β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway

Background/Aims: The activation of cannabinoid receptor 2 (CB2) has the beneficial effect of reducing neuroinflammatory response in the treatment of Alzheimer's disease (AD) and is suggested to trigger the peroxisome proliferator-activated receptor-gamma (PPAR gamma) pathway; agonists of both receptors improve AD. Recently, the plant metabolite beta-caryophyllene was shown to selectively bind to CB2 receptor and act as a full agonist. Methods: In this study, we examined the anti-inflammatory effect of beta-caryophyllene in a transgenic APP/PS1 AD model and analyzed whether this effect was mediated by CB2 and PPAR gamma. Results: beta-Caryophyllene, given orally, prevented cognitive impairment in APP/PS1 mice, and this positive cognitive effect was associated with reduced beta-amyloid burden in both the hippo campus and the cerebral cortex. Moreover, beta-caryophyllene reduced astrogliosis and microglial activation as well as the levels of COX-2 protein and the mRNA levels of the proinflammatory cytokines tumor necrosis factor-a and interleukin-1 beta in the cerebral cortex. The use of the CB2 antagonist AM630 or the PPAR gamma antagonist GW9662 significantly reversed the protective effects of beta-caryophyllene on APP/PS1 mice. Conclusion: These results demonstrate that the anti-inflammatory effect of the sesquiterpene beta-caryophyllene involves CB2 receptor activation and the PPAR gamma pathway and suggest beta-caryophyllene as an attractive molecule for the development of new drugs with therapeutic potential for the treatment of AD. (C) 2014 S. Karger AG, Basel