AM1241 alleviates MPTP-induced Parkinson’s disease and promotes the regeneration of DA neurons in PD mice.

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“The main pathological feature of Parkinson’s disease (PD) is the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the role of cannabinoid receptor 2 (CB2R) agonist AM1241 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a mouse model of PD. Upon treatment with AM1241, the decreased CB2R level in the PD mouse brain was reversed and the behavior score markedly elevated, accompanied with a dose-dependent increase of dopamine and serotonin. In addition, western blot assay and immunostaining results suggested that AM1241 significantly activated PI3K/Akt/MEK phosphorylation and increased the expression of Parkin and PINK1, both in the substantia nigra and hippocampus. The mRNA expression analysis further demonstrated that AM1241 increased expression of the CB2R and activated Parkin/PINK1 signaling pathways. Furthermore, the increased number of TH-positive cells in the substantia nigra indicated that AM1241 regenerated DA neurons in PD mice, and could therefore be a potential candidate for PD treatment. The clear co-localization of CB2R and DA neurons suggested that AM1241 targeted CB2R, thus also identifying a novel target for PD treatment. In conclusion, the selective CB2 agonist AM1241 has a significant therapeutic effect on PD mice and resulted in regeneration of DA neurons following MPTP-induced neurotoxicity. The possible mechanisms underlying the neurogenesis effect of AM1241 might be the induction of CB2R expression and an increase in phosphorylation of the PI3K/AKT signaling pathway.”

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Smoked marijuana attenuates performance and mood disruptions during simulated night shift work.

Drug and Alcohol Dependence Home

“Individuals who work nonstandard schedules, such as rotating or night shifts, are more susceptible to workplace injuries, performance decrements, and reduced productivity. This population is also almost twice as likely to use illicit drugs as individuals working a standard day shift. The purpose of this study was to examine the effects of smoked marijuana on performance, mood, and sleep during simulated shift work.

Ten experienced marijuana smokers completed this 23-day, within-participant residential study. They smoked a single marijuana cigarette (0, 1.9, 3.56% Δ9-THC) one hour after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an ‘off’ day. When participants smoked placebo cigarettes, psychomotor performance and subjective-effect ratings were altered during the night shift compared to the day shift: performance (e.g., vigilance) and a few subjective ratings were decreased (e.g., “Self-Confident”), whereas other ratings were increased (e.g., “Tired”). Objective and subjective measures of sleep were also disrupted, but to a lesser extent.

Marijuana attenuated some performance, mood, and sleep disruptions: participants performed better on vigilance tasks, reported being less miserable and tired and sleep a greater number of minutes. Limited negative effects of marijuana were noted. These data demonstrate that abrupt shift changes produce performance, mood, and sleep decrements during night shift work and that smoked marijuana containing low to moderate Δ9-THC concentrations can offset some of these effects in frequent marijuana smokers.”

https://www.ncbi.nlm.nih.gov/pubmed/28728115

http://www.drugandalcoholdependence.com/article/S0376-8716(17)30309-5/fulltext

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Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with In Vivo Efficacy in a Mouse Model of Multiple Sclerosis.

Journal of Medicinal Chemistry

“Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor.

We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor.

Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.”

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Activation of cannabinoid receptor type 2 attenuates surgery-induced cognitive impairment in mice through anti-inflammatory activity.

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“Neuroinflammation plays a major role in postoperative cognitive dysfunction (POCD).

Accumulated evidence indicates that cannabinoid receptor type 2 (CB2R) can mediate anti-inflammatory and immunomodulatory effects in part by controlling microglial activity.

These findings indicate that CB2R may modulate the neuroinflammatory and cognitive impairment in a mouse model of orthopedic surgery, and the activation of CB2R may effectively ameliorate the hippocampal-dependent memory loss of mice in the early postoperative stage.”

https://www.ncbi.nlm.nih.gov/pubmed/28724382

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-0913-7

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Delta-9-tetrahydrocannabinol decreases masticatory muscle sensitization in female rats through peripheral cannabinoid receptor activation.

European Journal of Pain

“This study investigated whether intramuscular injection of delta-9-tetrahydrocannabinol (THC), by acting on peripheral cannabinoid (CB) receptors, could decrease nerve growth factor (NGF)-induced sensitization in female rat masseter muscle; a model which mimics the symptoms of myofascial temporomandibular disorders.

It was found that CB1 and CB2 receptors are expressed by trigeminal ganglion neurons that innervate the masseter muscle and also on their peripheral endings.

These results suggest that reduced inhibitory input from the peripheral cannabinoid system may contribute to NGF-induced local myofascial sensitization of mechanoreceptors. Peripheral application of THC may counter this effect by activating the CB1 receptors on masseter muscle mechanoreceptors to provide analgesic relief without central side effects.

SIGNIFICANCE:

Our results suggest THC could reduce masticatory muscle pain through activating peripheral CB1 receptors. Peripheral application of cannabinoids could be a novel approach to provide analgesic relief without central side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/28722246

http://onlinelibrary.wiley.com/doi/10.1002/ejp.1085/abstract

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Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids.

“The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood.

We use a proteotoxicity model based upon the inducible expression of Aβ in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Aβ. It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell’s demise. Aβ induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death.

Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective.

Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Aβ, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors.”

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The synthetic cannabinoid WIN55212-2 ameliorates traumatic spinal cord injury via inhibition of GAPDH/Siah1 in a CB2-receptor dependent manner.

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“The essential role of GAPDH/Siah1 signaling pathway in the pathogenesis of various injurious conditions such as traumatic spinal cord injury (SCI) has been gradually recognized. However, the drugs targeting this signaling pathway are still lacking.

The endocannabinoid system, including its receptors (CB1 and CB2), act as neuroprotective and immunomodulatory modulators in SCI. WIN55212-2, an agonist for CB1 and CB2 receptors, has been demonstrated with anti-inflammatory and anti-apoptotic effects in multiple neurological diseases. Therefore, the present study aimed to investigate whether WIN55212-2 could promote functional recovery after traumatic SCI via inhibition of the GAPDH/Siah1 signaling.

In conclusion, our study indicates that, WIN55212-2 improves the functional recovery after SCI via inhibition of GAPDH/Siah1 cascades in a CB2 receptor dependent manner, indicative of its therapeutic potential for traumatic SCI or other traumatic conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/28716633

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Highly selective CB2 receptor agonist A836339 has gastroprotective effect on experimentally induced gastric ulcers in mice.

Naunyn-Schmiedeberg's Archives of Pharmacology

“Cannabinoid type 2 (CB2) receptors are distributed in central and peripheral tissues, including immunocytes and the gastrointestinal (GI) tract, suggesting that CB2 receptor agonists represent potential therapeutics in GI inflammatory states.

In this study, we investigated the effect of highly selective CB2 agonist, A836339, on the development of gastric lesions.

Activation of CB2 receptors exhibited gastroprotective effect through enhancement of anti-oxidative pathways in the stomach. Activation of CB2 receptors may thus become a novel therapeutic approach in the treatment of GU.”

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Sativex® effects on promoter methylation and on CNR1/CNR2 expression in peripheral blood mononuclear cells of progressive multiple sclerosis patients.

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“Multiple sclerosis (MS) is a chronic demyelinating central nervous system (CNS) disease that involve oligodendrocyte loss and failure to remyelinate damaged brain areas causing a progressive neurological disability.

Studies in MS mouse model suggest that cannabinoids ameliorate symptoms as spasticity, tremor and pain reducing inflammation via cannabinoid-mediated system.

The aim of our study is to investigate the changes in cannabinoid type 1 (CNR1) and 2 (CNR2) receptors mRNA expression levels and promoter methylation in peripheral blood mononuclear cells (PBMCs) of MS secondary progressive (MSS-SP) patients treated with Sativex®.

These results suggest that the different expression of cannabinoid receptors by Sativex® treatment in leukocytes might be regulated through a molecular mechanism that involve interferon modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/28716266

http://www.jns-journal.com/article/S0022-510X(17)30392-1/fulltext

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Identification of Terpenoid Chemotypes Among High (−)-trans-Δ9- Tetrahydrocannabinol-Producing Cannabis sativa L. Cultivars

Cover for Cannabis and Cannabinoid Research

Cannabis sativa L. (cannabis) is an annual diecious member of the Cannabaceae family. Since ancient times cannabis has been used by humans for its fiber, seed, as well as its psychoactive and medicinal resin. Despite a long history of use, the legal status of cannabis in modern times often depends on its intended use. Cannabis grown for its fiber or seed, commonly known as hemp, is legally cultivated in many nations. Cannabis used for its psychoactive properties, in North American commonly known as “marijuana,” has been illegal in most nations worldwide since the 1961 United Nations Single Convention on Narcotic Drugs. Recently however, laws concerning the legal status of cannabis are changing around the world. In the United States of America, many states have legalized cannabis for medical use, whereas some have even legalized cannabis for adult consumption. Uruguay recently legalized cannabis and laws in various countries within the European Union (EU) are also changing regarding cannabis. Due to its many and controversial uses, the taxonomic classification of cannabis has been the subject of both legal and scientific debate.

From a morphological perspective, three main types of cannabis have been described sativa, indica, and ruderalis. Generally sativa plants are described as taller and loosely branched, whereas indica is typically shorter, more densely branched, and conical in shape. Ruderalis is described as short (≤2 feet) at maturity and sparsely if at all branched.7Whether the genus Cannabis is monotypic and composed of just a single species (C. sativa) or polytypic and composed of multiple species is an old taxonomic debate. A more recent taxonomic classification dividing cannabis into seven putative taxa based on morphological, geographical, and genetic traits has been proposed.

Cannabinoids are a group of terpenophenolic compounds found in cannabis. Today over 100 cannabinoids from cannabis have been characterized. (−)-Trans-Δ9-tetrahydrocannabinol (THC) is considered the primary active ingredient responsible for the intoxicating and medical effects attributed to cannabis. THC has antiemetic, neuroprotectant, and anti-inflammatory properties as well as the ability to reduce certain forms of neuropathic and chronic pain. Another important cannabinoid, cannabidiol (CBD), has neuroprotective, anti-inflammatory, antipsychotic, and antiseizure properties without the intoxicating effects of THC. Other minor cannabinoids, such as cannabigerol (CBG), cannabichromene (CBC), and tetrahydrocannabivarin (THCV), also exhibit interesting pharmacological properties.

Since cannabinoids are the major active ingredients found in cannabis, it makes sense to classify cannabis from a chemotaxonomic perspective according to cannabinoid levels for both medical and legal purposes. Early studies noted that cannabis used for fiber tended to have higher levels of CBD, whereas cannabis used for drug purposes had higher levels of THC

Terpenoids represent another interesting group of biologically active compounds found in cannabis. Due to their volatile nature, the mono- and sesquiterpenoids found in cannabis contribute to the plants’ aroma and flavor. About 100 terpenoids have been identified in cannabis, many of which are found in other plants. Both cannabinoids and terpenoids are produced in the trichomes of cannabis, which are found at highest density on female flower buds.Terpenoids are usually present in cannabis flower buds in the 0.5–3.5% range and are found at significant levels in cannabis smoke and vapor. As biologically active compounds, terpenoids may play a role in the overall effects of herbal cannabis.

The popularly understood distinctions between indica and sativa may have more to do with aroma and subjective effects than plant morphology. Recent studies have shown that terpenoids are useful in distinguishing cannabis cultivars that have similar cannabinoid content. A study of cannabinoid and terpenoid profiles among medical cannabis samples analyzed by a cannabis testing laboratory in California found a continuum of terpenoid profiles among the wide variety of sample names.Another study found that cannabis samples described as indica contained more myrcene and hydroxylated terpenoids, whereas those described as sativa tended to contain more terpinolene, 3-carene, and a few specified sesquiterpenes.” http://online.liebertpub.com/doi/full/10.1089/can.2016.0040

“Due to its astonishing efficacy, nowadays cannabis is prescribed by physicians for the treatment of neurological, psychiatric, immunological, cardiovascular, gastrointestinal, and oncological conditions. The active principles inside plants have been exploited by humans for centuries, with Cannabis sativa being one of the oldest ever used for medicinal purposes. Surprisingly, contrary to whole plant extracts, medicinal products containing exclusively THC have been found to lack efficacy and lead to unbearable side effects. These results arise from the fact that these products lack other important co-factors typically found in the Phyto-complex, such as terpenoids and other cannabinoids that contribute to the synergistic effects seen with whole plant extracts.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482328/

“In silico discovery of terpenoid metabolism in Cannabis sativa. Due to their efficacy, cannabis based therapies are currently being prescribed for the treatment of many different medical conditions. Interestingly, treatments based on the use of cannabis flowers or their derivatives have been shown to be very effective, while therapies based on drugs containing THC alone lack therapeutic value and lead to increased side effects, likely resulting from the absence of other pivotal entourage compounds found in the Phyto-complex. Among these compounds are terpenoids,” https://www.ncbi.nlm.nih.gov/pubmed/28690830

 

“Terpenoids: natural products for cancer therapy.”  https://www.ncbi.nlm.nih.gov/pubmed/23092199

“Inhibition of tumor progression by naturally occurring terpenoids.”  https://www.ncbi.nlm.nih.gov/pubmed/21936626

“Terpenoids as anti-colon cancer agents – A comprehensive review on its mechanistic perspectives.” https://www.ncbi.nlm.nih.gov/pubmed/27940056

 

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