Curcumin protects neurons against oxygen‐glucose deprivation/reoxygenation‐induced injury through activation of peroxisome proliferator‐activated receptor‐γ function

Abstract

The turmeric derivative curcumin protects against cerebral ischemic injury. We previously demonstrated that curcumin activates peroxisome proliferator-activated receptor-γ (PPARγ), a ligand-activated transcription factor involved in both neuroprotective and anti-inflammatory signaling pathways. This study tested whether the neuroprotective effects of curcumin against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury of rat cortical neurons are mediated (at least in part) by PPARγ. Curcumin (10 μM) potently enhanced PPARγ expression and transcriptional activity following OGD/R. In addition, curcumin markedly increased neuronal viability, as evidenced by decreased lactate dehydrogenase release and reduced nitric oxide production, caspase-3 activity, and apoptosis. These protective effects were suppressed by coadministration of the PPARγ antagonist 2-chloro-5-nitrobenzanilide (GW9662) and by prior transfection of a small-interfering RNA (siRNA) targeting PPARγ, treatments that had no toxic effects on healthy neurons. Curcumin reduced OGD/R-induced accumulation of reactive oxygen species and inhibited the mitochondrial apoptosis pathway, as indicated by reduced release of cytochrome c and apoptosis-inducing factor and maintenance of both the mitochondrial membrane potential and the Bax/Bcl-2 ratio. Again, GW9662 or PPARγ siRNA transfection mitigated the protective effects of curcumin on mitochondrial function. Curcumin suppressed IκB kinase phosphorylation and IκB degradation, thereby inhibiting nuclear factor-κ B (NF-κB) nuclear translocation, effects also blocked by GW9662 or PPARγ siRNA. Immunoprecipitation experiments revealed that PPARγ interacted with NF-κB p65 and inhibited NF-κB activation. The present study provides strong evidence that at least some of the neuroprotective effects of curcumin against OGD/R are mediated by PPARγ activation.

Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation

“…Bergenin is an isocoumarin, and shows the characteristic of polyphenols at the chemical structure. Wang et al (2015) reported that sparstolonin B, an isocoumarin, significantly inhibited LPS-induced expressions of MCP-1, IL-6 and TNF-α in 3T3-L1 adipocytes by activating PPARγ; Liu et al (2014) reported that curcumin inhibited the expressions of inflammatory mediators and neuron apoptosis by increasing the nuclear translocation and the transcriptional activity of PPARγ; Serra et al (2016) reported that resveratrol activated PPARγ to up-regulate the ratio of GSH/GSSG and decrease the level of ROS. Based on this, we explored the key role of PPARγ in bergenin-mediated anti-inflammatory effects.…”

Curcumin prevents reperfusion injury following ischemic stroke in rats via inhibition of NF-κB, ICAM-1, MMP-9 and caspase-3 expression

“…By using in vivo models of reperfusion injury, the molecular mechanisms of anti-inflammatory and anti-apoptotic effects of curcumin have been widely demonstrated, including the decrease in interleukin (IL)-1β, IL-2, IL-6, cyclooxygenase-2, caspase-9, tumor necrosis factor (TNF-α, P-selectin, E-selectin, MMP-2, MMP-3, activator protein (AP)-1, p38 and/or c-Jun N-terminal kinase/ mitogen-activated protein kinase pathways ( 48 – 51 ). However, the regulatory effects of curcumin on NF-κB ( 52 , 53 ), ICAM-1 ( 54 , 55 ), MMP-9 ( 56 , 57 ) and caspase-3 ( 58 , 59 ) were mainly investigated in in vitro studies. To the best of our knowledge, the effects of curcumin on the expression of the above factors have not been previously investigated in in vivo models of cerebral I/R injury.…”

Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease

“…Activation of PPARγ signaling was shown to enhance Aβ uptake by microglia and thus improve cognitive function in AD mice (Yamanaka et al, 2012 ). In our previous study, we demonstrated that curcumin was a potent agent for promoting PPARγ activity, which played a critical role in protecting against cerebral ischemic injury because of its ability to suppress the inflammatory response (Liu et al, 2013 , 2014 ). In the present study, curcumin elicited a two-fold increase in the transcriptional activity of PPARγ and prompt expression of PPARγ protein, thereby indicating the up-regulated activity of PPARγ.…”

“…One proposed mechanism for the actions of PPARγ is that the anti-inflammatory effects of PPARγ linked to cognitive impairment. Our previous study demonstrated that curcumin is a potent PPARγ agonist (Liu et al, 2011 ), and has neuroprotective effects on ischemic injury in vitro and in vivo (Liu et al, 2013 , 2014 ). However, whether the activation of PPARγ of curcumin is responsible for its neuroprotection on AD remains unclear and needs to be further investigated.…”