Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and γ-irradiation in human glioblastoma cells.

Related image“Despite advances in glioblastoma (GBM) therapy, prognosis of the disease remains poor with a low survival rate.

Cannabidiol (CBD) can induce cell death and enhance radiosensitivity of GBM but not normal astrocytes.

Inhibition of ATM kinase is an alternative mechanism for radiosensitization of cancer cells.

In this study, we increased the cytotoxic effects of the combination of CBD and γ-irradiation in GBM cells through additional inhibition of ATM kinase with KU60019, a small molecule inhibitor of ATM kinase.

We observed in GBM cells treated by CBD, γ-irradiation and KU60019 high levels of apoptosis together with strong upregulation of the percentage of G2/M-arrested cells, blockade of cell proliferation and a massive production of pro-inflammatory cytokines.

Overall, these changes caused both apoptotic and non-apoptotic inflammation-linked cell death. Furthermore, via JNK-AP1 activation in concert with active NF-κB, CBD upregulated gene and protein expression of DR5/TRAIL-R2 and sensitize GBM cells to TRAIL-induced apoptosis. In contrast, CBD notably decreased in GBM surface levels of PD-L1, a critical immune checkpoint agent for T-lymphocytes. We also used in the present study TS543 human proneural glioma cells that were grown as spheroid culture. TS543 neurospheres exhibited dramatic sensitivity to CBD-mediated killing that was additionally increased in combination with γ-irradiation and KU60019.

In conclusion, treatment of human GBM by the triple combination (CBD, γ-irradiation and KU60019) could significantly increase cell death levels in vitro and potentially improve the therapeutic ratio of GBM.”

https://www.ncbi.nlm.nih.gov/pubmed/30783513

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26582&path[]=82682

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Cannabinoids: a new approach for pain control?

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“To analyze available data related to the use of cannabinoids in medicine, with a special focus on pain management in cancer. The use of cannabis for medical purposes is growing but there are still numerous questions to be solved: effectiveness, safety, and specific indications.

RECENT FINDINGS:

There is considerable variation between countries in the approaches taken, reflecting a variety of historical and cultural factors and despite few randomized controlled studies using natural cannabinoids, there is a trend to state that the use of cannabis should be taken seriously as a potential treatment of cancer-related pain. Cannabidiol, a nontoxic phytocannabinoid with few side-effects is promising in various indications in medicine.

SUMMARY:

The endocannabinoid system is a potential therapeutic target. Cannabinoids may be considered as potential adjuvant in cancer-related pain management. Cannabidiol appears to be the drug of choice. Analgesic trial designs should evolve to get closer to real-life practice and to avoid biases.”

https://www.ncbi.nlm.nih.gov/pubmed/30789867

https://insights.ovid.com/crossref?an=00001622-900000000-00002

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What are the psychological effects of using synthetic cannabinoids? A systematic review

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“Synthetic cannabinoids are, typically, full agonists at the cannabinoid CB1 receptor, and therefore considerably more potent than natural cannabis and may have correspondingly more serious psychological effects.

The purpose of this study was to synthesise the available research on the psychological consequences of synthetic cannabinoid use.

 

Non-controlled, cross-sectional studies generally showed that synthetic cannabinoid users had lower performance on cognitive tasks and showed elevated symptomatology (e.g. paranoia) compared to both natural cannabis and non-cannabis users.

 

Acute synthetic cannabinoid use can result in a range of psychological outcomes and, when non-intoxicated, synthetic cannabinoid users appear to differ from natural cannabis and non-users on various affective and cognitive domains.”

https://www.ncbi.nlm.nih.gov/pubmed/30789300

https://journals.sagepub.com/doi/abs/10.1177/0269881119826592?journalCode=jopa

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Preliminary results from a pilot study examining brain structure in older adult cannabis users and nonusers.

Cover image Psychiatry Research: Neuroimaging

“Exploring associations among cannabis use, brain structure, and cognitive function in older adults offers an opportunity to observe potential harm or benefit of cannabis.

This pilot study assessed structural magnetic resonance imaging in older adults who were either current cannabis users (n = 28; mean age 69.8 years, 36% female) or nonusers (n = 28; mean age 66.8 years, 61% female).

Users and nonusers did not differ in terms of total gray or white matter volumes controlling for age and depression symptoms, but users showed greater regional volume of left putamen, lingual cortex, and rostral middle frontal cortex.

No significant differences between groups were observed in performance on a brief computerized cognitive battery.

These results suggest that cannabis use likely does not have a widespread impact on overall cortical volume while controlling for age.”

https://www.ncbi.nlm.nih.gov/pubmed/30785022

https://www.sciencedirect.com/science/article/pii/S0925492718302683?via%3Dihub

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Cannabis use in youth is associated with limited alterations in brain structure

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“There were no significant differences by cannabis group in global or regional brain volumes, cortical thickness, or gray matter density, and no significant group by age interactions were found. Follow-up analyses indicated that values of structural neuroimaging measures by cannabis group were similar across regions, and any differences among groups were likely of a small magnitude. In sum, structural brain metrics were largely similar among adolescent and young adult cannabis users and non-users. Our data converge with prior large-scale studies suggesting small or limited associations between cannabis use and structural brain measures in youth.”

https://www.ncbi.nlm.nih.gov/pubmed/30780151

https://www.nature.com/articles/s41386-019-0347-2

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Activation of ATP-sensitive K-channel promotes the anticonvulsant properties of cannabinoid receptor agonist through mitochondrial ATP level reduction.

“Cannabinoid receptor (CBR) agonist could act as a protective agent against seizure susceptibility in animal models of epilepsy.

Studies have shown that potassium channels could play a key role in ameliorating neuronal excitability.

In this study, we attempted to evaluate how CBRs and Adenosine Tri-Phosphate (ATP)-sensitive potassium channels collaborate to affect seizure susceptibility by changing the clonic seizure threshold (CST).

In conclusion, CB1 agonist accomplishes at least a part of its anticonvulsant actions through ATP-sensitive potassium channels, probably by decreasing the mitochondrial ATP level to open the potassium channel to induce its anticonvulsant effect.”

https://www.ncbi.nlm.nih.gov/pubmed/30776677

https://linkinghub.elsevier.com/retrieve/pii/S1525505018308503

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WIN55,212-2 induces caspase-independent apoptosis on human glioblastoma cells by regulating HSP70, p53 and Cathepsin D.

Toxicology in Vitro

“Despite the standard approaches to treat the highly aggressive and invasive glioblastoma (GBM), it remains incurable.

In this sense, cannabinoids highlight as a promising tool, because this tumor overexpresses CB1 and/or CB2 receptors and being, therefore, can be susceptible to cannabinoids treatment.

Thus, this work investigated the action of the cannabinoid agonist WIN55-212-2 on GBM cell lines and non-malignant cell lines, in vitro and in vivo. WIN was selectively cytotoxic to GBM cells. These presented blebbing and nuclear alterations in addition to cell shrinkage and chromatin condensation. WIN also significantly inhibited the migration of GAMG and U251 cells.

Finally, the data also showed that the antitumor effects of WIN are exerted, at least to some extent, by the expression of p53 and increased cathepsin D in addition to the decreased expression of HSP70.This data can indicate caspase-independent cell death mechanism. In addition, WIN decreased tumoral perimeter as well as caused a reduction the blood vessels in this area, without causing lysis, hemorrhage or blood clotting.

So, the findings herein presented reinforce the usefulness of cannabinoids as a candidate for further evaluation in treatment in glioblastoma treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30776504

https://www.sciencedirect.com/science/article/pii/S0887233318307537?via%3Dihub

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New Insights in Cannabinoid Receptor Structure and Signaling.

“Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic targets for treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 and CB2, there are non-CB1 and non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, and GPR119. In addition, CB1 and CB2 display allosteric binding and biased signaling, revealing correlations between biased signaling and functional outcomes. Interestingly, new investigations have indicated that CB1 is functionally present within mitochondria of striated and heart muscles directly regulating intramitochondrial signaling and respiration.

CONCLUSION:

In this review, we summarize the recent progress in cannabinoid-related orphan GPCRs, CB1/CB2 structure, Gi/Gs coupling, allosteric ligands and biased signaling, and mitochondria-localized CB1, and discuss the future promise of this research.”

https://www.ncbi.nlm.nih.gov/pubmed/30767756

http://www.eurekaselect.com/170011/article

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Spontaneous, anecdotal, retrospective, open-label study on the efficacy, safety and tolerability of cannabis galenical preparation (Bedrocan).

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“Our main aim was to investigate the short-term therapeutic effects, safety/tolerability and potential side effects of the cannabis galenical preparation (Bedrocan) in patients with a range of chronic conditions unresponsive to other treatments.

METHODS:

In this retrospective, ‘compassionate use’, observational, open-label study, 20 patients (age 18-80 years) who had appealed to our ‘Second Opinion Medical Consulting Network’ (Modena, Italy), were instructed to take sublingually the galenical oil twice a day for 3 months of treatment. The usual starting dose was low (0.5 ml/day) and gradually titrated upward to the highest recommended dose (1 ml/day). Tolerability and adverse effects were assessed at baseline and monthly thereafter during the treatment period through direct contact (email or telephone) or visit if required. Patients’ quality of life was evaluated at baseline and 3 months using the medical outcome short-form health survey questionnaire (SF-36).

KEY FINDINGS:

From baseline to 6 months post-treatment, SF-36 scores showed: reductions in total pain (P < 0.03); improvements in the physical component (P < 0.02); vitality (P < 0.03); social role functioning (P < 0.02); and general health state (P < 0.02). No changes in role limitations (P = 0.02) due to emotional state (e.g. panic, depression, mood alteration) were reported. Monthly reports of psychoactive adverse effects showed significant insomnia reduction (P < 0.03) and improvement in mood (P < 0.03) and concentration (P < 0.01).

CONCLUSIONS:

These data suggest that a cannabis galenical preparation may be therapeutically effective and safe for the symptomatic treatment of some chronic diseases. Further studies on the efficacy of cannabis as well as cannabinoid system involvement in the pathophysiology are warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/30768819

https://onlinelibrary.wiley.com/doi/full/10.1111/ijpp.12514

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Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder.

Epilepsy Research

“Severe paediatric epilepsies such as CDKL5 Deficiency Disorder (CDD) are extremely debilitating, largely due to the early-onset and refractory nature of the seizures. Existing treatment options are often ineffective and associated with a host of adverse effects, causing those that are affected to seek alternative treatments.

Cannabis based products have attracted significant attention over recent years, primarily driven by reports of miraculous cures and a renewed public preference for ‘natural’ therapies, thus placing intense pressure on health professionals and the government for regulatory change.

This study provides a comprehensive overview of the potential role for cannabis in the treatment of CDD. Key areas discussed include the history, mechanism of action, efficacy and safety of cannabis based preparations as well as the burden related to CDD.

The evidence supports the use of cannabinoids, especially cannabidiol, in similar forms of refractory epilepsy including Dravet and Lennox-Gastaut syndromes. Evidence for cannabinoids specifically in CDD is limited but growing, with multiple anecdotal reports and an open-label trial showing cannabidiol to be associated with a significant reduction in seizure activity.

This review provides the first comprehensive overview of the potential role for cannabis based preparations in the treatment of CDD and provides justification for further clinical and observational research.”

https://www.ncbi.nlm.nih.gov/pubmed/30771550

https://www.sciencedirect.com/science/article/pii/S0920121118306107?via%3Dihub

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