Tag Archives: treatment

Arachidonylcyclopropylamide increases microglial cell migration through cannabinoid CB2 and abnormal-cannabidiol-sensitive receptors.

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“Microglial cells, the macrophages of the brain, express low, yet detectable levels of cannabinoid CB(1) receptors, which are known to modulate cell migration.

To determine if cannabinoid CB(1) receptors expressed by microglial cells modulate their migration, we assessed whether arachidonylcyclopropylamide (ACPA, an agonist shown to selectively activate CB(1) receptors) affects the migration of BV-2 cells, a mouse microglial cell line.

Our results suggest that cannabinoid CB(2) receptors and abn-CBD receptors, rather than cannabinoid CB(1) receptors, regulate microglial cell migration, and that ACPA is a broad cannabinoid receptor agonist.”

http://www.ncbi.nlm.nih.gov/pubmed/12921861

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

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“Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment.

Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects.

Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases.

Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group.

Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

Regarding the pharmacodynamics of the hybrid CB1R/iNOS inhibitor, two important principles have emerged from efforts to develop effective antifibrotic therapies. First, antifibrotic treatment strategies could aim to control the primary disease, to inhibit fibrogenic gene expression and signaling, to promote molecular mechanisms involved in fibrosis regression, or a combination of these. Second, with multiple molecular mechanisms and signaling pathways involved in fibrosis, targeting more than one could increase antifibrotic efficacy, and the hybrid CB1R/iNOS inhibitor embodies optimal characteristics on both accounts.

As to the first principle, both the endocannabinoid/CB1R system and iNOS are ideal targets, as they are known to be involved directly in the fibrotic process and also in the conditions predisposing to liver fibrosis, as detailed in the Introduction. An emerging major predisposing factor to liver fibrosis is nonalcoholic fatty liver disease, and CB1R blockade has proven effective in mitigating obesity-related hepatic steatosis in both rodent models and humans. The other two major predisposing factors, alcoholic fatty liver disease and viral hepatitis, also involve increased CB1R activity. Hepatic CB1R expression is induced either by chronic ethanol intake or the hepatitis C virus, and CB1R blockade mitigates alcohol-induced steatosis and inhibits hepatitis C virus production.

The dual targeting of peripheral CB1R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases.

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

http://insight.jci.org/articles/view/87336

Effect of combined oral doses of Δ9-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models.

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“The purpose of this study was to evaluate the potential of oral combined cannabis constituents to reduce nausea.

The objective of this study was to determine the effect of combining subthreshold oral doses of Δ9-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models of conditioned gaping.

RESULTS:

For acute nausea, i.g. administration of subthreshold doses of THC (0.5 and 1 mg/kg) or CBDA (0.5 and 1 μg/kg) significantly suppressed acute nausea-induced gaping, whereas higher individual doses of both THC and CBDA were maximally effective. Combined i.g. administration of higher doses of THC and CBDA (2.5 mg/kg THC-2.5 μg/kg CBDA; 10 mg/kg THC-10 μg/kg CBDA; 20 mg/kg THC-20 μg/kg CBDA) also enhanced positive hedonic reactions elicited by saccharin solution during conditioning. For anticipatory nausea, combined subthreshold i.g. doses of THC (0.1 mg/kg) and CBDA (0.1 μg/kg) suppressed contextually elicited conditioned gaping. When administered i.g., THC was effective on its own at doses ranging from 1 to 10 mg/kg, but CBDA was only effective at 10 μg/kg. THC alone was equally effective by intraperitoneal (i.p.) and i.g. administration, whereas CBDA alone was more effective by i.p. administration (Rock et al. in Psychopharmacol (Berl) 232:4445-4454, 2015) than by i.g. administration.

CONCLUSIONS:

Oral administration of subthreshold doses of THC and CBDA may be an effective new treatment for acute nausea and anticipatory nausea and appetite enhancement in chemotherapy patients.”

http://www.ncbi.nlm.nih.gov/pubmed/27438607

Subjective aggression during alcohol and cannabis intoxication before and after aggression exposure.

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“Alcohol and cannabis use have been implicated in aggression.

Alcohol consumption is known to facilitate aggression, whereas a causal link between cannabis and aggression has not been clearly demonstrated.

OBJECTIVES:

This study investigated the acute effects of alcohol and cannabis on subjective aggression in alcohol and cannabis users, respectively, following aggression exposure. Drug-free controls served as a reference. It was hypothesized that aggression exposure would increase subjective aggression in alcohol users during alcohol intoxication, whereas it was expected to decrease subjective aggression in cannabis users during cannabis intoxication.

RESULTS:

Subjective aggression significantly increased following aggression exposure in all groups while being sober. Alcohol intoxication increased subjective aggression whereas cannabis decreased the subjective aggression following aggression exposure. Aggressive responses during the PSAP increased following alcohol and decreased following cannabis relative to placebo. Changes in aggressive feeling or response were not correlated to the neuroendocrine response to treatments.

CONCLUSIONS:

It is concluded that alcohol facilitates feelings of aggression whereas cannabis diminishes aggressive feelings in heavy alcohol and regular cannabis users, respectively.”

http://www.ncbi.nlm.nih.gov/pubmed/27422568

Cannabinoids, inflammation, and fibrosis.

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“Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs).

As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis.

A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented.

Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations-Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)-that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (CT-3, AJA; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals.

The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances.

Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.”

http://www.ncbi.nlm.nih.gov/pubmed/27435265

VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington’s disease.

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“Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ.

We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiophilic VCE-003 derivative named VCE-003.2 that preserves the ability to activate PPARγ and analyzed its neuroprotective activity.

This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPARγ antagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells.

The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropionic acid (3NP) administration. VCE-003.2 prevented medium spiny DARPP32(+) neuronal loss in these Huntington’s-like disease mice models improving motor deficits, reactive astrogliosis and microglial activation. In the 3NP model VCE-003.2 inhibited the upregulation of proinflammatory markers and improved antioxidant defenses in the brain.

These data lead us to consider VCE-003.2 to have high potential for the treatment of Huntington’s disease (HD) and other neurodegenerative diseases with neuroinflammatory traits.”

http://www.ncbi.nlm.nih.gov/pubmed/27430371

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/

Δ9-tetrahydrocannabinol treatment improved endothelium-dependent relaxation on streptozotocin/nicotinamide-induced diabetic rat aorta.

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“In this study, we investigated the possible effect of Δ(9)-tetrahydrocannabinol (THC), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, on metabolic control and vascular complications of diabetes in streptozotocin/nicotinamide (STZ/NIC) induced type 2 diabetes mellitus.

These results suggested that THC improved endothelium-dependent relaxation in STZ/NIC induced diabetic rat aorta and that these effects were mediated at least in part, by control of hyperglycemia and enhanced endothelial nitric oxide bioavailability.”