Tag Archives: therapeutic

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

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“The cannabinoids are a structurally diverse family of compounds with a large number of different biological targets.

Although CB1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism.

We have, therefore, investigated the ability of a range of cannabinoids to activate PPARα and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection.

These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARα and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

In summary, the data presented here provide strong evidence that selected cannabinoids are PPARα agonists, and suggest a novel means by which the multiple effects of cannabinoids, in both the CNS and periphery, could be brought about.

In addition to its well-recognized role in lipid metabolism, PPARα activation showed obvious beneficial effects in ischaemic brain damage, which is likely to be connected with its anti-inflammatory action through the NF–κB pathway.

These discoveries not only broaden the potential use of cannabinoids as therapeutic agents, but also support PPARα as a new target for neuroprotective treatment.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190030/

Evaluation of Δ(9)-tetrahydrocannabinol metabolites and oxidative stress in type 2 diabetic rats.

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“Cannabis has been known to be the oldest psychoactive plant for years. It is classified in the Cannabis genus, which is part of the Cannabacea family.

Cannabis sativa L. is the most common species. Δ9-tetrahydrocannabinol (THC) is the main psychoactive constituent identified in Cannabis sativa L.

THC is the most notable cannabinoid among all phytocannabinoids.

THC is exposed to degradation and converted into its active and inactive metabolites that are conjugated with glucuronic acid, and excreted in urine. THC is converted to active metabolite, 11-hydroxy-Δ9-THC (11-OH-THC), and then converted to an inactive metabolite, 11-nor-9-carboxy- Δ9-THC (THC – COOH).

ElSohly and Slade mention that C. sativa and its products have been used as medicinal agents.

Cannabinoids show a variety of therapeutic effects against chronic pain and muscle spasms, nausea and anorexia caused by HIV treatment, vomiting and nausea caused by cancer chemotherapy as well as anorexia associated with weight loss caused by immune deficiency syndrome.

Many studies report that THC provides protection against neuronal injury in a cell culture model of Parkinson disease and experimental models of Huntington disease, exhibits anti-oxidative action and mitigates the severity of the autoimmune response in an experimental model of diabetes.

The development and progression of diabetes mellitus and its complications arise out of increased oxidative damage. Kassab and Piwowar report that the best-known pathways of diabetic complications include oxidative stress.

The aims of the study presented in this paper were: (a) to explain the effects of THC on oxidative stress in T2DM treated with THC and (b) to determine the level of THC metabolites in the urine of diabetic and control rats induced by THC injection.

The object of the study is to examine the effects of Δ(9)-tetrahydrocannabinol (THC) against oxidative stress in the blood and excretion of THC metabolites in urine of type 2 diabetic rats.

These findings highlight that THC treatment may attenuate slightly the oxidative stress in diabetic rats.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818362/

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory and cell death signaling pathways in diabetic cardiomyopathy

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“CBD, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts antiinflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans.

In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrosative stress, cell death and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose.

 A previous study has demonstrated cardiac protection by CBD in myocardial ischemic reperfusion injury; therefore, we have investigated the potential protective effects of CBD in diabetic hearts and in primary human cardiomyocytes exposed to high glucose.
Our findings underscore the potential of CBD for the prevention/treatment of diabetic complications.
Collectively, these results coupled with the excellent safety and tolerability profile of cannabidiol in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrosative stress, inflammation, cell death and fibrosis.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026637/

Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption.

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“Cannabinoids, components of the Cannabis sativa (marijuana) plant, are known to exert potent anti-inflammatory, immunomodulatory and analgesic effects through activation of cannabinoid-1 and -2 (CB1 and CB2) receptors located in the central nervous system and immune cells.

The limitation of the therapeutic utility of the major cannabinoid, Δ9-tetrahydrocannabinol, is the development of psychoactive effects through central nervous system CB1 receptor. In contrast, cannabidiol (CBD), one of the most abundant cannabinoids of Cannabis sativa with reported antioxidant, anti-inflammatory, and immunomodulatory effects is well tolerated without side effects when chronically administered to humans and is devoid of psychoactive properties due to a low affinity for the CB1 and CB2 receptors.

A nonpsychoactive cannabinoid cannabidiol (CBD) has been shown to exert potent anti-inflammatory and antioxidant effects and has recently been reported to lower the incidence of diabetes in nonobese diabetic mice and to preserve the blood-retinal barrier in experimental diabetes.

In this study we have investigated the effects of CBD on high glucose (HG)-induced, mitochondrial superoxide generation, NF-κB activation, nitrotyrosine formation, inducible nitric oxide synthase (iNOS) and adhesion molecules ICAM-1 and VCAM-1 expression, monocyte-endothelial adhesion, transendothelial migration of monocytes, and disruption of endothelial barrier function in human coronary artery endothelial cells (HCAECs).

HG markedly increased mitochondrial superoxide generation (measured by flow cytometry using MitoSOX), NF-κB activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, transendothelial migration of monocytes, and monocyte-endothelial adhesion in HCAECs. HG also decreased endothelial barrier function measured by increased permeability and diminished expression of vascular endothelial cadherin in HCAECs.

Remarkably, all the above mentioned effects of HG were attenuated by CBD pretreatment.

Since a disruption of the endothelial function and integrity by HG is a crucial early event underlying the development of various diabetic complications, our results suggest that CBD, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans, may have significant therapeutic benefits against diabetic complications and atherosclerosis.

Collectively, our results suggest that the nonpsychoactive cannabinoid CBD have significant therapeutic benefits against diabetic complications and atherosclerosis by attenuating HG-induced mitochondrial superoxide generation, increased NF-κB activation, upregulation of iNOS and adhesion molecules, 3-NT formation, monocyte-endothelial adhesion, TEM of monocytes, and disruption of the endothelial barrier function.

This is particularly encouraging in light of the excellent safety and tolerability profile of CBD in humans.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2228254/

Abnormal cannabidiol attenuates experimental colitis in mice, promotes wound healing and inhibits neutrophil recruitment.

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“Non-psychotropic atypical cannabinoids have therapeutic potential in a variety of inflammatory conditions including those of the gastrointestinal tract.

Here we examined the effects of the atypical cannabinoid abnormal cannabidiol (Abn-CBD) on wound healing, inflammatory cell recruitment and colitis in mice.

TNBS-induced colitis was attenuated by treatment with Abn-CBD.

Abn-CBD is protective against TNBS-induced colitis, promotes wound healing of endothelial and epithelial cells and inhibits neutrophil accumulation on HUVEC monolayers.

Thus, the atypical cannabinoid Abn-CBD represents a novel potential therapeutic in the treatment of intestinal inflammatory diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27418880

Potential therapeutic targets and the role of technology in developing novel cannabinoid drugs from cyanobacteria.

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“Cyanobacteria find several applications in pharmacology as potential candidates for drug design. The need for new compounds that can be used as drugs has always been on the rise in therapeutics. Cyanobacteria have been identified as promising targets of research in the quest for new pharmaceutical compounds as they can produce secondary metabolites with novel chemical structures. Cyanobacteria is now recognized as a vital source of bioactive molecules like Curacin A, Largazole and Apratoxin which have succeeded in reaching Phase II and Phase III into clinical trials.

The discovery of several new clinical cannabinoid drugs in the past decade from diverse marine life should translate into a number of new drugs for cannabinoid in the years to come. Conventional cannabinoid drugs have high toxicity and as a result, they affect the efficacy of chemotherapy and patients’ life very much. The present review focuses on how potential, safe and affordable drugs used for cannabinoid treatment could be developed from cyanobacteria.”

http://www.ncbi.nlm.nih.gov/pubmed/27416557

5-lipoxygenase mediates docosahexaenoyl ethanolamide and N-arachidonoyl-L-alanine-induced reactive oxygen species production and inhibition of proliferation of head and neck squamous cell carcinoma cells.

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“Endocannabinoids have recently drawn attention as promising anti-cancer agents. We previously observed that anandamide (AEA), one of the representative endocannabinoids, effectively inhibited the proliferation of head and neck squamous cell carcinoma (HNSCC) cell lines in a receptor-independent manner. In this study, using HNSCC cell lines, we examined the anti-cancer effects and the mechanisms of action of docosahexaenoyl ethanolamide (DHEA) and N-arachidonoyl-L-alanine (NALA), which are polyunsaturated fatty acid (PUFA)-based ethanolamides like AEA. From these findings, we suggest that ROS production induced by the 5-LO pathway mediates the anti-cancer effects of DHEA and NALA on HNSCC cells. Finally, our findings suggest the possibility of a new cancer-specific therapeutic strategy, which utilizes 5-LO activity rather than inhibiting it.”  http://www.ncbi.nlm.nih.gov/pubmed/27411387

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2499-3

The CB2 receptor and its role as a regulator of inflammation.

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“The CB2 receptor is the peripheral receptor for cannabinoids.

It is mainly expressed in immune tissues, highlighting the possibility that the endocannabinoid system has an immunomodulatory role.

In this respect, the CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases.

In this regard, numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype.

This suggests that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions.

Herein, we review the pharmacology of the CB2 receptor, its expression pattern, and the signaling pathways induced by its activation. We next examine the regulation of immune cell functions by the CB2 receptor and the evidence obtained from primary human cells, immortalized cell lines, and animal models of inflammation.

Finally, we discuss the possible therapies targeting the CB2receptor and the questions that remain to be addressed to determine whether this receptor could be a potential target to treat inflammatory disease.”

http://www.ncbi.nlm.nih.gov/pubmed/27402121

Microglia activation states and cannabinoid system: Therapeutic implications.

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“Microglial cells are recognized as the brain’s intrinsic immune cells, mediating actions that range from the protection against harmful conditions that modify CNS homeostasis, to the control of proliferation and differentiation of neurons and their synaptic pruning. To perform these functions, microglia adopts different activation states, the so-called phenotypes that depending on the local environment involve them in neuroinflammation, tissue repair and even the resolution of the inflammatory process.

There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity.

Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs.

The expression of cannabinoid receptors – mainly CB2 – and the production of eCBs have been related to the activation profile of these cells and therefore, the microglial phenotype, emerging as one of the mechanisms by which microglia becomes alternatively activated.

Here, we will discuss recent studies that provide new insights into the role of CBs and their endogenous counterparts in defining the profile of microglia activation.

These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27373505

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases.

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“Psychoactive substances are associated with the idea of drugs with high addictive liability, affecting mental states, cognition, emotion and motor behavior. However these substances can modify synaptic transmission and help to disclose some mechanisms underlying alterations in brain processing and pathophysiology of motor disease. Hence, the “bright side” of cannabinoid-based drugs must be thoroughly examined to be identified within the latter framework.

We will analyze the preclinical and clinical evidence of cannabinoid-based drugs, discussing their therapeutic value in basal ganglia motor disorders such as Parkinson’s disease and Huntington disease.

Expert commentary: despite the knowledge acquired in the last years, the therapeutic potential of cannabinoid-based drugs should be further tested by novel routes of investigation. This should be focused on the role of cannabinoid signaling system in mitochondrial function as well as on the physical and functional interaction with other key receptorial targets belonging to this network.”

http://www.ncbi.nlm.nih.gov/pubmed/27373318