A systematic review on the neuroprotective perspectives of beta-caryophyllene.

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“Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect.

This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords “beta (β)-caryophyllene” and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action.

A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer’s disease.

Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.”

https://www.ncbi.nlm.nih.gov/pubmed/30281175

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/23138934

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Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor.

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“Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer.

CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke.

In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion.

These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R-/- mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.”

https://www.ncbi.nlm.nih.gov/pubmed/30223868

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-018-0395-2

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Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity.

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“Microglia, the resident immune cells of the brain, play important roles in defending the brain against pathogens and supporting neuronal circuit plasticity. Chronic or excessive pro-inflammatory responses of microglia damage neurons, therefore their activity is tightly regulated.

Pharmacological and genetic studies revealed that cannabinoid type 1 (CB1) receptor activity influences microglial activity, although microglial CB1 receptor expression is very low and activity-dependent. The CB1 receptor is mainly expressed on neurons in the central nervous system (CNS)-with an especially high level on GABAergic interneurons.

Here, we determined whether CB1 signaling on this neuronal cell type plays a role in regulating microglial activity.

Our result suggests that CB1 receptor agonists can modulate microglial activity indirectly, through CB1 receptors on GABAergic neurons.

Altogether, we demonstrated that GABAergic neurons, despite their relatively low density in the hippocampus, have a specific role in the regulation of microglial activity and cannabinoid signaling plays an important role in this arrangement.”

https://www.ncbi.nlm.nih.gov/pubmed/30210289

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00295/full

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Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload.

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“Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats.

In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction.

Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed.

These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action.”

“In summary, we have shown that iron treatment in the neonatal period disrupts the apoptotic intrinsic pathway. This finding may place iron excess as a central component in neurodegenerative processes since many neurodegenerative disorders are accompanied by iron accumulation in brain regions. Moreover, indiscriminate iron supplementation to toddlers and infants, modeled here by iron overload in the neonatal period, has been considered a potential environmental risk factor for the development of neurodegenerative disorders later in life. Our findings also strongly suggest that CBD has neuroprotective effects, at least in part by blocking iron-induced apoptosis even at later stages, following iron overload, which puts CBD as a potential therapeutic agent in the treatment of neurodegenerative diseases.”
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Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system.

 Biochemical Pharmacology “The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis.

Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum of actions of cannabinoids allows targeting different aspects of these multifactorial diseases.

In this review, we examine the therapeutic potential of the ECS for the treatment of chronic neurodegenerative diseases of the CNS focusing on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.

First, we describe the localization of the molecular components of the ECS and how they are altered under neurodegenerative conditions, either contributing to or protecting cells from degeneration.

Second, we address recent advances in the modulation of the ECS using experimental models through different strategies including the direct targeting of cannabinoid receptors with agonists or antagonists, increasing the endocannabinoid tone by the inhibition of endocannabinoid hydrolysis, and activation of cannabinoid receptor-independent effects.

Preclinical evidence indicates that cannabinoid pharmacology is complex but supports the therapeutic potential of targeting the ECS.

Third, we review the clinical evidence and discuss the future perspectives on how to bridge human and animal studies to develop cannabinoid-based therapies for each neurodegenerative disorder.

Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to each disease and the multiple unexplored pathways in cannabinoid pharmacology that could be useful for the treatment of neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/30121249

https://www.sciencedirect.com/science/article/abs/pii/S000629521830337X

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Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model.

Biochemical Pharmacology

“Activating CB1 cannabinoid receptor has been demonstrated to produce certain therapeutic effects in animal models of Alzheimer’s disease (AD).

In this study, we evaluated the specific contribution of CB1 receptor to the progression of AD-like pathology in double transgenic APP/PS1 mice.

In summary, our results suggest a crucial role for CB1 receptor in the progression of AD-related pathological events.”

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Therapeutic applications of cannabinoids.

Chemico-Biological Interactions

“The psychoactive properties of cannabinoids are well known and there has been a continuous controversy regarding the usage of these compounds for therapeutic purposes all over the world. Their use for medical and research purposes are restricted in various countries. However, their utility as medications should not be overshadowed by their negative physiological activities.

This review article is focused on the therapeutic potential and applications of phytocannabinoids and endocannabinoids. It highlights their mode of action, overall effects on physiology, various in vitro and in vivo studies that have been done so far and the extent to which these compounds can be useful in different disease conditions such as cancer, Alzheimer’s disease, multiple sclerosis, pain, inflammation, glaucoma and many others.

Thus, this work is an attempt to make the readers understand the positive implications of these compounds and indicates the significant developments that can occur upon utilizing cannabinoids as therapeutic agents.”  https://www.ncbi.nlm.nih.gov/pubmed/30040916

“Cannabinoids can be used as therapeutic agents.”   https://www.sciencedirect.com/science/article/pii/S0009279718307373?via%3Dihub
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Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer’s Disease.

“The pathogenesis of Alzheimer’s disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent.

The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition.

It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in microglia and in immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated migroglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD.

The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.”

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GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol.

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“The G protein-coupled receptors 3, 6, and 12 (GPR3, GPR6, and GPR12) comprise a family of closely related orphan receptors with no confirmed endogenous ligands. These receptors are constitutively active and capable of signaling through G protein-mediated and non-G protein-mediated mechanisms. These orphan receptors have previously been reported to play important roles in many normal physiological functions and to be involved in a variety of pathological conditions.

Although they are orphans, GPR3, GPR6, and GPR12 are phylogenetically most closely related to the cannabinoid receptors. Using β-arrestin2 recruitment and cAMP accumulation assays, we recently found that the nonpsychoactive phytocannabinoid cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12.

This discovery highlights these orphan receptors as potential new molecular targets for CBD, provides novel mechanisms of action, and suggests new therapeutic uses of CBD for illnesses such as Alzheimer’s disease, Parkinson’s disease, cancer, and infertility. Furthermore, identification of CBD as a new inverse agonist for GPR3, GPR6, and GPR12 provides the initial chemical scaffolds upon which potent and efficacious agents acting on these receptors can be developed, with the goal of developing chemical tools for studying these orphan receptors and ultimately new therapeutic agents.”

https://www.ncbi.nlm.nih.gov/pubmed/29941868

https://www.nature.com/articles/s41401-018-0031-9

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