diseases to a larger extent than in healthy individuals. Many studies aimed to develop effective and safe antioxidant strategies for the therapy or prevention of brain diseases. Nevertheless, it became clear that rigorous suppression of ROS is deleterious for normal cell functioning. Thus, approaches that can regulate the ROS levels over a wide range, from inhibition to induction, will be a powerful tool for neuroprotection. A most prominent target for such ROS management is the family of peroxisome proliferator-activated receptors (PPARs). All three members (PPAR-α, -β/δ and -γ) of this nuclear receptor subfamily form a tightly connected triad. For individual PPAR isoforms, neuroprotective properties have been well proven. Their involvement in regulation of ROS production and degradation underlies the therapeutic effects. Nevertheless, the current paradigms of the involvement of PPAR in neuroprotective therapy ignore such interconnections of PPARs and aim at antioxidant effects of individual PPAR isoforms, but do not take into account the necessity of careful regulation of ROS levels. The present review (i) summarizes the data, which support the concept of the PPAR triad in brain, (ii) demonstrates that usage of the PPAR triad allows the regulation of PPAR-dependent genes over a wide range, from inhibition to upregulation, and (iii) summarizes the known data concerning the PPAR triad involvement in regulation of ROS. Our report opens new directions in the field of PPAR/ROS-related neuroscience research.

Supplementation of omega 3 fatty acids improves oxidative stress in activated BV2 microglial cell line

“…Another way for PPAR-dependent down-regulation of ROS levels is the ability to reduce levels of ROS-producing pathways, such as NO synthase, myeloperoxidase, NAPH oxidase, cofactor tetrahydrobiopterin and argininosuccinate lyase. The PPAR receptors may induce ROS levels via upregulation of peroxisomal oxidation and, especially, by induction of Acyl-CoA oxidases (Aleshin & Reiser, 2013). Thus, the PPAR-dependent positive and negative ROS regulation is important to maintain balanced ROS levels.…”

mRNA Expression Levels of PGC-1α in a Transgenic and a Toxin Model of Huntington’s Disease

“…Furthermore, we detected a considerable elevation of cerebellar mRNA expression of NT-PGC-1a as well, in a very similar pattern to that of FL-PGC-1a. The background of this preferential increased expression of the NT variant is currently unknown; however, it might represent an important shift in the transcriptional regulation of mitochondrial functions in HD, and implicate the potential role of the N-terminal domain-regulated NRs, especially the known neuroprotective PPARs (Aleshin and Reiser 2013), as endogenous compensatory mechanisms in HD.…”

Peroxisome Proliferator-Activated Receptor α Protects Renal Tubular Cells from Gentamicin-Induced Apoptosis via Upregulating Na+/H+ Exchanger NHE1

“…A full exploration of the protective mechanism of PPARα will help to develop an effective remedy for gentamicin-induced AKI. Some studies show that reactive oxygen species downregulation is involved in the PPARα protective function in brain and renal tubular cells (10,17). The protective effect of PPARα is associated with heme oxygenase-1 expression and nuclear factor (NF)-κB inhibition (6,12 Figure 3.…”