CBD Promotes Neuronal Survival and Neurogenesis Figure 3. Effects of CBD on Ab-induced iNOS, GFAP, S100B, calbindin, and p50/p65 expression in rat hippocampi. Results of Western blot analyses of iNOS, GFAP, S100B, calbindin, and p50/p65 performed on rat hippocampus homogenates (A) and densitometric analysis of corresponding bands (B). Results are the mean 6 S.E.M. of three separate experiments. *** p,0.001 vs. vehicle inoculated rats; uup,0.01 and uuu p,0.001 vs. Ab-inoculated rats. doi:10.1371/journal.pone.0028668.g003 versus controls. In line with the previously obtained results, CBD activity was unaffected by PPARa antagonism, whereas its effect was almost completely abolished by GW9662, the PPARc antagonist (Figure 4, C). Discussion Chronic neuroinflammation implicates protracted activation of both microglial and astroglial cells, with the consequent sustained release of pro-inflammatory molecules [15,16], that act in an autocrine way to self-perpetuate reactive gliosis and in a paracrine way to kill neighboring neurons, thus expanding the neuropath- ological damage. Once started, neuroinflammation promotes neuronal death, powering a vicious cycle responsible for the progression of the pathology [17]. The possibility of interfering with this detrimental cycle by molecules which can reduce reactive gliosis has been proposed as a novel rationale to develop drugs able to blunt neuronal damage and consequently slow the course of AD. Results from the present study prove the selective involvement of PPARc in the anti-inflammatory and neuroprotective effects of CBD here observed either in vitro and in vivo. In addition, CBD significantly promoted neurogenesis in Ab injured rat hippocampi, much expanding its already wide spectrum of beneficial actions exerted in AD models, a non negligible effect, due to its capability to activate PPARc. CBD was already reported to exert a marked anti-inflammatory effect through the A2A and 5HT1A receptors [18,19], as well as to improve brain function [20]. In addition, it has been already demonstrated that CBD markedly downregulate reactive gliosis by PLoS ONE | www.plosone.org 4 December 2011 | Volume 6 | Issue 12 | e28668