Therapeutical strategies for anxiety and anxiety-like disorders using plant-derived natural compounds and plant extracts.

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“Anxiety and anxiety-like disorders describe many mental disorders, yet fear is a common overwhelming symptom often leading to depression. Currently two basic strategies are discussed to treat anxiety: pharmacotherapy or psychotherapy. In the pharmacotherapeutical clinical approach, several conventional synthetic anxiolytic drugs are being used with several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being sought by researchers. The results of a plethora experimental studies demonstrated that dietary phytochemicals like alkaloids, terpenes, flavonoids, phenolic acids, lignans, cinnamates, and saponins or various plant extracts with the mixture of different phytochemicals possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms of anxiolytics action include interaction with γ-aminobutyric acid A receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine receptors, noradrenergic and dopaminergic systems, glutamate receptors, and cannabinoid receptors. This review focuses on the use of both plant-derived natural compounds and plant extracts with anxiolytic effects, describing their biological effects and clinical application.”

https://www.ncbi.nlm.nih.gov/pubmed/28863384

 

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The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress.

Biomed Central

“The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid receptor, whose exact role in anxiety remains unknown. The present study was conducted to explore the possible mechanisms by which GPR55 regulates anxiety and to evaluate the effectiveness of O-1602 in the treatment of anxiety-like symptoms. Mice were exposed to two types of acute stressors: restraint and forced swimming. Anxiety behavior was evaluated using the elevated plus maze and the open field test. We found that O-1602 alleviated anxiety-like behavior in acutely stressed mice. We used lentiviral shRNA to selective ly knockdown GPR55 in the medial orbital cortex and found that knockdown of GPR55 abolished the anxiolytic effect of O-1602. We also used Y-27632, a specific inhibitor of ROCK, and U73122, an inhibitor of PLC, and found that both inhibitors attenuated the effectiveness of O-1602. Western blot analysis revealed that O-1602 downregulated the expression of GluA1 and GluN2A in mice. Taken together, these results suggest that GPR55 plays an important role in anxiety and O-1602 may have therapeutic potential in treating anxiety-like symptoms.”

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An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol.

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“Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.”  https://www.ncbi.nlm.nih.gov/pubmed/28701957

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Cannabidiol in Medical Marijuana: Research Vistas and Potential Opportunities.

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“The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects.

The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC.

Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties.

It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD.

Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.” https://www.ncbi.nlm.nih.gov/pubmed/28501518

http://www.sciencedirect.com/science/article/pii/S1043661817303559

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The Direct Actions of Cannabidiol and 2-Arachidonoyl Glycerol at GABAA Receptors.

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“Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties.

Despite evidence that some endogenous and synthetic cannabinoids interact with GABAA receptors, no-one has yet investigated the effects of CBD.

Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABAA receptors (synaptic α1-6βg2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes.

Taken together these results reveal a mode of action of CBD on specifically configured GABAA receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound.”

https://www.ncbi.nlm.nih.gov/pubmed/28249817

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Cannabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine1A Receptor–Dependent Mechanism

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“Cannabis contains ≈80 different cannabinoids, including the psychoactive component Δ9-tetrahydrocannabinol, and nonpsychoactive components, which include cannabidiol, cannabinol, and cannabigerol.

In those components, cannabidiol, a nonpsychoactive constituent of cannabis, was found to be an anticonvulsant in animal models of epilepsy and in humans with epilepsy. Moreover, cannabidiol has been shown to have antispasmodic, anxiolytic, antinausea, and antirheumatoid arthritic properties. In addition, cannabidiol has been shown to be protective against global and focal ischemic injury.

Cannabidiol has been reported to be a neuroprotectant, but the neuroprotective mechanism of cannabidiol remains unclear. We studied the neuroprotective mechanism of cannabidiol in 4-hour middle cerebral artery (MCA) occlusion mice.

Cannabidiol significantly reduced the infarct volume induced by MCA occlusion in a bell-shaped curve. Similarly, abnormal cannabidiol but not anandamide or methanandamide reduced the infarct volume.

Cannabidiol and abnormal cannabidiol reduced the infarct volume.

These results suggested that the neuroprotective effect of cannabidiol may be related to the increase in CBF through the serotonergic 5-HT1A receptor.”

http://stroke.ahajournals.org/content/36/5/1071

http://www.thctotalhealthcare.com/category/stroke-2/

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Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons

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“Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury.

In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD), a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen–glucose-deprivation/reperfusion (OGD/R) model in a mouse hippocampal neuronal cell line.

This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance.

Cannabidiol (CBD) is a nonpsychoactive cannabinoid derived from Cannabis sativa and a weak CB1 and CB2 cannabinoid receptor antagonist, with very low toxicity for humans. It has recently been demonstrated in vivo and in vitro that CBD has a variety of therapeutic properties, exerting antidepressant, anxiolytic, anti-inflammatory, immunomodulatory, and neuroprotective effects.  Our results provide novel insight into the neuroprotective properties of CBD, which involves the regulation of the mitochondrial bioenergetics and the glucose metabolism of hippocampal neurons during OGD/R injury.

In summary, our results suggest that CBD exerts a potent neuroprotective effect against ischemia/reperfusion injury by attenuating intracellular oxidative stress, enhancing mitochondrial bioenergetics, and optimizing glucose metabolism via the pentose-phosphate pathway, thus strengthening the antioxidant defenses and preserving the energy homeostasis of neurons. More in-depth studies are required to investigate the precise mechanism underlying the success of CBD treatment and to determine the actual role of CBD in cerebral ischemia.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247568/

“Cannabidiol may soon be used in the emergency room to fight effects of stroke and cardiac emergencies” http://www.naturalnews.com/2017-02-21-cannabidiol-may-soon-be-used-in-the-emergency-room-to-fight-effects-of-stroke-cardiac-emergencies.html

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Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction

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“Cannabidiol (CBD) is the major non-psychotropic constituent of the Cannabis plant and has anxiolytic therapeutic potential.

Cannabidiol (CBD) has been established to have both acute and long-lasting effects to reduce fear memory expression.

We showed that under conditions of strong fear conditioning, CBD reduced contextual fear memory expression both acutely during the extinction session as well as later at a fear retention test.

This pattern of results is consistent with CBD enhancing contextual fear memory extinction when the initial conditioning is strong, but impairing extinction when conditioning is weak. This bidirectional effect of CBD may be related to stress levels induced by conditioning and evoked at retrieval during extinction, rather than the strength of the memory per se.

 In summary, CBD had bidirectional effects on the extinction of contextual fear conditioning, depending on the nature of the initial fear conditioning. Nevertheless, in the more translationally-relevant stronger conditioning setting, CBD both acutely inhibited fear expression and enhanced extinction to produce longer lasting reductions in fear.
These observations provide further support for the potential translational use of CBD in conditions such as posttraumatic stress disorder and specific phobias.”

http://journal.frontiersin.org/article/10.3389/fphar.2016.00493/full?utm_source=S-TWT&utm_medium=SNET&utm_campaign=ECO_FPHAR_XXXXXXXX_auto-dlvrit%0A

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Therapeutic potential of fatty acid amide hydrolase, monoacylglycerol lipase, and N-acylethanolamine acid amidase inhibitors.

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“Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anti-cancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2), or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation.

FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase-2 (COX-2).

Over the last decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their anti-nociceptive and anti-inflammatory effects, as well as protecting the nervous system.”

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Cannabidiol Prevents Motor and Cognitive Impairments Induced by Reserpine in Rats.

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“Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects.

In Parkinson’s disease patients, CBD is able to attenuate the psychotic symptoms induced by L-DOPA and to improve quality of life.

Repeated administration of reserpine in rodents induces motor impairments that are accompanied by cognitive deficits, and has been applied to model both tardive dyskinesia and Parkinson’s disease.

The present study investigated whether CBD administration would attenuate reserpine-induced motor and cognitive impairments in rats.

Our data show that CBD is able to attenuate motor and cognitive impairments induced by reserpine, suggesting the use of this compound in the pharmacotherapy of Parkinson’s disease and tardive dyskinesia.”

https://www.ncbi.nlm.nih.gov/pubmed/27733830

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