Tag Archives: therapeutic

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis.

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“Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease without effective treatment, highlighting the need for identifying new targets and treatment modalities. The pathogenesis of IPF is complex, and engaging multiple targets simultaneously might improve therapeutic efficacy.

To assess the role of the endocannabinoid/cannabinoid receptor 1 (endocannabinoid/CB1R) system in IPF and its interaction with inducible nitric oxide synthase (iNOS) as dual therapeutic targets, we analyzed lung fibrosis and the status of the endocannabinoid/CB1R system and iNOS in mice with bleomycin-induced pulmonary fibrosis (PF) and in lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF, as well as controls. In addition, we investigated the antifibrotic efficacy in the mouse PF model of an orally bioavailable and peripherally restricted CB1R/iNOS hybrid inhibitor.

We report that increased activity of the endocannabinoid/CB1R system parallels disease progression in the lungs of patients with idiopathic PF and in mice with bleomycin-induced PF and is associated with increased tissue levels of interferon regulatory factor-5. Furthermore, we demonstrate that simultaneous engagement of the secondary target iNOS by the hybrid CB1R/iNOS inhibitor has greater antifibrotic efficacy than inhibition of CB1R alone. This hybrid antagonist also arrests the progression of established fibrosis in mice, thus making it a viable candidate for future translational studies in IPF.”  https://www.ncbi.nlm.nih.gov/pubmed/28422760

 “The limited success of medications with a single target suggests that multitargeted therapies may be more effective, considering the multifactorial pathology of IPF. Here, we report that a dual-target hybrid inhibitor of peripheral CB1R and iNOS completely arrested the progression of BL-PF and dramatically improved the survival rate in a progression arrest treatment paradigm, providing proof of principle for a polypharmacology approach in this preclinical model of IPF. “
 https://insight.jci.org/articles/view/92281

“Our results show that CB1 signaling plays a key pathological role in the development of radiation-induced pulmonary inflammation and fibrosis, and peripherally restricted CB1 antagonists may represent a novel therapeutic approach against this devastating complication of radiotherapy/irradiation. In summary, we provide the first evidence on the key pathological role of CB1 signaling in radiation-induced pulmonary fibrogenesis and show that peripherally restricted CB1 antagonists may represent a novel therapeutic approach against this devastating and untreatable complication of radiotherapy/irradiation. Our results also suggest that targeting CB1 may provide benefits in other lung diseases associated with inflammation and fibrosis.”  http://www.atsjournals.org/doi/10.1165/rcmb.2014-0331OC

“Pure Δ9-tetrahydrocannabivarin and a Cannabis sativa extract with high content in Δ9-tetrahydrocannabivarin inhibit nitrite production in murine peritoneal macrophages. THCV down-regulated the over-expression of inducible nitric oxide synthase (iNOS). THCV counteracted LPS-induced up-regulation of CB1 receptors.  Cannabis use has immunomodulatory and anti-inflammatory effects.”  http://www.ncbi.nlm.nih.gov/pubmed/27498155

 “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. 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.”  https://www.ncbi.nlm.nih.gov/pubmed/27435265

Cannabinoid receptor 2 as a novel target for promotion of renal cell carcinoma prognosis and progression.

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Journal of Cancer Research and Clinical Oncology

“Renal cell carcinoma (RCC) is the most common malignancy of urogenital system, and patients with RCC may face a poor prognosis. However, limited curable therapeutic options are currently available.

The aim of this study is to investigate the role of Cannabinoid receptor 2 (CB2) in RCC progression.

CB2 expression is functionally related to cellular proliferation, migration, and cell cycle of RCC cells.

Our data suggest that CB2 might be a potential therapeutic target for RCC.”

https://www.ncbi.nlm.nih.gov/pubmed/28993942
https://link.springer.com/article/10.1007%2Fs00432-017-2527-y

Effects of cannabinoid receptor type 2 in respiratory syncytial virus infection in human subjects and mice.

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“An accumulating body of evidence suggests that the endocannabinoid system plays a significant role in pathophysiological processes and impacts disease severity. Here we investigate the possible role of a cannabinoid receptor type 2 (CB2) functional variant in determining disease severity and the potential pharmacological therapeutic effects of CB2 activation in viral respiratory infection. The common missense variant (CAA/CGG; Q63R) of the gene-encoding CB2 receptor (CNR2) was evaluated in 90 inpatient and 90 outpatient children with acute respiratory tract infection (ARTI). The frequency distribution of respiratory syncytial virus (RSV)-the main cause of severe cases of bronchiolitis and pneumonia in children-was studied in all collected samples. The mechanism through which CB2 affects clinical outcomes in case of RSV infection was studied in Balb/c mice model using AM630 as a CB2 antagonist. The potential therapeutic effect of CB2 activation during RSV infection was studied using a selective agonist, JWH133. The CB2 Q63R variation was associated with increased risk of hospitalization in children with ARTI. Children carrying the QQ genotype were more prone to developing severe ARTI (OR = 3.275, 95% CI: 1.221-8.705; p = 0.019). Of all the children enrolled in the study, 83 patients (46.1%) were found positive for RSV infection. The associated risk of developing severe ARTI following RSV infection increased more than two-fold in children carrying the Q allele (OR = 2.148, 95% CI: 1.092-4.224; p = 0.026). In mice, the blockade of CB2 by AM630 during RSV infection enhanced the influx of BAL cells and production of cytokines/chemokines while exaggerating lung pathology. CB2 activation by JWH133 reduces the influx of BAL cells and production of cytokines/chemokines while alleviating lung pathology. Collectively, CB2 is associated with RSV severity during infancy and may serve as a therapeutic target in RSV infection through the alleviation of virus-associated immunopathology.”

 https://www.ncbi.nlm.nih.gov/pubmed/28992427
http://www.tandfonline.com/doi/abs/10.1080/21505594.2017.1389369?journalCode=kvir20

Endocannabinoid-related compounds in gastrointestinal diseases.

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Journal of Cellular and Molecular Medicine

“The endocannabinoid system (ECS) is an endogenous signalling pathway involved in the control of several gastrointestinal (GI) functions at both peripheral and central levels. In recent years, it has become apparent that the ECS is pivotal in the regulation of GI motility, secretion and sensitivity, but endocannabinoids (ECs) are also involved in the regulation of intestinal inflammation and mucosal barrier permeability, suggesting their role in the pathophysiology of both functional and organic GI disorders. Genetic studies in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease have indeed shown significant associations with polymorphisms or mutation in genes encoding for cannabinoid receptor or enzyme responsible for their catabolism, respectively. Furthermore, ongoing clinical trials are testing EC agonists/antagonists in the achievement of symptomatic relief from a number of GI symptoms. Despite this evidence, there is a lack of supportive RCTs and relevant data in human beings, and hence, the possible therapeutic application of these compounds is raising ethical, political and economic concerns. More recently, the identification of several EC-like compounds able to modulate ECS function without the typical central side effects of cannabino-mimetics has paved the way for emerging peripherally acting drugs. This review summarizes the possible mechanisms linking the ECS to GI disorders and describes the most recent advances in the manipulation of the ECS in the treatment of GI diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28990365

http://onlinelibrary.wiley.com/doi/10.1111/jcmm.13359/abstract

Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome.

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“Worldwide medicinal use of cannabis is rapidly escalating, despite limited evidence of its efficacy from preclinical and clinical studies. Here we show that cannabidiol (CBD) effectively reduced seizures and autistic-like social deficits in a well-validated mouse genetic model of Dravet syndrome (DS), a severe childhood epilepsy disorder caused by loss-of-function mutations in the brain voltage-gated sodium channel NaV1.1.

The duration and severity of thermally induced seizures and the frequency of spontaneous seizures were substantially decreased. Treatment with lower doses of CBD also improved autistic-like social interaction deficits in DS mice.

Phenotypic rescue was associated with restoration of the excitability of inhibitory interneurons in the hippocampal dentate gyrus, an important area for seizure propagation. Reduced excitability of dentate granule neurons in response to strong depolarizing stimuli was also observed.

The beneficial effects of CBD on inhibitory neurotransmission were mimicked and occluded by an antagonist of GPR55, suggesting that therapeutic effects of CBD are mediated through this lipid-activated G protein-coupled receptor.

Our results provide critical preclinical evidence supporting treatment of epilepsy and autistic-like behaviors linked to DS with CBD. We also introduce antagonism of GPR55 as a potential therapeutic approach by illustrating its beneficial effects in DS mice.

Our study provides essential preclinical evidence needed to build a sound scientific basis for increased medicinal use of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/28973916

http://www.pnas.org/content/early/2017/09/26/1711351114

Efficacy and Tolerability of Phytomedicines in Multiple Sclerosis Patients: A Review.

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 CNS Drugs

“Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder of the central nervous system (CNS) that can cause cognition, mobility, and sensory impairments. It is considered one of the most common non-traumatic causes of disability in the world.

The aim of the present article was to review the clinical evidence related to medicinal plants in the management of MS symptoms.

Electronic databases, including the Cochrane Library, Pubmed, and Scopus, were searched for entries from 1966 to February 2017. Only clinical studies were included in this review. Different medicinal plants have positive effects on MS, including Andrographis paniculata, Boswellia papyrifera, Ruta graveolens, Vaccinium spp., Camellia sinensis, Panax ginseng, Aloysia citrodora, Ginkgo biloba, Oenothera biennis, and Cannabis sativa.

C. sativa had the highest level of clinical evidence, supporting its efficacy in MS symptoms.

Proanthocyanidins, ginkgo flavone glycosides, ginsenosides, epigallocatechin-3-gallate, cannabinoids (including delta-9-tetrahydrocannabinol and cannabidiol), boswellic acid, and andrographolide were presented as the main bioactive components of medicinal plants with therapeutic benefits in MS.

The main complications of MS in which natural drugs were effective include spasticity, fatigue, scotoma, incontinence, urinary urgency, nocturia, memory performance, functional performance, and tremor. Herbal medicines were mostly well tolerated, and the adverse effects were limited to mild to moderate. Further well-designed human studies with a large sample size and longer follow-up period are recommended to confirm the role of medicinal plants and their metabolites in the management of MS.”

https://www.ncbi.nlm.nih.gov/pubmed/28948486

https://link.springer.com/article/10.1007%2Fs40263-017-0466-4

Cannabinoid CB1 Discrimination: Effects of Endocannabinoids and Catabolic Enzyme Inhibitors.

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Journal of Pharmacology and Experimental Therapeutics

“An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type-1 (CB1) receptor agonists such as Δ9-tetrahydrocannabinol are increasingly utilized for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB1 agonist-like subjective effects, as reflected in the presence or absence of CB1-related discriminative-stimulus effects in laboratory subjects. Squirrel monkeys (n=8) that discriminated the CB1 full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB1 agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB1-related discriminative-stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were non-surmountably antagonized by low doses of rimonabant. Additionally, FAAH- or MGL-inhibition revealed CB1-like subjective effects produced by AEA, but not 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB1 receptor-mediated subjective effects.”

https://www.ncbi.nlm.nih.gov/pubmed/28947487

http://jpet.aspetjournals.org/content/early/2017/09/25/jpet.117.244392

Targeting the Endocannabinoid System to Treat Sepsis

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“Sepsis is a complex immune disorder that can affect the function of almost all organ systems in the body. This disorder is characterised by a malfunctioning immune response to an infection that involves both pro-inflammatory and immunosuppressive mediators. This leads to severe damage and failure of vital organs, resulting in patient death. Sepsis, septic shock, and systemic inflammatory response syndrome are the leading causes of mortality in surgical intensive care unit patients internationally.

The current lack of viable therapeutic treatment options for sepsis underscores our insufficient understanding of this complex disease. The endocannabinoid system, a key regulator of essential physiological functions including the immune system, has recently emerged as a potential therapeutic target for sepsis treatment. The endocannabinoid system acquires its name from the plant Cannabis Sativa, which has been used medically to treat a variety of ailments, as well as recreationally for centuries. Cannabis Sativa contains more than 60 active phytocannabinoids with the primary phytocannabinoid Δ9-tetrahydrocannabinol (THC), (6) activating both endogenous endocannabinoid receptors.

The endocannabinoid system represents a potential therapeutic target in sepsis due to the presence of cannabinoid receptors (CB2) on immune cells. In this review we discuss how various targets within the endocannabinoid system can be manipulated to treat the immune consequences of sepsis. One of the targets outlined are the endocannabinoid receptors and modulation of their activity through pharmacological agonists and antagonists. Another therapeutic target covered in this review is the modulation of the endocannabinoid degradative enzyme’s activity. Modulation of degradative enzyme activity can change the levels of endogenous cannabinoids thereby altering immune activity. Overall, activation of the CB2 receptors causes immunosuppression and can be beneficial during the hyperactivated immune state of sepsis, while suppression of the CB2 receptors may be beneficial during a hypoimmune septic state.

The endocannabinoid system modulates the immune response in experimental sepsis. Manipulating the endocannabinoid system may have potential therapeutic benefit in clinical sepsis where immune and inflammatory dysfunction can be detrimental. Multiple targets exist within the endocannabinoid system, e.g. the system can be targeted at the level of receptors by administration of synthetic compounds, similar to the endocannabinoids, which either increase or inhibit receptor activation to provide the desired therapeutic effect. Alternatively, the endogenous enzymes that degrade endocannabinoids or cannabinoid-like lipids can also be targeted in order to manipulate the levels of endocannabinoids. Proper identification of the septic stage is crucial to determine the adequate therapeutic response that will be most beneficial. Due to the biphasic nature of sepsis immunopathology, immune suppression through endocannabinoid modulation can help mitigate the hyper-immune response during the early septic state, while immune activation may be beneficial in later stages.” http://www.signavitae.com/2013/05/targeting-the-endocannabinoid-system-to-treat-sepsis/

Targeting the Endocannabinoid System to Treat Sepsis

Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury.

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“Cannabidiol (CBD) is a non-psychoactive component of marijuana, which has anti-inflammatory effects. It has also been approved by FDA for various orphan diseases for exploratory trials. Herein, we investigated the effects of CBD on liver injury induced by chronic plus binge alcohol feeding in mice. CBD may have therapeutic potential in the treatment of alcoholic liver diseases associated with inflammation, oxidative stress and steatosis, which deserves exploration in human trials.”  https://www.ncbi.nlm.nih.gov/pubmed/28935932

“Cannabidiol (CBD) is the most abundant non-psychoactive constituent of marijuana plant (Cannabis Sativa) with excellent safety profile in humans even after chronic use. In conclusion, we demonstrate that CBD treatment significantly attenuates liver injury induced by chronic plus binge alcohol in a mouse model and oxidative burst in human neutrophils. CBD ameliorates alcohol-induced liver injury by attenuating inflammatory response involving E-selectin expression and neutrophil recruitment, and consequent oxidative/nitrative stress, in addition to attenuation of the alcohol-induced hepatic metabolic dysregulation and steatosis. These beneficial effects, coupled with the proven safety of CBD in human clinical trials and its current orphan drug approval by FDA for various indications suggest that it may have therapeutic potential in liver disease associated with inflammation, oxidative stress, metabolic dysregulation and steatosis.” https://www.nature.com/articles/s41598-017-10924-8

[Delta-9-tetrahydrocannabinol-cannabidiol in the treatment of spasticity in chronic spinal cord injury: a clinical experience].

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“Spasticity in chronic spinal cord injury is a condition that can have negative repercussions on the patient’s quality of life. Its treatment is complex and sometimes the outcome is insufficient.

Cannabinoids have recently been used in multiple sclerosis to successfully treat spasticity that is refractory to other therapies.

AIM:

To quantify the clinical response of a group of patients with spastic chronic spinal cord injury to the orally administered drug delta-9-tetrahydrocannabinol-cannabidiol (Sativex ®) as medication for use in special situations.

RESULTS:

Fifteen patients took part in this study. A significant improvement was observed on three of the scales recorded: modified Ashworth scale (z = -2.97; p = 0.003), Penn spasm frequency scale (z = -2.76; p = 0.006) and Numeric Rating Scale (z = -3.21; p = 0.001).

CONCLUSIONS:

Sativex can be considered an alternative in patients with spasticity associated with chronic spinal cord injury for whom other therapeutic measures have been insufficient. Further studies need to be conducted before the use of this drug can be recommended and so as to define a complete profile of its long-term side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/28929471