inflammatory degenerative diseases, as well. PPARc is expressed in the CNS at low levels under physiological condition [13]. However, in some pathological situations, including AD, PPARc expression, but not other isoforms, was shown to be elevated [14]. These findings suggested that PPARc could play a role in regulating pathophysiological features of AD and established the basis for modulation of PPARc activity in the treatment of the disease. Therefore the present study was aimed at exploring whether CBD neuroprotective effects depend upon its activity on PPARs receptors, particularly on PPARc isoform. To this purpose, the involvement of PPARs receptors in mediating anti-inflammatory and neuroprotective effects of CBD both in vitro in primary cultured astrocytes and in vivo, in a rat model of AD-related neuroinflammation induced by the intrahippocampal injection of fibrillar Ab (1–42) peptide was evaluated. Results CBD blunted neuroinflammation sustained by astrocytes through PPARc selective activation in vitro and in vivo The first set of experiments was aimed at assessing the role of CBD (1029–1027 M) on the release of inflammatory mediators CBD Promotes Neuronal Survival and Neurogenesis induced by Ab challenge (1 mg/ml). Treatment with Ab for 24 h resulted in a significant increase of NO, IL-1b, TNFa, and S100B release, as determined by Griess reaction and ELISA experiments (Figure 1). CBD concentration dependently antagonized the enhanced release of these pro-inflammatory molecules, and blockade of PPARc with GW9662 (PPARc antagonist, 9 nM) reversed this effect. In astrocyte lysates, made 24 h after treatment, the parallel expression of iNOS, GFAP, and S100B was evaluated. CBD, in a concentration dependent manner, attenuated the Ab-induced protein up-regulation and such an effect was related to the inhibition of NFkB. In fact, in astrocyte lysates prepared 3 h after treatment, CBD down-regulated the expression of both p50 and p65. The reduction of reactive gliosis displayed by CBD was to be considered as the result of a selective PPARc dependent NFkB inhibition (Figure 2). Results from hippocampal homogenates, isolated from rats Ab- injected in the dorsal hippocampus and intraperitoneally admin- istered with CBD in the presence or absence of MK886 (PPARa antagonist) and GW9662, demonstrated that Ab induced the up- regulation of iNOS, GFAP, and S100B towards vehicle injected rats. CBD blunted Ab effect through a reasonable inhibition of NFkB, as revealed by the parallel down-regulation of both p50 Figure 1. Effect of CBD on the release of inflammatory mediators by in vitro cultured astrocytes. Ab-challenged astrocytes (1 mg/ml) were treated with CBD (1029–1027 M) in the presence of PPARa (MK886, 3 mM) or PPARc (GW9662, 9 nM) antagonist. 24 h later, NO production was determined by measuring nitrite (NO22) accumulation in the culture medium (A), whereas IL-1b, TNFa, and S100B release was determined by ELISA experiments (B,C,D). Each bar shows the mean 6 S.E.M. of five separate experiments. ***p,0.001 vs. control; up,0.05, uup,0.01, and uuup,0.001 vs. Ab-challenged cells. doi:10.1371/journal.pone.0028668.g001 PLoS ONE | www.plosone.org 2 December 2011 | Volume 6 | Issue 12 | e28668