Gender differences in brain susceptibility to oxidative stress are mediated by levels of paraoxonase-2 expression

Abstract

Paraoxonase 2 (PON2), a member of a gene family that also includes PON1 and PON3, is expressed in most tissues, including the brain. In mouse brain, PON2 levels are highest in dopaminergic areas (e.g. striatum), and are higher in astrocytes than in neurons. PON2 is primarily located in mitochondria and exerts a potent antioxidant effect, protecting mouse CNS cells against oxidative stress. The aim of this study was to characterize PON2 expression and functions in the brains of male and female mice. Levels of PON2 (protein, mRNA, and lactonase activity) were higher in brain regions and cells of female mice. Astrocytes and neurons from male mice were significantly more sensitive (by 3–4-fold) to oxidative stress-induced toxicity than the same cells from female mice. Glutathione levels did not differ between genders. Importantly, no significant gender differences in susceptibility to the same oxidants were seen in cells from PON2−/− mice. Treatment with estradiol induced a time- and concentration-dependent increase in the levels of PON2 protein and mRNA in male (4.5-fold) and female (1.8-fold) astrocytes, which was dependent on activation of estrogen receptor alpha. In ovariectomized mice, PON2 protein and mRNA were decreased to male levels in brain regions and in liver. Estradiol protected astrocytes from wild-type mice against oxidative stress-induced neurotoxicity, but did not protect cells from PON2−/− mice. These results suggest that PON2 is a novel major intracellular factor that protects CNS cells against oxidative stress, and confers gender-dependent susceptibility to such stress. The lower expression of PON2 in males may have broad ramifications for susceptibility to diseases involving oxidative stress, including neurodegenerative diseases.

Sex differences in mitochondrial (dys)function: Implications for neuroprotection

“…Another study finds higher F 2 -isoprostane in CSF of children and infants following severe TBI independent of sex (Varma et al 2003). Further supporting the notion of sex-dependent oxidative damage are animal studies showing mitochondrial antioxidant enzymes paraoxynase-2 (PON2) (Costa et al 2013; Giordano et al 2013), thioredoxin (Trx) (Saeed et al 2009; Chen et al 2010), peroxiredoxin 6 (Prdx6) (Di et al 2012), GPx (Borras et al 2003) and glutaredoxin (GRx) (Diwakar et al 2007; Saeed et al 2009) at higher levels/activity in the female vs . male brain.…”

Altered Astrocyte–Neuronal Interactions After Hypoxia-Ischemia in the Neonatal Brain in Female and Male Rats

“…It is conceivable that these differences in mitochondrial metabolism may be connected to the identified sex-linked differential apoptotic pathways in the delayed injury cascade after HI 44,45 or increased susceptibility to oxidative stress in astrocytes from male brains. 46 …”

The neuroprotective effect of lovastatin on MPP + -induced neurotoxicity is not mediated by PON2

“…Thus, our results suggest a mechanism of 255 antioxidant action of lovastatin unrelated to the induction of PON2 256 in the striatum. However, there are in vitro and in vivo reports that 257 strongly support the differential PON2 cell expression in striatum 258 brain region induced by these compounds (Giordano et al, 2013;259 Costa et al, 2014). It is possible that PON2 may have been induced 260 by lovastatin in a smaller select group of cells.…”