Modulation of Paraoxonase 2 (PON2) in Mouse Brain by the Polyphenol Quercetin: A Mechanism of Neuroprotection?

Costa, Lucio G.; Tait, Leah J.; Laat, Rian de; Dao, Khoi; Giordano, Gennaro; Pellacani, Claudia; Cole, Toby B.; Furlong, Clement E.

doi:10.1007/s11064-013-1085-1

Cited by 49 publications

(48 citation statements)

References 84 publications

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“…The hypothesis of sex differences was primarily based on recent findings in our laboratory on the differential expression of the enzyme paraoxonase 2 (PON2) between males and females (Giordano et al 2011; 2013; Costa et al 2014b). In brain and in other tissues, PON2 was shown to exert antioxidant and anti-inflammatory effects (Ng et al,, 2001; Horke et al, 2007; Giordano et al, 2011; Bourquard et al, 2011; Levy et al, 2007), and higher levels of PON2 are associated with decreased susceptibility to oxidative stress and neuroinflammation (Giordano et al 2013; Costa et al 2013). We found that females express higher levels of PON2 than males, possibly because this enzyme is modulated by estrogens (Giordano et al 2013; Costa et al 2014b).…”

Section: Introductionmentioning

confidence: 99%

Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain

et al. 2016

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In addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also contribute to central nervous system (CNS) diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. DE contains more than 40 toxic air pollutants and is a major constituent of ambient particulate matter (PM), particularly of ultrafine-PM. Limited information suggest that exposure to DE may cause oxidative stress and neuroinflammation in the CNS. We hypothesized that males may be more susceptible than females to DE neurotoxicity, because of a lower level of expression of paraoxonase 2 (PON2), an intracellular anti-oxidant and anti-inflammatory enzyme. Acute exposure of C57BL/6 mice to DE (250–300 µg/m3 for 6h) caused significant increases in lipid peroxidation and of pro-inflammatory cytokines (IL-1α, IL-1β, IL-3, IL-6, TNF-α) in various brain regions (particularly olfactory bulb and hippocampus). In a number of cases the observed effects were more pronounced in male than in female mice. DE exposure also caused microglia activation, as measured by increased Iba1 (ionized calcium-binding adapter molecule 1) expression, and of TSPO (translocator protein) binding. Mice heterozygotes for the modifier subunit of glutamate cysteine ligase (the limiting enzyme in glutathione biosynthesis; Gclm+/− mice) appeared to be significantly more susceptible to DE-induced neuroinflammation than wild type mice. These findings indicate that acute exposure to DE causes neuroinflammation and oxidative stress in brain, and suggests that sex and genetic background may play important roles in modulating susceptibility to DE neurotoxicity.

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Section: Introductionmentioning

confidence: 99%

Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain

et al. 2016

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“…Quercetin is a kind of flavonoid compound with biological activities. Abundant research in the past 10 years has confirmed the anti-tumor, anti-inflammatory, anti-platelet aggregation, anti-oxygen free radicals, and pro-vascular dilation properties of quercetin (Yao et al, 2011;Costa et al, 2013). In this study, the effects of quercetin on inflammatory factors, cell apoptosis, and oxygen free radicals in the myocardial tissue of AMI rats were investigated.…”

Section: Introductionmentioning

confidence: 81%

Protective mechanism of quercetin on acute myocardial infarction in rats

Li¹,

Yang²,

Liu³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. To investigate the protective mechanism of quercetin on acute myocardial infarction (AMI) rats, an AMI rat model was established by ligating the left coronary anterior descending branch. The rats were randomly divided into the model group and low-and high-dose quercetin groups. The control group comprised sham-operated rats. The rats in the low-and high-dose quercetin groups were administered 100 and 400 mg/ kg quercetin, respectively, by gavage. The rats in the control and model groups were administered isometric normal saline once daily for one week. The mRNA and protein levels of TNF-α and IL-1β in the myocardial tissue of rats were detected in each group by real time polymerase chain reaction and enzyme-linked immunosorbent assay. Malondialdehyde (MDA) content in the myocardial tissue and superoxide dismutase (SOD) and catalase (CAT) activities were detected using a colorimetric method. The level of apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. Compared with those in the control group, the mRNA and protein levels of TNF-α, IL-1β and MDA content in the model, low-, and high-dose groups significantly increased. SOD and CAT activities decreased significantly. The cell apoptosis index increased significantly (P < 0.05). Compared with those in the model group, the mRNA and protein levels of TNF-α and IL-1β and MDA content in myocardial tissue of rats in the low-dose and high-dose groups decreased significantly. SOD and CAT activities increased significantly. The cell apoptosis index significantly reduced (P < 0.05). In conclusion, quercetin has significant anti-inflammatory, antioxidant, and anti-apoptotic effects on AMI rats and can effectively protect against myocardium damage.

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“…Because of the role of PON2 as a potent intracellular antioxidant and anti-inflammatory factor, strategies attempting to modulate its level of expression [20] should also consider sex and age as additional variables.…”

Section: Discussionmentioning

confidence: 99%

“…Female mice have consistently higher levels of PON2 than male mice, most likely owing to the differences in estradiol between sexes, as PON2 expression appears to be modulated by estrogens [11]. The polyphenolic compound quercetin, a phytoestrogen, also modulates PON2 expression and may utilize similar signaling pathways as estrogen to influence PON2 transcription [20]. Also of relevance is that, in addition to differential susceptibility to oxidative stress between wild-type and PON2-null mice [10], significant differences in oxidant susceptibility have been associated with different levels of PON2 expression, exemplified by male and female differences in PON2 levels [11], or after positive modulation of PON2 by estradiol [11] or quercetin [20].…”

Section: Introductionmentioning

confidence: 99%

Developmental expression of paraoxonase 2

Garrick

Dao

Laat

et al. 2016

Chemico-Biological Interactions

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Paraoxonase 2 (PON2) is a member of the paraoxonase gene family also comprising PON1 and PON3. PON2 functions as a lactonase and exhibits anti-bacterial as well as antioxidant properties. At the cellular level, PON2 localizes to the mitochondrial and endoplasmic reticulum membranes where it scavenges reactive oxygen species. PON2 is of particular interest as it is the only paraoxonase expressed in brain tissue and appears to play a critical role in mitigating oxidative stress in the brain. The aim of this study was to investigate the expression of PON2 at the protein and mRNA level in the brain and liver of mice through development to identify potential age windows of susceptibility to oxidative stress, as well as to compare expression of hepatic PON2 to expression of PON1 and PON3. Overall, PON2 expression in the brain was lower in neonatal mice and increased with age up to postnatal day (PND) 21, with a significant decrease observed at PND 30 and 60. In contrast, the liver showed continuously increasing levels of PON2 with age, similar to the patterns of PON1 and PON3. PON2 protein levels were also investigated in brain samples from non-human primates, with PON2 increasing with age up to the infant stage and decreasing at the juvenile stage, mirroring the results observed in the mouse brain. These variable expression levels of PON2 suggest that neonatal and young adult animals may be more susceptible to neurological insult by oxidants due to lower levels of PON2 in the brain.

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Modulation of Paraoxonase 2 (PON2) in Mouse Brain by the Polyphenol Quercetin: A Mechanism of Neuroprotection?

Cited by 49 publications

References 84 publications

Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain

Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain

Protective mechanism of quercetin on acute myocardial infarction in rats

Developmental expression of paraoxonase 2

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