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

Abstract

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-γ (PPARγ) pathway; agonists of both receptors improve AD. Recently, the plant metabolite β-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 β-caryophyllene in a transgenic APP/PS1 AD model and analyzed whether this effect was mediated by CB2 and PPARγ. Results: β-Caryophyllene, given orally, prevented cognitive impairment in APP/PS1 mice, and this positive cognitive effect was associated with reduced β-amyloid burden in both the hippocampus and the cerebral cortex. Moreover, β-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-α and interleukin-1β in the cerebral cortex. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effects of β-caryophyllene on APP/PS1 mice. Conclusion: These results demonstrate that the anti-inflammatory effect of the sesquiterpene β-caryophyllene involves CB2 receptor activation and the PPARγ pathway and suggest β-caryophyllene as an attractive molecule for the development of new drugs with therapeutic potential for the treatment of AD.

Terpenes from Forests and Human Health

“…Neuroprotective effects of BCP have been reported in both AD and PD animal models. Oral treatment with BCP prevented AD-like phenotype such as cognitive impairment and activation of inflammation through CB2 receptor activation and the PPARγ pathway (105). As described above, BCP administration also exerts neuroprotective effects in rotenone-challenged rat model of PD by reducing neuroinflammation (44).…”

Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist

“…[13][14][15][16] Within this spectrum of diseases, intervention in neurodegenerative disorders using CB2 agonists and inverse agonists is arguably one of the most exciting developments in the cannabinoid field. Specifically, microglia, the resident immune and inflammatory mediators in the central nervous system (CNS), express CB2 in Alzheimer's 17,18 and Parkinson's disease 19 and amyotrophic lateral sclerosis. 6,20 The CB2 is also up-regulated during microglial migration, bacterial insult, and in response to CNS trauma.…”

“…[21][22][23] The apparent selective up-regulation of CB2 on microglia in response to insult indicates that CB2 ligands would provide selective effects in only the damaged CNS tissue. In fact, both agonists and inverse agonists of CB2 have been evaluated for efficacy in ameliorating disease progression in in vivo models of traumatic brain injury, 24,25 Alzheimer's 17,18,[26][27][28][29][30] and Parkinson's disease, 19,31,32 amyotrophic lateral sclerosis, 6,20 and multiple sclerosis. 5,[33][34][35][36][37][38][39] The comparable efficacy of agonists and inverse agonists highlights one of the major unanswered questions in this field, what is the optimum functional activity of CB2 ligands?…”

β-Caryophyllene/Hydroxypropyl-β-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the Cannabinoid Receptor Type 2 -Mediated Pathway

“…BCP generates neuroprotective effects against ischemic diseases and AD models (Choi et al, 2013; Cheng et al, 2014) through its anti-inflammation, anti-apoptosis, antioxidation effects, as well as the activation of CB2. However, studies on the effects of BCP on VD are few.…”

“…BCP can effectively prevent Alzheimer's disease (AD) (Cheng et al, 2014). Some studies revealed that BCP exerts a prominent protective effect on cerebral neurons (Assis et al, 2014) and thus might be beneficial in the prevention and treatment of cerebral diseases (Guo et al, 2014).…”