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

Lou, Jie; Teng, Zhipeng; Zhang, Liangke; Yang, Jiadan; Ma, Lianju; Wang, Fang; Tian, Xingui; An, Ruidi; Yang, Mei; Zhang, Qian; Xu, Li; Dong, Zhi

doi:10.3389/fphar.2017.00002

Cited by 38 publications

(22 citation statements)

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“…This pathway is involved in the regulation of cell growth, proliferation and differentiation through a series of responses and is a classic anti-apoptotic and pro-survival signal transduction pathway. In recent years, studies have shown that the CB 2 R agonist exhibits a neuroprotective effect in the CNS by activating the PI3K/Akt signaling pathway [ 42 ], which reduces cognitive impairment, increases cerebral blood flow, and inhibits neuronal apoptosis in an animal model of VD [ 43 ]. Akt is a common upstream regulator of both mTOR and NF-κB pathways.…”

Section: Discussionmentioning

confidence: 99%

Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2

Luo

Yang

et al. 2018

Chin Med

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BackgroundCerebral hypoperfusion is a pivotal risk factor for vascular dementia (VD), for which effective therapy remains inadequate. Persistent inflammatory responses and excessive chemotaxis of microglia/macrophages in the brain may accelerate the progression of VD. Endocannabinoids are involved in neuronal protection against inflammation-induced neuronal injury. Cannabinoids acting at cannabinoid receptor 2 (CB2R) can decrease inflammation. Based on the identification of paeoniflorin (PF) as a CB2R agonist, we investigated the neuroprotective and microglia/macrophages M1 to M2 polarization promoting effects of PF in a permanent four-vessel occlusion rat model.MethodsOne week after surgery, PF was intraperitoneally administered at a dose of 40 mg/kg once a day for 28 successive days. The effects of PF on memory deficit were investigated by a Morris water maze test, and the effects of PF on hippocampal neuronal damage were evaluated by light microscope and electron microscope. The mRNA and protein expression levels of key molecules related to the M1/M2 polarization of microglia/macrophages were assessed by RT-qPCR and Western blotting, respectively.ResultsAdministration of PF could significantly attenuate cerebral hypoperfusion-induced impairment of learning and memory and reduce the morphological and ultrastructural changes in the hippocampal CA1 region of rats. Moreover, PF promoted an M1 to M2 phenotype transition in microglia/macrophages in the hippocampus of rats. In addition to its inhibitory property against proinflammatory M1 mediator expression, such as IL-1β, IL-6, TNF-α and NO, PF dramatically up-regulated expression of anti-inflammatory cytokines IL-10 and TGF-β1. Importantly, CB2R antagonist AM630 abolished these beneficial effects produced by PF on learning, memory and hippocampus structure in rats, as well as the polarization of microglia/macrophages to the M2 phenotype. Additionally, PF treatment significantly inhibited cerebral hypoperfusion-induced mTOR/NF-κB proinflammatory pathway and enhanced PI3K/Akt anti-inflammatory pathway. Effects of PF on these signaling pathways were effectively attenuated when rats were co-treated with PF and AM630, indicating that the mTOR/NF-κB and PI3K/Akt signaling pathways were involved in the PF effects through CB2R activation.ConclusionThese findings demonstrated PF exerts its neuroprotective effect and shifts the inflammatory milieu toward resolution by modulation of microglia/macrophage polarization via CB2R activation.Electronic supplementary materialThe online version of this article (10.1186/s13020-018-0173-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2

Luo

Yang

et al. 2018

Chin Med

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“…Di Sotto et al [ 242 ] also highlighted that the lipid-to-drug ratio should be considered as a critical parameter for enabling β-caryophyllene release from a lipid-based nanocarrier, in order to avoid the substance condensing effect on the bilayer, and for increasing its cytotoxic power in cancer cells. According to previous pharmaceutical studies [ 246 , 247 , 248 , 249 ], this evidence suggests that improving the bioavailability of these sesquiterpenes is an important goal for exploiting their pharmacological potential and strengthens the need of developing optimized delivery formulations.…”

Section: Caryophyllane Sesquiterpenes In Cancer Chemopreventionmentioning

confidence: 96%

Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence

Sotto

Mancinelli

Gullì

et al. 2020

Cancers

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Chemoprevention is referred to as a strategy to inhibit, suppress, or reverse tumor development and progression in healthy people along with high-risk subjects and oncologic patients through using pharmacological or natural substances. Numerous phytochemicals have been widely described in the literature to possess chemopreventive properties, although their clinical usefulness remains to be defined. Among them, caryophyllane sesquiterpenes are natural compounds widely occurring in nature kingdoms, especially in plants, fungi, and marine environments. Several structures, characterized by a common caryophyllane skeleton with further rearrangements, have been identified, but those isolated from plant essential oils, including β-caryophyllene, β-caryophyllene oxide, α-humulene, and isocaryophyllene, have attracted the greatest pharmacological attention. Emerging evidence has outlined a complex polypharmacological profile of caryophyllane sesquiterpenes characterized by blocking, suppressing, chemosensitizing, and cytoprotective properties, which suggests a possible usefulness of these natural substances in cancer chemoprevention for both preventive and adjuvant purposes. In the present review, the scientific knowledge about the chemopreventive properties of caryophyllane sesquiterpenes and the mechanisms involved have been collected and discussed; moreover, possible structure–activity relationships have been highlighted. Although further high-quality studies are required, the promising preclinical findings and the safe pharmacological profile encourage further studies to define a clinical usefulness of caryophyllane sesquiterpenes in primary, secondary, or tertiary chemoprevention.

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“…Machado et al [81] have recently reviewed the neuroprotective perspective of this natural product. β-Caryophyllene appears to act as a neuroprotective agent by controlling inflammation and oxidative stress as well as various effects on cannabinoid receptor 2 (CB2) [80][81][82]. In a vascular dementia rat model study, Lou et al [82] reported that β-caryophyllene-hydroxypropyl-β-cyclodextrin inclusion complex could alleviate cognitive deficits by increasing the expression of CB2 in the brain, along with the expression levels of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt).…”

Section: β-Caryophyllenementioning

confidence: 99%

“…β-Caryophyllene appears to act as a neuroprotective agent by controlling inflammation and oxidative stress as well as various effects on cannabinoid receptor 2 (CB2) [80][81][82]. In a vascular dementia rat model study, Lou et al [82] reported that β-caryophyllene-hydroxypropyl-β-cyclodextrin inclusion complex could alleviate cognitive deficits by increasing the expression of CB2 in the brain, along with the expression levels of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt). β-Caryophyllene also acted as agonist for CB2 and PPAR-α receptors in an animal hypoperfusion-reperfusion model of oxidative stress, and modulated activation of the endocannabinoid system and lipoperoxidation as well ▶ Table 2 Continued…”

Section: β-Caryophyllenementioning

confidence: 99%

Pistacia Genus as a Potential Source of Neuroprotective Natural Products

et al. 2019

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Neuroprotective agents are able to defend the central nervous system against acute or chronic neuronal injuries. Even with the progress made over the last decades, most of the medications prescribed for the management of neurodegenerative diseases can only reduce their symptoms and slow down their progression. Based on natural product research, there are potential effective medicinal plants and phytochemicals for modulating neuronal functions and protecting against neurodegeneration. Plants in the genus Pistacia are also among valuable natural resources for neuroprotection research based on experiences in traditional medicine. Studies have supported the value of bioactive compounds of the genus Pistacia for central nervous system disorders such as Alzheimerʼs, Parkinsonʼs, multiple sclerosis, cerebral ischemia, depression, and anxiety. Related literature has also revealed that most of the evidence on neuroprotection in the genus Pistacia is in the form of preliminary studies, mainly including models of behavior, motor function, and memory impairments in animals, neural toxicity, cerebral ischemia and seizure models, evaluation of their effects on antioxidant and inflammatory biomarkers, amyloid β aggregation, and acetylcholinesterase as well as investigations into some cellular pathways. Along with the phytonutrients in kernels such as pistachios, various phytochemicals, mostly terpenes, and phenolic compounds have also been identified in different plant parts, in particular their oleoresins, of species in the genus Pistacia. In this review, the pharmacology of neurological effects and related molecular mechanisms of the plants belonging to the genus Pistacia and its active constituents, as well as pharmacokinetics aspects, are discussed.

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

Cited by 38 publications

References 44 publications

Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2

Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2

Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence

Pistacia Genus as a Potential Source of Neuroprotective Natural Products

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