Cannabidiol Reduces Ab-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARc Involvement Giuseppe Esposito1., Caterina Scuderi1., Marta Valenza2, Giuseppina Ines Togna1, Valentina Latina1, Daniele De Filippis3, Mariateresa Cipriano 3 , Maria Rosaria Carratu` 2, Teresa Iuvone3, Luca Steardo 1 * 1 Department of Physiology and Pharmacology ‘‘Vittorio Erspamer’’, Sapienza University of Rome, Rome, Italy, 2 Department of Pharmacology and Human Physiology, University of Bari, Bari, Italy, 3 Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy Abstract Peroxisome proliferator-activated receptor-c (PPARc) has been reported to be involved in the etiology of pathological features of Alzheimer’s disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARc, which has been recently indicated as its putative binding site. CBD actions on b- amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARc was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARc, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported. Citation: Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, et al. (2011) Cannabidiol Reduces Ab-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARc Involvement. PLoS ONE 6(12): e28668. doi:10.1371/journal.pone.0028668 Editor: Rafael Linden, Universidade Federal do Rio de Janeiro, Brazil Received September 12, 2011; Accepted November 12, 2011; Published December 5, 2011 Copyright: 2011 Esposito et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was partially supported by the Italian Ministry of Education, University and Research (FIRB 2006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Competing Interests: The authors have declared that no competing interests exist. * E-mail: luca.steardo@uniroma1.it . These authors contributed equally to this work. Introduction Despite a significant increase in the understanding of the pathogenesis of Alzheimer’s disease (AD) over the past two decades, therapeutic options for treating this condition are still very disappointing. Depending on the heterogeneity of pathways that could initiate and drive sporadic AD, effective treatment for this illness rests on the ability to develop a multi-targeted approach, as used in current practice for other multi-factorial disorders [1]. According to this assumption, both natural and synthetic cannabinoids have been proposed as novel potential pharmacological tools able to blunt underlying disease processes, thus ameliorating symptoms and slowing down illness progression [2,3]. Unfortunately, Cannabis derivatives are therapeutically limited by their unwanted psychotropic effects. However, one interesting exception to this is represented by cannabidiol (CBD), the major constituent of the plant, which lacks any undesired psychomimetic action. Converging evidence provided over the last years, also by our group, demonstrated that CBD may account for a significant reduction of b amyloid (Ab) induced neuronal cell death, due to its ability to scavenge reactive oxygen species and reduce lipid peroxidation [4]. That CBD exerts anti-inflammatory properties, impairing the inducible form of nitric oxide synthase (iNOS) and interleukin 1b (IL-1b) expression which consequently decreases their release was also proved in an in vivo model of AD [5]. Moreover, CBD was reported to blunt t hyperphosphorylation in cultured neurons by reducing phosphorylation of glycogen synthase kinase 3b (GSK3b), acting as a Wnt/b-catenin pathway rescuer, although alternative mechanisms may be implicated in inducing this effect [6]. Indeed, since GSK3b also promotes amyloid precursor protein (APP) processing, and so increasing Ab generation [7], the CBD-mediated inhibition of GSK3b is likely to be effective in reducing the amyloid burden. Moreover, CBD was also described to protect neurons against glutamate toxicity [8], an effect occurring independently of the cannabinoid receptor 1 (CB1) signalling [9]. Despite such impressive properties and promising actions, the precise site at which CBD could exert its neuroinflammatory and neuroprotective effects is still not fully elucidated. The recently discovered ability of different cannabi- noids, including CBD, to display an extra-cannabinoid receptor binding activity has been highlighted by the observation that these compounds may go nuclear to exert their activity through the interaction with peroxisome proliferator-activated receptors (PPARs) [10]. The PPARs belong to the family of nuclear hormone receptors and their activity is generally regulated by steroids and lipid metabolites. At present three different PPAR isoforms (PPARa, PPARb, also called d, and PPARc) have been identified [11]; they have been reported to control the expression of genes related to lipid and glucose homeostasis and inflammatory responses [12]. A growing body of evidence suggests PPARs as drug targets for treating several dysmetabolic conditions and PLoS ONE | www.plosone.org 1 December 2011 | Volume 6 | Issue 12 | e28668