Effect Of β-Caryophyllene On Alzheimer-Like Phenotype And Its Mechanism

Objective:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Neuroinflammation is an invariant feature of AD. Increasing evidence indicated that modulating neuroinflammation has been a therapeutic measure for AD. Activation of cannabinoid receptor 2 (CB2) and the peroxisome proliferator-activated receptor-gamma (PPARy) pathway has beneficial effects of reducing neuroinflammatory response in the treatment of Alzheimer’s disease (AD). CB2 is suggested to trigger PPAR.y pathway. Recently, the plant metabolite β-caryophyllene was shown to selectively bind to CB2 receptor and act as a full agonist. In this study, we examined the anti-inflammatory effect of β-caryophyllene in a transgenic APP/PS1 AD model and analyzed whether this effect was mediated by CB2 and PPARy.Methods:Male double transgenic APP/PS1 mice and wild-type littermates were used. In the first set of experiments, animals were orally treated by gavage with 16,48 or 144 mg/kg of P-caryophyllene starting at the age of seven months for 10 weeks. In the second set of experiments, animals received an intraperitoneal injection of the CB2 antagonist AM630 or the PPARy antagonist GW9662 before β-caryophyllene (48 mg/kg) starting at the age of seven months for 10 weeks. The spatial memory was estimated by Morris water maze test. Immunohistochemical reaction analysis was performed to evaluate the β-amyloid. Protein levels of GFAP, Iba-1 and COX-2 were measured by western blotting. Levels of cytokines TNF-a, IL-1β and IL-10 mRNA were measured by real-time PCR. Statistical analysis was assessed by using one-way analysis of variance.Results:Administration of β-caryophyllene rescued the memory impairment of APP/PS1 mice, decreased β-amyloid burden, and reduced astrogliosis, microglial activation and expression of COX-2, TNF-a and IL-1β. AM630 or GW9662 significantly reversed protective effects of p-caryophyllene on APP/PS1 mice.Conclusions:These results suggest β-caryophyllene as an attractive molecule for development of new drugs with therapeutic potential for the treatment of AD, and the anti-inflammatory effect involves activation of CB2 receptor and PPARγ.