Tag Archives: Cannabinoids

Neuronal preservation and reactive gliosis attenuation following neonatal sciatic nerve axotomy by a fluorinated cannabidiol derivative.

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Neuropharmacology

“Immature peripheral nervous system damage, such as the transection of a peripheral nerve, results in the extensive degeneration of motoneurons and dorsal root ganglia (DRG) sensory neurons, mostly due to apoptotic events.

We have previously shown that cannabidiol (CBD), the most abundant non-psychotropic molecule present in the Cannabis sativa plant, exhibits neuroprotective action when administered daily at a dose of 15 mg/kg.

This study shows that use of the fluorinated synthetic version of CBD (4′-fluoro-cannabidiol, HUF-101) significantly improves neuronal survival by 2-fold compared to that achieved with traditional CBD at one-third the dose. Furthermore, we show that HUF-101 administration significantly upregulates anti-apoptotic genes and blocks the expression of pro-apoptotic nuclear factors.

Two-day-old Wistar rats were subjected to unilateral sectioning of the sciatic nerve and treated daily with HUF-101 (1, 2.5, 5 mg/kg/day, i.p.) or a vehicle solution for five days.

The results were evaluated by Nissl staining, immunohistochemistry, and qRT-PCR. Neuronal counting revealed a 47% rescue of spinal motoneurons and a 79% rescue of DRG neurons (HUF-101, 5 mg/kg). Survival was associated with complete depletion of p53 and a 60-fold elevation in BCL2-like 1 gene expression.

Additionally, peroxisome proliferator-activated receptor gamma (PPAR-gamma) gene expression was downregulated by 80%. Neuronal preservation was coupled with a high preservation of synaptic coverage and a reduction in astroglial and microglial reactions that were evaluated in nearby spinal motoneurons present in the ventral horn of the lumbar intumescence.

Overall, these data strongly indicate that HUF-101 exerts potent neuroprotective effects that are related to anti-apoptotic protection and the reduction of glial reactivity.”

 https://www.ncbi.nlm.nih.gov/pubmed/30096328
https://www.sciencedirect.com/science/article/pii/S0028390818304830?via%3Dihub

Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.

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Kidney International Home

“The cannabinoid receptor type 2 (CB2) is a G protein-coupled seven transmembrane receptor that transmits endogenous cannabinoid signaling. The role of CB2 in the pathogenesis of kidney injury and fibrosis remains poorly understood.

Here we demonstrate that CB2 was induced, predominantly in kidney tubular epithelium, in various models of kidney disease induced by unilateral ureteral obstruction, adriamycin or ischemia/reperfusion injury.

By using in silico screening and medicinal chemistry modifications, we discovered a novel compound, XL-001, that bound to CB2 with high affinity and selectivity and acted as an inverse agonist. Delayed administration of XL-001 was also effective in ameliorating kidney fibrosis and inflammation.

Thus, CB2 is a pathogenic mediator in kidney fibrosis and targeted inhibition with the novel inverse agonist XL-001 may provide a strategy in the fight against fibrotic kidney diseases.”

 https://www.ncbi.nlm.nih.gov/pubmed/30093080
https://www.kidney-international.org/article/S0085-2538(18)30397-1/fulltext

Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD1G93A transgenic mice, an experimental model of amyotrophic lateral sclerosis.

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“Antioxidant phytocannabinoids, synthetic compounds targeting the CB2 receptor, and inhibitors of the endocannabinoid inactivation afforded neuroprotection in SOD1G93A mutant mice, a model of ALS. These effects may involve the activation of PPAR-γ too.

Here, we have investigated the neuroprotective effects in SOD1G93A mutant mice of the cannabigerol derivative VCE-003.2, which works as by activating PPAR-γ.

As expected, SOD1G93Atransgenic mice experienced a progressive weight loss and neurological deterioration, which was associated with a marked loss of spinal cholinergic motor neurons, glial reactivity, and elevations in several biochemical markers (cytokines, glutamate transporters) that indirectly reflect the glial proliferation and activation in the spinal cord. The treatment with VCE-003.2 improved most of these neuropathological signs.

It attenuated the weight loss and the anomalies in neurological parameters, preserved spinal cholinergic motor neurons, and reduced astroglial reactivity. VCE-003.2 also reduced the elevations in IL-1β and glial glutamate transporters. Lastly, VCE-003.2 attenuated the LPS-induced generation of TNF-α and IL-1β in cultured astrocytes obtained from SOD1G93Atransgenic newborns, an effect also produced by rosiglitazone, then indicating a probable PPAR-γ activation as responsible of its neuroprotective effects.

In summary, our results showed benefits with VCE-003.2 in SOD1G93A transgenic mice supporting PPAR-γ as an additional neuroprotective target available for cannabinoids in ALS. Such benefits would need to be validated in other ALS models prior to be translated to the clinical level.”

https://www.ncbi.nlm.nih.gov/pubmed/30076846

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303198

EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, alleviates bleomycin-induced skin and lung fibrosis.

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Elsevier

“Systemic sclerosis (SSc) or scleroderma is a chronic multi-organ autoimmune disease characterized by vascular, immunological, and fibrotic abnormalities.

The etiology of SSc is unknown, but there is growing evidence that dysfunction of the endocannabinoid system (ECS) plays a critical role in its development.

Since the semi-synthetic cannabinoquinoid VCE-004.8 could alleviate bleomycin (BLM)-induced skin fibrosis, we have investigated an oral lipid formulation (EHP-101) of this dual PPARγ/CB2 receptors activator for the prevention of skin- and lung fibrosis and of collagen accumulation in BLM challenged mice.

Taken together, these data provide a rationale for further developing VCE-004.8 as an orally active agent to alleviate scleroderma and, possibly, other fibrotic diseases as well.”

 https://www.ncbi.nlm.nih.gov/pubmed/30076848
https://www.sciencedirect.com/science/article/abs/pii/S0006295218303174

Cannabinoid pharmacology and therapy in gut disorders.

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Biochemical Pharmacology

“Cannabis sp and their products (marijuana, hashish…), in addition to their recreational, industrial and other uses, have a long history for their use as a remedy for symptoms related with gastrointestinal diseases.

After many reports suggesting these beneficial effects, it was not surprising to discover that the gastrointestinal tract expresses endogenous cannabinoids, their receptors, and enzymes for their synthesis and degradation, comprising the so-called endocannabinoid system.

This system participates in the control of tissue homeostasis and important intestinal functions like motor and sensory activity, nausea, emesis, the maintenance of the epithelial barrier integrity, and the correct cellular microenvironment. Thus, different cannabinoid-related pharmacological agents may be useful to treat the main digestive pathologies.

To name a few examples, in irritable bowel syndrome they may normalize dysmotility and reduce pain, in inflammatory bowel disease they may decrease inflammation, and in colorectal cancer, apart from alleviating some symptoms, they may play a role in the regulation of the cell niche.

This review summarizes the main recent findings on the role of cannabinoid receptors, their synthetic or natural ligands and their metabolizing enzymes in normal gastrointestinal function and in disorders including irritable bowel syndrome, inflammatory bowel disease, colon cancer and gastrointestinal chemotherapy-induced adverse effects (nausea/vomiting, constipation, diarrhea).”

 https://www.ncbi.nlm.nih.gov/pubmed/30076849
https://www.sciencedirect.com/science/article/abs/pii/S0006295218303186

Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice.

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“Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, results in chronic inflammation and irreversible skeletal muscle degeneration. Moreover, the associated impairment of autophagy leads to the accumulation of damaged intracellular organelles that greatly contribute to the aggravation of muscle damage.

We explored the possibility of using non-euphoric compounds present in Cannabis sativa, including cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabidivarin (THCV) to reduce inflammation, restore functional autophagy and positively enhance muscle function in vivo.

We found that CBD and CBDV promote the differentiation of murine C2C12 myoblast cells into myotubes by increasing [Ca2+ ]i mostly via TRPV1 activation, an effect that undergoes rapid desensitization. CBD and CBDV also promoted the differentiation of myoblasts from DMD donors. In primary cultures prepared from satellite cells isolated from healthy donors, not only CBD and CBDV but also THCV promoted myotube formation, in this case mostly via TRPA1 activation. In mdx mice, CBD (60 mg Kg-1), CBDV (60 mg Kg-1 ) prevented the loss of locomotor activity at two distinct ages (from 5 to 7 and 32 to 34 weeks of age). This effect was associated with a reduction in tissue and plasma pro-inflammatory markers, together with the restoration of autophagy.

CONCLUSION AND IMPLICATIONS:

We provide new insights into plant cannabinoid interactions with TRP channels in skeletal muscle, highlighting a potential opportunity for novel co-adjuvant therapies to prevent muscle degeneration in DMD patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30074247

GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine

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“The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed.

Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression.

Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival.

Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone.

Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice.

Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p.

Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients’ outcome.”

https://www.nature.com/articles/s41388-018-0390-1

“Cannabinoid improves survival rates of mice with pancreatic cancer”  https://medicalxpress.com/news/2018-07-cannabinoid-survival-mice-pancreatic-cancer.html

“Study: CBD From Marijuana Plus Chemotherapy Tripled Cancer Survival Rates In Mice” https://www.forbes.com/sites/daviddisalvo/2018/07/31/study-cbd-from-marijuana-plus-chemotherapy-triples-cancer-survival-rates-in-mice/#491942d44630

“Cannabis drug may help pancreatic-cancer patients live almost THREE TIMES longer, study finds” http://www.dailymail.co.uk/health/article-6007275/Cannabis-drug-help-pancreatic-cancer-patients-live-THREE-TIMES-longer-study-finds.html

“Substance in cannabis ‘could boost pancreatic cancer treatments’. Scientists say cannabidiol could extend patients’ lives by a matter of years”  https://www.theguardian.com/science/2018/jul/30/substance-in-cannabis-could-boost-pancreatic-cancer-treatments

“Cannabinoid mice trial holds hope for pancreatic cancer patients”  https://www.smh.com.au/national/cannabinoid-mice-trial-holds-hope-for-pancreatic-cancer-patients-20180731-p4zuls.html

“Medical cannabis extract could help pancreatic cancer patients live longer, early study suggests” https://www.independent.co.uk/news/health/pancreatic-cancer-medical-cannabis-cbd-oil-cannabidiol-chemotherapy-a8470406.html

“Cancer ‘remarkable’ treatment – cannabis CBD could improve survival rate by THREE times. CANCER symptoms could be prevented with a “remarkable” new treatment, which includes cannabis CBD, scientists have revealed. Pancreatic cancer survival rates could be improved by three times, by adding CBD into chemotherapy treatments, they said.” https://www.express.co.uk/life-style/health/996657/cancer-treatment-pancreatic-symptoms-cannabis-cbd

“Compound in cannabis could help pancreatic cancer patients live significantly longer” https://www.deccanchronicle.com/lifestyle/health-and-wellbeing/310718/compound-in-cannabis-could-help-pancreatic-cancer-patients-live-signif.html

Elucidation of structure-function relationship of THCA and CBDA synthase from Cannabis sativa L.

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Journal of Biotechnology

“Cannabinoids are secondary natural products from the plant Cannabis sativa L.

Therapeutic indications of cannabinoids currently comprise a significant area of medicinal research.

We have expressed the Δ9-tetrahydrocannabinolic acid synthase (THCAS) and cannabidiolic acid synthase (CBDAS) recombinantly in Komagataella phaffii and could detect eight different products with a cannabinoid scaffold after conversion of the precursor cannabigerolic acid (CBGA).

Besides five products remaining to be identified, both enzymes were forming three major cannabinoids of C. sativa – Δ9-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA).

These studies lay the groundwork for further research as well as biotechnological cannabinoid production.”

 https://www.ncbi.nlm.nih.gov/pubmed/30053500
https://www.sciencedirect.com/science/article/pii/S0168165618305698?via%3Dihub

Chronic treatment with the phytocannabinoid Cannabidivarin (CBDV) rescues behavioural alterations and brain atrophy in a mouse model of Rett syndrome.

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Neuropharmacology

“Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in the MECP2 gene in about 95% of cases and to date no cure is available.

The endocannabinoid system modulates several physiological processes and behavioural responses that are impaired in RTT and its deregulation has been associated with neuropsychiatric disorders which have symptoms in common with RTT.

The present study evaluated the potential therapeutic efficacy for RTT of cannabidivarin (CBDV), a non-psychotropic phytocannabinoid from Cannabis sativa that presents antagonistic properties on the G protein-coupled receptor 55 (GPR55), the most recently identified cannabinoid receptor.

Present results demonstrate that systemic treatment with CBDV (2, 20, 100 mg/Kg ip for 14 days) rescues behavioural and brain alterations in MeCP2-308 male mice, a validated RTT model. The CBDV treatment restored the compromised general health status, the sociability and the brain weight in RTT mice. A partial restoration of motor coordination was also observed. Moreover, increased levels of GPR55 were found in RTT mouse hippocampus, suggesting this G protein-coupled receptor as new potential target for the treatment of this disorder.

Present findings highlight for the first time for RTT the translational relevance of CBDV, an innovative therapeutic agent that is under active investigation in the clinical setting.”

 https://www.ncbi.nlm.nih.gov/pubmed/30056123
https://www.sciencedirect.com/science/article/pii/S0028390818304131?via%3Dihub