Trans-caryophyllene inhibits amyloid β (Aβ) oligomer-induced neuroinflammation in BV-2 microglial cells

doi:10.1016/j.intimp.2017.07.009

International Immunopharmacology

Volume 51, October 2017, Pages 91-98

https://doi.org/10.1016/j.intimp.2017.07.009 Get rights and content

Highlights

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TC inhibits the expression of TNF-α, IL-6, and IL-1β induced by Aβ1–42 in BV2 cells.
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TC suppresses the expression of NO, PGE2, iNOS and COX-2 in BV2 cells.
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TC inhibits the expression of TLR4 induced by Aβ1–42 in BV2 cells.
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TC suppresses phosphorylation and degradation of IκBα, nuclear translocation of p65.
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TC suppresses the activation of NF-κB transcriptional activity.

Abstract

Amyloid β (Aβ) is the major component of senile plaques (SP) in the brains of Alzheimer's disease (AD) patients, and serves as an inflammatory stimulus for microglia. Trans-caryophyllene (TC), a major component in the essential oils derived from various species of medicinal plants, has displayed its neuro-protective effects in previous studies. However, whether TC has a protective role in AD remains unknown. In this study, the effects of TC on Aβ_1–42-induced neuro-inflammation were investigated. We found that TC reduced the release of LDH in BV-2 microglial cells treated with Aβ_1–42. In addition, pretreatment of BV2 microglia with TC at concentrations of 10, 25, and 50 μM prior to Aβ stimulation led to significant inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2) production, expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and secretion of pro-inflammatory cytokines. Notably, our results indicate that TC remarkably attenuated Aβ_1–42-activated overexpression of toll-like receptor 4 (TLR4). We further demonstrated that TC markedly reversed Aβ_1–42-induced phosphorylation and degradation of IκBα, nuclear translocation of p65, and NF-κB transcriptional activity. These findings suggest that TC may have therapeutic potential for the treatment of AD.

Introduction

Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder among aging people worldwide. One of the major pathological hallmarks of AD is extra-neuronal accumulation of beta-amyloid (Aβ) [46]. Aβ is the major component of senile plaques and recent studies have shown that AD-related pathologies are caused primarily by oligomeric forms of the Aβ peptide [35]. A neuro-inflammatory response from the central nervous system (CNS) is a well-known feature of AD. These responses are interceded by the activation of microglia, the resident immune cells of the CNS [47]. Microglia are activated around the amyloid plaques in the AD brain [47]. It is well-known that oligomeric forms of Aβ serve as an inflammatory stimulus for neuronal cells. Neuronal death is caused by the release of several mediators, including inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) [2]. In addition, excessive production of reactive oxygen species (ROS), nitric oxide (NO), proteolytic enzymes, and complement factors are also involved in neuronal death in Alzheimer's disease [13]. It is well-known that microglia-mediated neuroinflammation plays a critical role in the pathogenesis of AD [50]. Microglia can identify and bind to Aβ oligomers and fibrils through receptors present on the cell surface [6]. Treatment with oligomeric Aβ stimulates the activation of microglia, which leads to the production of various pro-inflammatory cytokines, chemokines, prostaglandin E2 (PGE2), NO, ROS, and matrix metalloproteinases (MMPs), thus causing direct neuronal cell damage and furthering the pathogenesis of AD [1]. Excessive release of these factors causes neurotoxic effects and is correlated with deteriorated Aβ pathology in post-mortem AD brains and the brains of transgenic pathological rodent models [36]. One of the Toll-like receptors, Toll-like receptor 4 (TLR4) acts as an inflammation mediator. TLR4 signaling has been shown to be involved in the progression of AD [26]. It is possible that the TLR4/NF-кB signaling pathway plays a major role in Aβ-induced neuro-inflammation [28]. Multiple lines of evidence have demonstrated that nonsteroidal anti-inflammatory drugs attenuate neuro-inflammation, suggesting that inhibition of the release of pro-inflammatory mediators may offer promising therapeutic benefits for AD [14]. Intervention with drugs targeting modulation of microglia and productions of proinflammatory cytokines has become an important strategy for subverting the course of the disease [49].

Trans-caryophyllene (TC), a major component in essential oils derived from various species of medicinal plants, including clove stem oil from Syzygium aromaticum, rosemary essential oil from Rosmarinus officinalis, and hempseed oil from Cannabis sativa [17], [18], [30], [42], has been reported to possess many pharmacological properties [29]. It has been reported to exert an anti-spasmodic effect in rat tracheal smooth muscle [43]. Importantly, a recent in vivo study demonstrated that systemic treatment with TC reduced the production of cytokines, such as tumor necrosis factor-α (TNF-α), induced by intraplantar injection of carrageenan in rats, which suggests that TC may represent an important tool for the management and/or treatment of inflammatory diseases [22]. In addition, the neuroprotective effects of TC were identified in a rodent model of cerebral ischemic injury based on the finding that activation of cortical CB2R by TC ameliorates ischemic injury, potentially through modulation of AMPK/CREB signaling [12]. A recent study reported that TC could be used preventatively or therapeutically to block the development and progression of clinical and neurological signs of experimental autoimmune encephalomyelitis (EAE), which was correlated with the hindrance of immune cell activation, neuroinflammation, and demyelinating processes in the central nervous system (CNS) [3]. Interestingly, TC has been identified as a functional nonpsychoactive ligand of cannabinoid receptor type 2 (CB2R) [17]. An elevated level of CB2R has been reported in certain brain regions in human AD patients, and is mainly expressed in the microglia that surround senile plaques [44]. Notably, specific CB2R agonists have been reported to attenuate neuro-inflammation associated with the pathological progression of AD [4]. These findings suggest that TC may be able to exert a protective effect against Aβ-induced neuroinflammation in AD. In this study, our results demonstrated that TC could inhibit Aβ 1–42 oligomer-induced neuro-inflammation in BV-2 microglial cells.

Section snippets

Preparation of Aβ_1–42 solution

To generate soluble oligomers, Aβ_1–42 peptide (American Peptide Co., USA) or a scrambled Aβ_42–1 peptide was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). Vacuum evaporation was carried out for 24 h under a fume hood to remove HFIP. The peptide film was dissolved to make 5 mM stock followed by sonication for 10 min. HFIP/DMSO and DMSO were used as vehicle controls. Scrambled Aβ_42–1 peptide was used as a control for Aβ_1–42. Successful oligomerization of Aβ_1–42 was evaluated by Tris-Tricine

Results

The molecular structure of TC is shown in Fig. 1A. To determine the cellular compatibility of TC with BV-2 cells, LDH assay was performed at different TC concentrations ranging from 1 to 100 μM. TC exerted a toxic effect on cultured BV-2 cells at concentrations above 50 μM (Fig. 1B). As shown, this effect was 6 fold at 100 μM what it was at 50 μM. In addition, treatment with TC only at concentrations of 10, 25, and 50 μM did not affect the basal levels of TNF-α, IL-6, and IL-1β section, the

Discussion

AD is the most common clinically recognized form of dementia. The fundamental pathogenesis of AD remains controversial. However, increasing evidence suggests that Aβ is a critical factor in the development and progression of AD (Coomaraswamy et al., 2010). Aβ exerts both direct and indirect neurotoxicity [23]. In terms of direct toxicity, Aβ can directly cause neuronal cell death. In terms of indirect toxicity, Aβ can induce microglial cells to produce inflammatory and toxic factors that then

Acknowledgement

This work has been funded by:

1. National Natural Science Foundation of China (NO, 81671183, 81171171).

2. Science and Technology Development Foundation of Shandong Province (NO.2014GSF118117).

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Trans-caryophyllene inhibits amyloid β (Aβ) oligomer-induced neuroinflammation in BV-2 microglial cells

Highlights

Abstract

Introduction

Section snippets

Preparation of Aβ1–42 solution

Results

Discussion

Acknowledgement

Life Sci.

Am. J. Pathol.

J. Biol. Chem.

Neurosci. Lett.

Farmaco

Eur. J. Pharmacol.

Int. Immunol.

Nat. Prod. Res.

J. Neuroimmunol.

J. Biol. Chem.

Neuron

Neuropharmacology

Neuron

Int. Rev. Neurobiol.

Ann Transl Med.

Neuroscience

Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease

Curr. Pharm. Des.

Inflammatory process in Alzheimer's and Parkinson's diseases: central role of cytokines

Curr. Pharm. Des.

(−)-β-caryophyllene, a CB2 receptor-selective phytocannabinoid, suppresses motor paralysis and neuroinflammation in a murine model of multiple sclerosis

Int. J. Mol. Sci.

CB2 cannabinoid receptor as potential target against Alzheimer's disease

Front. Neurosci.

Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity

J. Neurosci.

Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E

Nature

Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways

Proc. Natl. Acad. Sci. U. S. A.

β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 mice through CB2 receptor activation and the PPARγ pathway

Pharmacology

Preparation of Aβ_1–42 solution