Peroxisome proliferator-activated receptor (PPAR) transcription factors are pharmaceutical drug targets for treating diabetes, atherosclerosis, and inflammatory degenerative diseases. The possible mechanism of interaction between the three PPAR isotypes (␣, ␤/␦, and ␥) is not yet clear. However, this is important both for understanding transcription factor regulation and for the development of new drugs. The present study was designed to compare the effects of combinations of synthetic agonists of PPAR␣ [2-[4-[2-[4-cyclohexylbutyl (cyclohexylcarbamoyl), and PPAR␥ (rosiglitazone, ciglitazone) on inflammatory gene regulation in rat primary astrocytes. We measured cyclooxygenase-2 (COX-2) expression and prostaglandin E 2 synthesis in lipopolysaccharide (LPS)-stimulated cells. PPAR␣, PPAR␤/␦, and PPAR␥ knockdown models served to delineate the contribution of each PPAR isotype. Thiazolidinediones enhanced the LPSinduced COX-2 expression via PPAR␥-dependent pathway, whereas L-165041 and GW7647 had no influence. However, the addition of L-165041 potentiated the effect of PPAR␥ activation through PPAR␤/␦-dependent mechanism. On the contrary, PPAR␣ activation (GW7647) suppressed the effect of the combined L-165041/rosiglitazone application. The mechanism of the interplay arising from combined applications of PPAR agonists involves changes in PPAR expression levels. A PPAR␤/␦ overexpression model confirmed that PPAR␤/␦ expression level is the point at which PPAR␥ and PPAR␣ pathways converge in control of COX-2 gene expression. Thus, we discovered that in primary astrocytes, PPAR␥ has a positive influence and PPAR␣ has a negative influence on PPAR␤/␦ expression and activity. A positive/negative-feedback loop is formed by PPAR␤/␦-dependent increase in PPAR␣ expression level. These findings elucidate a novel principle of regulation in the signaling by synthetic PPAR agonists that involves modulating the interaction between PPAR␣, -␤/␦, and -␥ isoforms on the level of their expression.

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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.

The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 through assembly of extracellular perineuronal nets, which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision.

Peroxisome proliferator-activated receptor b/d (PPARb/d) is a potential regulator of neuroinflammation. Toll-like receptors (TLR) are innate immunity-related receptors of inflammatory stimuli. In the present report, we evaluate the molecular mechanisms of regulation of mRNA, protein, and transcriptional activity levels of PPARb/d by agonists of TLR4, TLR1/2, and TLR5, using lipopolysaccharide (LPS), peptidoglycan, and flagellin, respectively. We found that these stimuli increase the PPARb/d levels in astrocytes. Expression and activity of PPARb/d are separately regulated by inhibitors of p38, MEK1/ 2, extracellular signal-regulated kinases 1/2, and c-Jun Nterminal Kinase mitogen-activated protein kinases. The LPSinduced kinetics of PPARb/d expression is similar to that of the proinflammatory gene cyclooxygenase 2. Moreover, for both genes the expression depends on nuclear factor kappa-lightchain-enhancer of activated B cells and p38, and is induced after inhibition of protein synthesis. The up-regulation of the expression after inhibition of protein synthesis signifies the participation of a labile protein in regulation of PPARb/d expression. In contrast to cyclooxygenase 2, the cycloheximide-sensitive PPARb/d expression was not responsive to nuclear factor kappa-light-chain-enhancer of activated B cells inhibition. Measurements of PPARb/d mRNA stability showed that the PPARb/d mRNA levels are regulated post-transcriptionally. We found that in LPS-stimulated astrocytes, the halflife of PPARb/d mRNA was 50 min. Thus, we demonstrate that PPARb/d expression and activity are regulated in TLR agoniststimulated astrocytes by mechanisms that are widely used for regulation of proinflammatory genes.