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Published in final edited form as: Neurotoxicology. 2013 Sep 4;43:3–9. doi: 10.1016/j.neuro.2013.08.011

Paraoxonase-2 (PON2) in brain and its potential role in neuroprotection

Lucio G Costa 1,4, Rian de Laat 1, Khoi Dao 1, Claudia Pellacani 4, Toby B Cole 1,2,3, Clement E Furlong 3
PMCID: PMC3942372  NIHMSID: NIHMS523053  PMID: 24012887

Abstract

Paraoxonase 2 (PON2) is a member of a gene family which also includes the more studied PON1, as well as PON3. PON2 is unique among the three PONs, as it is expressed in brain tissue. PON2 is a lactonase and displays anti-oxidant and anti-inflammatory properties. PON2 levels are highest in dopaminergic regions (e.g. striatum), are higher in astrocytes than in neurons, and are higher in brain and peripheral tissues of female mice than male mice. At the sub-cellular level, PON2 localizes primarily in mitochondria, where it scavenges superoxides. Lack of PON2 (as in PON2−/− mice), or lower levels of PON2 (as in male mice compared to females) increases susceptibility to oxidative stress-induced toxicity. Estradiol increases PON2 expression in vitro and in vivo, and provides neuroprotection against oxidative stress. Such neuroprotection is not present in CNS cells from PON2−/− mice. Similar results are also found with the polyphenol quercetin. PON2, given its cellular localization and antioxidant and anti-inflammatory actions, may represent a relevant enzyme involved in neuroprotection, and may represent a novel target for neuroprotective strategies. Its differential expression in males and females may explain gender differences in the incidence of various diseases, including neurodevelopmental, neurological, and neurodegenerative diseases.

Introduction

The paraoxonases (PONs) are a family of three genes (PON1, PON2, PON3) clustered in tandem on the long arm of human chromosome 7q21–22, and on mouse chromosome 6 (Primo-Parmo et al. 1996). Phylogenetic analysis suggests that PON2 is the oldest PON family member, from which PON1 and PON3 have evolved (Draganov and LaDu, 2004). The name of these enzymes derives from paraoxon, the active metabolite of the organophosphorus (OP) insecticide parathion, which is hydrolyzed by PON1 in vitro, though not efficiently in vivo (Li et al. 2000). The name has been extended to the other two PONs, though they do not have OP esterase activity. In contrast, all three PONs are lactonases, displaying overlapping but distinct substrate specificities for lactone hydrolysis (Draganov et al. 2005). For example, all three PONs can hydrolyze a number of acyl-homoserine lactones (acyl-HCL), molecules which mediate bacterial quorum-sensing signals, important in regulating expression of virulence factors and in inducing a host inflammatory response. PON2 has the highest acyl-HCL hydrolytic activity of the three PON isozymes (Draganov et al. 2005; Stoltz et al. 2007; Teiber et al. 2008; Horke et al. 2010). Among the three PONs, the most studied is PON1, because of its long- known role in OP metabolism and in cardiovascular disease, and the presence of several relevant polymorphisms (Costa et al. 2003; Furlong et al. 2008). Table 1 summarizes the main enzymatic activities and localization of the three PONs.

Table 1.

Enzymatic activities and localization of PONs

Characteristic PON1 PON2 PON3
Lactonase ++ +++ ++
Paraoxonase +++ − −
Arylesterase +++ + +
Statinase − − +++
Antioxidant +++ +++ +++
Localization Liver, plasma HDL Wide tissue distribution Liver, plasma HDL, other tissues
Chromosome:
 Human 7 7 7
 Mouse 6 6 6
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This paper focuses on PON2, a PON isozyme less studied than PON1, which is nevertheless emerging as an important defense system toward oxidative stress and inflammation and, most importantly, was also recently found to be expressed in nervous system tissue. The focus will indeed be on recent findings which have identified and characterized PON2 in brain, identified its potential roles, and discovered gender differences in expression with potential important ramifications and novel modulators of its expression. In peripheral tissues, PON2 is considered important in modulating sensitivity to bacterial infections because of its high acyl-HCL hydrolytic activity, and may represent a pharmaceutical or dietary target for the prevention of infections (Precourt et al. 2011). PON2 also plays a significant role in atherosclerosis, as shown by studies indicating that PON2 over-expression decreases atherosclerotic lesions, while the opposite is true in PON2-null (PON2−/−) mice (Ng et al. 2006a; 2006b). In macrophages, PON2 has been suggested to protect against accumulation of triglycerides and oxidative stress, thereby attenuating the development of vascular complications in diabetes (Rosenblat et al. 2009; Meilin et al. 2010). In the gastrointestinal tract, PON2 antagonizes oxidative and inflammatory processes that may affect mucosal integrity (Levy et al. 2007).

Two common polymorphisms have been found in human PON2, an Ala/Gly substitution at position 147, and a Ser/Cys substitution at position 311 (Primo-Parmo et al. 1996; Mochizuki et al. 1998). The PON2 Ser311Cys polymorphism has been shown to affect lactonase activity (Stoltz et al. 2009). Carriers of the Cys311 allele have been found to be at risk for myocardial infarction and other cardiovascular diseases, as well as for Alzheimer’s disease in several studies (Chen et al. 2003; Shi et al. 2004; Mackness et al. 2005; Marchegiani et al. 2009; Li et al. 2012).

While PON1 and PON3 are expressed primarily in the liver, and their protein products are associated with high-density lipoproteins (HDL) in the plasma, PON2 is a ubiquitously expressed intracellular enzyme, but is not present in plasma (Mochizuki et al. 1998; Ng et al. 2001; Marsillach et al. 2008; Giordano et al. 2011). PON2 mRNA and/or protein have been detected in several tissues including liver, lung, kidney, heart, pancreas, small intestine, muscle, testis, endothelial cells, tracheal epithelial cells, and macrophages (Mochizuki et al., 1998; Ng et al., 2001; Rosenblat et al., 2003; Levy et al., 2007; Stoltz et al., 2007; Marsillach et al., 2008; Precourt et al., 2009). In mice, the highest levels were found in lung and small intestine, followed by heart and liver, with lower levels in testis, kidney and brain (Giordano et al. 2011). Of great interest in the latter study is the novel observation that in all tissues PON2 expression was always significantly higher in female mice than in male animals (Giordano et al. 2011).

PON2 as an antioxidant and anti-inflammatory factor

In several tissues, PON2 has been shown to exert an antioxidant effect (Ng et al., 2001). PON2 antagonizes oxidative stress generated by various sources in the intestine of humans and rats (Levy et al., 2007), in human vascular endothelial cells (Horke et al., 2007), in lung epithelial carcinoma cells (Horke et al., 2010), in Caco-2/15 intestinal epithelial cells (Precourt et al., 2009), and in mouse macrophages (Rosenblat et al., 2003). These anti-oxidant effects of PON2 are believed to play a major role in preventing the atherosclerotic process, as shown directly in PON2−/− mice (Horke et al. 2007; Devarajan et al. 2011). Sub-cellular distribution studies have shown that PON2 is localized primarily in the mitochondria (Devarajan et al. 2011; Giordano et al. 2011). Mitochondria are a major source of free radical-related oxidative stress (Higgins et al. 2010), and the preponderant localization of PON2 in mitochondria would support a role for this enzyme in protecting cells from oxidative damage. In HeLa cells, PON2 has been shown to bind to Coenzyme Q10 that associates with mitochondrial Complex III, and PON2 deficiency causes mitochondrial dysfunction (Devarajan et al. 2011). In human endothelial cells PON2 has been shown to reduce, indirectly but specifically, the release of superoxide from the inner mitochondrial membrane, without affecting levels of other radicals such as hydrogen peroxide and peroxynitrite (Altenhofer et al. 2010). Also of interest is that the Cys311Ser mutation, which influences lactonase activity (Stoltz et al. 2009), does not appear to affect PON2’s antioxidant properties, suggesting independent hydrolytic and antioxidant functions (Altenhofer et al. 2010).

PON2 also appears to exert anti-inflammatory effects. In the gastrointestinal tract, PON2 antagonizes oxidative and inflammatory processes that may affect mucosal integrity (Levy et al. 2007). The absence of PON2 in PON2−/− mice exacerbates the macrophage inflammatory response (Bourquard et al. 2011). Furthermore, PON2 acts as a potent anti-inflammatory agent against the inflammatory response caused by administration of pyocyanin (a quorum sensing signal factor) (Schweikert et al. 2012).

PON2 expression in the central nervous system

PON2 mRNA has been found in mouse and human brain (Primo-Parmo et al., 1996; Mochizuki et al., 1998; Ng et al., 2006a; Mackness et al. 2010), and PON2 protein had been detected in mouse (Ng et al., 2006a; Marsillach et al., 2008) and monkey brain (de Laat et al., unpublished). In a series of recent studies, the expression of PON2 has been characterized in mouse brain (Giordano et al. 2011; 2013a; Costa et al. 2013). The highest levels of PON2 protein were found in three dopaminergic regions, the substantia nigra, the striatum, and the nucleus accumbens, with lower levels in cerebral cortex, cerebellum, hippocampus and brainstem. In every brain region, PON2 levels were higher (by ~2–3-fold) in female mice than in male mice. The higher levels of PON2 in dopaminergic areas are of interest, as they may be related to the higher level of oxidative stress, due to dopamine metabolism, present in these regions. The regional distribution and gender difference of PON2 was confirmed by measurements of its lactonase activity [measured by dihydrocoumarin (DHC) hydrolysis] and of PON2 mRNA levels (Giordano et al. 2011).

In brain, and to a lesser extent in kidney and testis, but not in all tissues, the PON2 antibody recognized two bands, the lower at MW ~43 kDa, which corresponds to the reported MW of PON2, and an upper band at MW ~55 kDa. This upper band had been found at times by some investigators (Shamir et al. 2005; Ng et al. 2006a; Horke et al. 2007; 2010; Witte et al. 2011), but not by others (Ng et al. 2001; Shiner et al. 2004; Levy et al. 2007; Precourt et al. 2009), and may represent a PON2 alloform, in accordance with the two mRNA splice variants (Mochizuki et al. 1998; Horke et al. 2007; 2010). However, its exact nature has not been defined yet. Though PON2 is known to have four putative N-linked glycosylation sites at asparagine residues (Stoltz et al. 2009), deglycosylation experiments indicated that both putative isoforms are glycosylated (Giordano et al. 2011). Thus, purification of the upper band, and its analysis (e.g. by mass spectrometry) are needed to identify its structural features and other potential post-translational modifications. Nevertheless, neither band was detected in brain from PON2-deficient mice (Giordano et al. 2011).

PON1 was detected at very low levels (20- to 40-fold less than PON2) in all brain areas and did not show any regional or gender difference (Giordano et al. 2011). Such low level in tissue homogenates may be due to residual blood, as no PON1 could be detected in striatal astrocytes or neurons (Costa et al. 2013). PON3 was not detected in any brain region (either homogenate or cells).

PON2 protein (by Western blot), mRNA (by qRT-PCR) and activity (by DHC hydrolysis) levels were also examined in astrocytes and in neurons isolated from several brain regions. PON2 was significantly higher in astrocytes than in neurons in all brain regions, with the highest levels in cells isolated from the striatum. Striatal neurons and astrocytes isolated from female mice expressed higher levels of PON2 that the same cells from male animals. PON2 was also present in cortical microglia, at levels similar to those found in neurons (Giordano et al. 2011). The sub-cellular distribution of the PON2 protein was assessed in cerebellar granule neurons and cerebellar astrocytes, and found to be similar in astrocytes and neurons. Differences were found in the localization of the 43 kDa lower band (the putative PON2) and the upper 55 kDa band (the putative PON2 alternate isoform). In both cell types, the highest levels of 43 kDa PON2 were found in mitochondria, followed by membranes (microsomes), in agreement with previous observations in HeLa cells (Devarajan et al. 2011). PON2 was not detected in the cytosolic, nuclear, or cytoskeletal fractions. In contrast, the upper band PON2 isoform was expressed at highest levels in the nucleus and the cytoskeleton, neither of which contained significant levels of the 43 kDa band (Giordano et al. 2011).

PON2 protein levels were also measured in whole brain from female mice during development. Highest levels were found before birth (gestational day 20) and early after birth (postnatal days 1–7) with a gradual decline with age. A plateau of ~30% of the highest level was reached between 1 and 2 months of age (Giordano et al. 2011). Previously, PON1 hepatic mRNA and plasma paraoxonase activity were shown to increase with age, reaching adult levels at approximately 21 days of age (Li et al. 1997; Cole et al. 2003). This apparent differential developmental profile of PON1 and PON2 is of much interest, and further studies are underway in the authors’ laboratories to substantiate and expand the findings. Nevertheless, the high level of PON2 in early brain development may be relevant to protect brain cells from oxidative stress during this critical period (Hayashi, 2009).

To provide a direct indication of whether PON2 exerts a protective effect toward oxidative stress in brain cells, as observed in other tissues and cell types (Ng et al. 2001; Levy et al. 2007; Horke et al. 2007; 2010), the cytotoxicity of two known oxidants, hydrogen peroxide (H2O2) and 2,3-dimethoxy-1,4-naphtoquinone (DMNQ), was investigated in cerebellar and striatal astrocytes, and in cerebellar granule neurons (CGNs) and striatal neurons, isolated from wild-type (PON2+/+) and PON2−/− mice. Table 2 shows an example of such findings. In all instances, cells from mice lacking PON2 were more susceptible to the toxicity of both compounds, by a factor of 5 to 11-fold. The differential susceptibility was higher in astrocytes than in neurons, and was higher in cells from striatum than in those from the cerebellum, in accordance with the relative levels of PON2 expression. The protection afforded by PON2 to neurons and astrocytes was related to its ability to scavenge reactive oxygen species (ROS) upon exposure to oxidants. For example DMNQ (10 μM) increased ROS to ~400% of basal in CGNs from PON2−/− mice, and only 170% in the same cells from PON2+/+ mice (Giordano et al. 2011). Glutathione (GSH) represents the main cellular defense factor against oxidative stress. However, levels of GSH did not differ between cells (either astrocytes or neurons) isolated from striatum and cerebellum of PON2−/− and PON2+/+ mice, suggesting that the differential susceptibility to oxidants was primarily due to the presence or absence of PON2 (Giordano et al. 2011).

Table 2.

PON2 protects neurons and astrocytes from oxidant-induced toxicity

Striatal neurons PON2+/+ PON2−/−
ROS (% of basal) 180 600
Toxicity (IC50, μM) 9.6 1.2
Striatal astrocytes
ROS (% of basal) 130 500
Toxicity (IC50, μM) 42.0 3.7
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Striatal neurons or astrocytes from PON2+/+ and PON2−/− mice were treated for 60 min (for ROS measurements) or 24 h (for cytotoxicity) with 10 μM H2O2 or 5 concentrations of H2O2, respectively. ROS levels were measured by the dichlorofluorescein method, while cytotoxicity was assessed by the MTT assay. Adapted from Giordano et al. (2011).

Gender differences in PON2 expression

As indicated earlier, initial studies found different levels of expression of PON2 protein between male and female mice in all tissues examined; similarly, in brain regions, PON2 levels and lactonase activity were always higher in female than in male mice (Giordano et al. 2011), and the same gender differences in PON2 protein, mRNA and activity were found at the cellular level, in astrocytes and neurons isolated from different brain regions (Giordano et al. 2011; 2013a). As indicated earlier, the antibody recognized two bands (the 43 kDa band, corresponding to PON2, and the 55 kDa band, which may represent a PON2 alloform, but whose identity has not been clarified). The variability in the levels of the upper 55 kDa band is high, possibly due to instability of this protein or to conditions used in the Western blot, which are optimized for the detection of PON2. Of interest, however, is that the abundance of the 55 kDa band appears to differ between genders, though to a lesser extent (e.g. 2-fold vs. 3-fold in striatal astrocytes) than that of the 43 kDa band corresponding to PON2 (Giordano et al. 2013a).

The higher levels of PON2 in brain tissue from female mice may be related to a positive modulatory effect by estrogens. In striatal astrocytes from male mice, 17β-estradiol caused a time-and concentration-dependent increase in the levels of PON2 protein; a 12–24 h exposure with 200 nM estradiol increased PON2 expression to the levels found in female striatal astrocytes (Giordano et al. 2013a). Interestingly, in female astrocytes, estradiol could further increase PON2 expression, by a factor of about 2.5-fold. The estradiol effect was due to transcriptional activation of the PON2 gene, and was mediated by activation of estrogen receptors alpha (Giordano et al. 2013a). In ovariectomized mice, PON2 levels (protein and mRNA) were significantly reduced in striatum, cerebral cortex and liver, approaching the levels found in male mice. Given the previous findings of enhanced susceptibility to oxidative stress due to lack of PON2 (Giordano et al. 2011; Table 2), it was of interest to ascertain whether the 2–3-fold difference in PON2 levels between genders was sufficient to confer differential susceptibility to oxidants. This was indeed the case, as striatal astrocytes and neurons from male mice were more sensitive to H2O2 and DMNQ-induced oxidative stress and ensuing cytotoxicity (Giordano et al. 2013a). Though gender-dependent differences in other cell defense mechanisms cannot be excluded, it is noteworthy that levels of GSH did not differ between genders; as expected, they were higher in striatal astrocytes than in neurons (20 vs. 9 nmol/mg protein), but with no gender differences. Another important aspect is related to the lack of gender difference in susceptibility in cells from PON2−/− mice. Striatal astrocytes from PON2−/− mice of either gender were highly susceptible to oxidant-induced toxicity, as expected, but there were no significant female/male differences. Further evidence for a central role of PON2 in mediating gender differences in susceptibility to oxidative stress toxicity was provided by experiments with estradiol. Some of these findings are shown in Table 3. In CNS cells from PON2+/+ male mice, exposure to estradiol (200 nM, 24 h) provided protection toward toxicity induced by the two oxidants. This is not surprising, as neuroprotective actions of estrogens are well known (Simpkins et al. 2010; Arevalo et al. 2010; Azcoita et al. 2011; Arnold et al. 2012). However, the protective effect of estradiol was absent in cells from PON2−/− mice, suggesting that a major mechanism of estrogen neuroprotection may be represented by induction of PON2 (Giordano et al. 2013a).

Table 3.

Neuroprotection by estradiol and by quercetin against oxidant-induced toxicity is significantly reduced in striatal astrocytes from PON2−/− mice

PON2+/+ PON2+/+ (+E/Q) PON2−/− PON2−/− (+E/Q)
Estradiol
PON2 levels (% of basal) 100 320* 0 0
Cytotoxicity (μM) 20 53* 3 3
Quercetin
PON2 levels (% of basal) 100 210* 0 0
Cytotoxicity (μM) 37 131* 6 8
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Striatal astrocytes from PON2+/+ or PON2−/− mice were treated for 24 h with estradiol (E, 200 nM) or quercetin (Q, 20 μM). PON2 levels were measured by Western blot and are indicated as percent of control. After washout, cells were incubated for 24 h with DMNQ (4–5 concentrations), and cytotoxicity was determined by the MTT assay. Numbers shown represent IC50 values. Experiments with estradiol were carried out in astrocytes from male mice, while those with quercetin utilized mixed gender culture. Results show also the effect of gender (i.e. mixed gender cultures are less sensitive to DMNQ toxicity). Adapted from Giordano et al. (2013a) and Costa et al. (2013).

The functional consequences of a higher expression of PON2 in females may have several ramifications. First, though all the findings summarized above have been obtained in mice, initial evidence indicated that similar gender differences were present, at least in astrocytes, also in rats and humans (Giordano et al. 2013a). With regard to neurodegenerative diseases, the role of oxidative stress in the etiopathology of Parkinson’s disease (PD) is well established (Surmeier et al. 2011); of note is that the incidence of PD is 90% higher in males (Van den Eeden et al. 2003; Wirdefeld et al. 2011). Even though dopaminergic areas (striatum, substantia nigra, and nucleus accumbens) have the highest level of PON2 in both genders, levels in females are still 2 to 3-fold higher than in males (Giordano et al. 2011; 2013a; Costa et al. 2013). Lower PON2 levels in dopaminergic neurons in males may thus provide fewer defenses against oxidative stress. In this regard, of much interest are the recent findings that activation of dopamine D2 receptors in the kidney positively modulates PON2 expression, leading to a decrease in ROS production (Yang et al. 2012). In the CNS, the highest levels of dopamine D2 receptors are found in the striatum, nucleus accumbens, substantia nigra and olfactory tubercle (Beaulieu and Gainetdinov, 2011), areas that also have the highest level of PON2 expression (Giordano et al. 2011; unpublished results). If a similar mechanism as observed in kidneys also occurs in the CNS, the loss of dopamine associated with PD would lead to decreased PON2 levels, thus fostering a spiral of events further aggravating neurodegeneration. Of interest in this regard are also in vitro results showing an enhanced susceptibility of male mesencephalic astrocytes to the toxicity of the dopaminergic neurotoxin MPP+ (Sundar-Boyalla et al. 2011). Additional evidence that males may be more sensitive than females to oxidative stress-mediated CNS toxicity is provided by studies with 6-hydroxydopamine (Tamas et al. 2005; Misiak et al. 2010), methamphetamine (Dluzen et al. 2010; Bourque et al. 2011), or manganese (Madison et al. 2011), or by analysis of oxidative changes in brain mitochondria (Guevara et al. 2011). Furthermore, as PON2 is expressed in most tissues, and levels appear to be higher in females in each tissue examined (Giordano et al. 2011), the reported higher sensitivity of males to oxidative stress in heart, the higher susceptibility of males to atherosclerosis and to infections, may all be related to a differential expression of PON2 (Klein et al. 2000; Kardys et al. 2007; Wang et al. 2010).

As discussed earlier, PON2 also appears to have anti-inflammatory properties in peripheral tissues (Levy et al. 2007; Bourquard et al. 2011; Schweikert et al. 2011), and may have similar properties in the CNS. Since most neurodevelopmental and neurodegenerative disorders appear to involve neuroinflammatory processes (Niranjan, 2013; Depino, 2013), gender differences in response to neuroinflammation may also be expected. In support of this hypothesis, we have recently found that neuroinflammation (e.g. increase in levels of pro-inflammatory cytokines such as TNF-alpha and several interleukins) observed in several brain regions of mice upon exposure to diesel exhaust, is significantly more pronounced in male than in female mice (Giordano et al. 2013b).

Modulation of PON2

While there is a substantial amount of work on the modulation of PON1, which has been summarized in several reviews (Costa et al. 2005; 2011; Camps et al. 2009), more limited research has been carried out on PON2. In macrophages, PON2 expression is increased by oxidative stress (Rosenblat et al. 2003), and in vascular cells an endoplasmic reticulum stress element-like sequence was found to be present in the promoter region of PON2 (Horke et al. 2007). Arachidonic acid (Rosenblat et al. 2010), unesterified cholesterol (Shiner et al. 2007a), the licorice phytoestrogen glabidrin (Yehuda et al. 2011), and the hypocholesterolemic drug atorvastatin (Rosenblat et al. 2004) also upregulate PON2 expression in various cell types. Urokinase plasminogen activator upregulates PON2 in macrophages via NADPH oxidase and the transcription factor SREBP-2 (Fuhrman et al. 2008; 2009), while in mouse fibroblasts dexamethasone increases PON2 mRNA levels (Lim and Kim, 2009).

In one study, pomegranate juice was found to increase PON2 in macrophages through activation of the PPAR-γ and AP-1 pathways (Shiner et al. 2007b), while quercetin was reported to increase PON2 mRNA and protein in macrophages in vitro, though administration of 150 mg/day to human volunteers for six weeks was without effects (Boesch-Saadatmandi et al. 2009). Extracts of Yerba mate (Ilex paraguariensis) have been reported to increase PON2 mRNA and lactonase activity in macrophages in vitro and after in vivo administration to healthy women (Stucker Fernandez et al. 2012). A recent study has examined the induction of PON2 by quercetin in vitro (Costa et al. 2013). Quercetin was found to increase PON2 protein expression in mouse striatal astrocytes (mixed gender) by ~2-fold, and the effect was antagonized by a JNK/AP-1 inhibitor. Quercetin may thus induce a very low-level of oxidative stress (Halliwell, 2008), which in turn would modulate the JNK/AP-1 pathway (Granado-Serrano et al. 2010), causing an increase in PON2 expression. Alternatively, quercetin may induce PON2 expression by activating estrogen receptors alpha (Galluzzo et al. 2009), though this would need to be investigated further. Independent of the underlying mechanism(s), the ability of quercetin to induce PON2 may play a role in the reported neuroprotective actions of this polyphenol, which have been observed in vitro (Mercer et al. 2005; Ossola et al. 2009; Bournival et al. 2009), as well as in vivo (Barcelos et al. 2011; Lv et al. 2012; Selvakumar et al. 2012). In striatal astrocytes from PON2+/+ mice (mixed gender), exposure for 24 h to quercetin abolished the increase in ROS levels caused by H2O2 or DMNQ, and resulted in protection against the cytotoxicity of these oxidants. In contrast very limited neuroprotection was observed in the same cells isolated from PON2−/− mice (Costa et al. 2013). Some of these findings are shown in Table 3.

Conclusion and future perspectives

In recent years, PON2 has emerged as a potentially important intracellular defense mechanism against oxidative stress, particularly given its widespread tissue distribution and mitochondrial localization. Its identification and initial characterization in brain tissue suggest that this enzyme may play a relevant role in determining susceptibility to oxidative stress and neuroinflammation, and that its positive modulation may represent a novel strategy for neuroprotection.

Gender differences in PON2 expression also represent a finding of much interest. Results so far suggest that brain cells from male mice are intrinsically more susceptible to oxidative stress because of a lower expression of PON2. Gender is a variable that is often ignored in toxicological and neurotoxicological studies, though most scientists would readily acknowledge that major differences may exist between males and females in their response to toxicants, which may be ascribed to differences in exposure, toxicokinetics and metabolism, and to pharmacodynamic factors (Vahter et al. 2007; Wald and Wu, 2010; Weiss et al. 2011). As many adverse health outcomes in the CNS and other organs involve oxidative stress, this finding may explain the gender-dependent differential incidence of several diseases. The lactonase activity of PON2 and its potential anti-inflammatory actions may also pertain to other pathological processes, providing the stimulus for numerous investigations addressing gender effects.

The protective action of PON2 toward oxidative stress and neuroinflammation suggest that attempts aimed at increasing its levels of expression may be useful. So far, limited research has been carried out in this area. However, dietary or pharmacological modulation of PON2 may be of interest and may provide new avenues for neuroprotection or explanations for known neuroprotective effects. A caveat to this strategy is represented by the findings that in tumor cells PON2 is up-regulated, by still unknown mechanisms (Witte et al. 2011). Though CNS tumors have not been specifically investigated, the finding appeared to be valid for tumors of different tissues. Given its characteristics, it is not surprising that PON2 would thus provide resistance of these cells to apoptosis and that a useful therapeutic strategy would be one causing a decrease of PON2 (Witte et al. 2011).

Highlights.

  • Paraoxonase-2 (PON2) is a mitochondrial enzymes present in most tissues including the brain

  • PON2 has antioxidant effects in cells and protects cells from oxidative stress-mediated toxicity

  • Levels of PON2 are higher in brain from female mice

  • Level of expression of PON2 correspond to degree of neuroprotection

  • Estradiol and the polyphenol quercetin positively modulate PON2 expression

Acknowledgments

Research by the authors was supported by grants from the National Institute of Environmental Health Sciences under award numbers P30ES007033, P42ES004696, and R01ES009883, and from National Institute of Child Health and Human Development under award number P30HD02274. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

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