Tag Archives: therapeutic

Cannabinoid signalling in embryonic and adult neurogenesis: possible implications for psychiatric and neurological disorders.

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“Cannabinoid signalling modulates several aspects of brain function, including the generation and survival of neurons during embryonic and adult periods.

The present review intended to summarise evidence supporting a role for the endocannabinoid system on the control of neurogenesis and neurogenesis-dependent functions.

An understanding of the mechanisms by which cannabinoid signalling influences developmental and adult neurogenesis will help foster the development of new therapeutic strategies for neurodevelopmental, psychiatric and neurological disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/29764526

https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/cannabinoid-signalling-in-embryonic-and-adult-neurogenesis-possible-implications-for-psychiatric-and-neurological-disorders/E9DE9116DC604D976C9C7B0D2D254674

Medical Cannabis for Pediatric Moderate to Severe Complex Motor Disorders.

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SAGE Journals

“A complex motor disorder is a combination of various types of abnormal movements that are associated with impaired quality of life (QOL). Current therapeutic options are limited. We studied the efficacy, safety, and tolerability of medical cannabis in children with complex motor disorder. This pilot study was approved by the institutional ethics committee.

Two products of cannabidiol (CBD) enriched 5% oil formulation of cannabis were compared: one with 0.25% δ-9-tetrahydrocannabinol (THC) 20:1 group, the other with 0.83% THC 6:1 group. Patients aged 1 to 17 years (n = 25) with complex motor disorder were enrolled. The assigned medication was administered for 5 months.

Significant improvement in spasticity and dystonia, sleep difficulties, pain severity, and QOL was observed in the total study cohort, regardless of treatment assignment. Adverse effects were rare and included worsening of seizures in 2 patients, behavioral changes in 2 and somnolence in 1.”

https://www.ncbi.nlm.nih.gov/pubmed/29766748

http://journals.sagepub.com/doi/abs/10.1177/0883073818773028?journalCode=jcna

Effects of CB2 and TRPV1 receptors’ stimulation in pediatric acute T-lymphoblastic leukemia

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“T-Acute Lymphoblastic Leukemia (T-ALL) is less frequent than B-ALL, but it has poorer outcome. For this reason new therapeutic approaches are needed to treat this malignancy.

The Endocannabinoid/Endovanilloid (EC/EV) system has been proposed as possible target to treat several malignancies, including lymphoblastic diseases. The EC/EV system is composed of two G-Protein Coupled Receptors (CB1 and CB2), the Transient Potential Vanilloid 1 (TRPV1) channel, their endogenous and exogenous ligands and enzymes. CB1 is expressed mainly in central nervous system while CB2 predominantly on immune and peripheral cells, therefore we chose to selectively stimulate CB2 and TRPV1.

We treated T-ALL lymphoblasts derived from 4 patients and Jurkat cells with a selective agonist at CB2 receptor: JWH-133 [100 nM] and an agonist at TRPV1 calcium channel: RTX [5 uM] at 6, 12 and 24 hours. We analyzed the effect on apoptosis and Cell Cycle Progression by a cytofluorimetric assays and evaluated the expression level of several target genes (Caspase 3, Bax, Bcl-2, AKT, ERK, PTEN, Notch-1, CDK2, p53) involved in cell survival and apoptosis, by Real-Time PCR and Western Blotting.

We observed a pro-apoptotic, anti-proliferative effect of these compounds in both primary lymphoblasts obtained from patients with T-ALL and in Jurkat cell line. Our results show that both CB2 stimulation and TRPV1 activation, can increase the apoptosis in vitro, interfere with cell cycle progression and reduce cell proliferation, indicating that a new therapeutic approach to T-cell ALL might be possible by modulating CB2 and TRPV1 receptors.”

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=25052

Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease.

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SAGE Journals

“Cardiovascular disease is currently not adequately managed and has become one of the main causes of morbidity and mortality worldwide. Current therapies are inadequate in terms of preventing its progression. There are several limitations, such as poor oral bioavailability, side effects, low adherence to treatment, and high dosage frequency of formulations due to the short half-life of the active ingredients used, among others.

This review aims to highlight the most relevant aspects of the relationship between the cardiovascular system and the endocannabinoid system, with special attention to the possible translational effect of the use of anandamide in cardiovascular health. The deep and detailed knowledge of this interaction, not always beneficial, and that for years has gone unnoticed, is essential for the development of new therapies.

We discuss the most recent and representative results obtained in the field of basic research, referring to the aforementioned subject, emphasizing fundamentally the main role of nitric oxide, renal physiology and its deregulation in pathological processes.”

 https://www.ncbi.nlm.nih.gov/pubmed/29764302
http://journals.sagepub.com/doi/10.1177/1753944718773690

A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery

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Drug Delivery and Translational Research

“Most medications targeting optic neuropathies are administered as eye drops. However, their corneal penetration efficiencies are typically < 5%.

There is a clear, unmet need for novel transcorneal drug delivery vehicles. To this end, we have developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs into the aqueous humor of the eye.

We subsequently tested the efficacy of our formulation in whole-eye experiments by loading the nanoparticles with cannabigerolic acid (CBGA). Our formulation exhibits over a 300% increase in transcorneal penetration over control formulations.

We have successfully developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs such as cannabinoids into the aqueous humor of the eye.

Our therapeutic strategy leverages the proven potential of cannabinoids to confer neuroprotection to ganglion cells.

This work paves the way for the introduction of novel products targeting ocular diseases to the market.”

https://link.springer.com/article/10.1007/s13346-018-0504-x

2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain.

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“2-Arachidonoylglycerol (2-AG) is a signaling lipid in the central nervous system that is a key regulator of neurotransmitter release. 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. It is involved in a wide array of (patho)physiological functions, such as emotion, cognition, energy balance, pain sensation and neuroinflammation. In this review, we describe the biosynthetic and metabolic pathways of 2-AG and how chemical and genetic perturbation of these pathways has led to insight in the biological role of this signaling lipid. Finally, we discuss the potential therapeutic benefits of modulating 2-AG levels in the brain.”

 https://www.ncbi.nlm.nih.gov/pubmed/29751000
https://www.sciencedirect.com/science/article/pii/S0163782717300619

Cannabinoids and gastrointestinal motility: Pharmacology, clinical effects, and potential therapeutics in humans.

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Neurogastroenterology &amp; Motility banner

“Cannabinoid agents and cannabis are frequently used for relief of diverse gastrointestinal symptoms.

PURPOSE:

The objective of this article is to increase the awareness of gastroenterologists to the effects of cannabinoids on gastrointestinal motility, as gastroenterologists are likely to encounter patients who are taking cannabinoids, or those with dysmotility that may be associated with cannabinoid mechanisms.

The non-selective cannabinoid agonist, dronabinol, retards gastric emptying and inhibits colonic tone and phasic pressure activity.

In summary, cannabinoid mechanisms and pharmacology are relevant to the current and future practice of clinical gastroenterology.”

https://www.ncbi.nlm.nih.gov/pubmed/29745439

https://onlinelibrary.wiley.com/doi/abs/10.1111/nmo.13370

Emerging Role of (Endo)Cannabinoids in Migraine.

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“In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain.

Individual sections of this review cover key aspects of this topic, such as: (i) the current knowledge on the endocannabinoid system (ECS) with emphasis on expression of its components in migraine related structures; (ii) distinguishing peripheral from central site of action of cannabinoids, (iii) proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv) therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v) dual (possibly opposing) actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors.

We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD) hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD) underlying the migraine aura.

Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components) or novel endocannabinoid therapeutics in migraine treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/29740328

https://www.frontiersin.org/articles/10.3389/fphar.2018.00420/full

Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease.

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CNS Drugs

“Alzheimer’s disease is a multifactorial disorder for which there is no disease-modifying treatment yet.

CB2 receptors have emerged as a promising therapeutic target for Alzheimer’s disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects.

OBJECTIVE:

The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer’s disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer’s disease, contributing to the instigation of the disease.

METHODS:

Lymphoblastoid cell lines from patients with Alzheimer’s disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in β-amyloid-treated neuronal cells.

RESULTS:

We report here that PGN33 normalized the increased proliferative activity of Alzheimer’s disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented β-amyloid-induced cell death in neuronal cells.

CONCLUSION:

Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/29736745

https://link.springer.com/article/10.1007%2Fs40263-018-0515-7

Enhanced endocannabinoid tone as a potential target of pharmacotherapy.

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“The endocannabinoid system is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain, and cancer. It has been suggested that this phenomenon primarily serves an autoprotective role in inhibiting disease progression and/or diminishing signs and symptoms.

Accordingly, enhancement of endogenous endocannabinoid tone by inhibition of endocannabinoid degradation represents a promising therapeutic approach for the treatment of many diseases. Importantly, this allows for the avoidance of unwanted psychotropic side effects that accompany exogenously administered cannabinoids.

The effects of endocannabinoid metabolic pathway modulation are complex, as endocannabinoids can exert their actions directly or via numerous metabolites. The two main strategies for blocking endocannabinoid degradation are inhibition of endocannabinoid-degrading enzymes and inhibition of endocannabinoid cellular uptake.

To date, the most investigated compounds are inhibitors of fatty acid amide hydrolase (FAAH), an enzyme that degrades the endocannabinoid anandamide. However, application of FAAH inhibitors (and consequently other endocannabinoid degradation inhibitors) in medicine became questionable due to a lack of therapeutic efficacy in clinical trials and serious adverse effects evoked by one specific compound.

In this paper, we discuss multiple pathways of endocannabinoid metabolism, changes in endocannabinoid levels across numerous human diseases and corresponding experimental models, pharmacological strategies for enhancing endocannabinoid tone and potential therapeutic applications including multi-target drugs with additional targets outside of the endocannabinoid system (cyclooxygenase-2, cholinesterase, TRPV1, and PGF2α-EA receptors), and currently used medicines or medicinal herbs that additionally enhance endocannabinoid levels.

Ultimately, further clinical and preclinical studies are warranted to develop medicines for enhancing endocannabinoid tone.”

https://www.ncbi.nlm.nih.gov/pubmed/29729263

https://www.sciencedirect.com/science/article/pii/S0024320518302352