Tag Archives: anti-inflammatory

Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved.

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Abstract

“This study aimed to give a rationale for the employment of phytocannabinoid formulations to treat neuropathic pain. It was found that a controlled cannabis extract, containing multiple cannabinoids, in a defined ratio, and other non-cannabinoid fractions (terpenes and flavonoids) provided better antinociceptive efficacy than the single cannabinoid given alone, when tested in a rat model of neuropathic pain. The results also demonstrated that such an antihyperalgesic effect did not involve the cannabinoid CB1 and CB2 receptors, whereas it was mediated by vanilloid receptors TRPV1. The non-psychoactive compound, cannabidiol, is the only component present at a high level in the extract able to bind to this receptor: thus cannabidiol was the drug responsible for the antinociceptive behaviour observed. In addition, the results showed that after chronic oral treatment with cannabis extract the hepatic total content of cytochrome P450 was strongly inhibited as well as the intestinal P-glycoprotein activity. It is suggested that the inhibition of hepatic metabolism determined an increased bioavailability of cannabidiol resulting in a greater effect. However, in the light of the well known antioxidant and antiinflammatory properties of terpenes and flavonoids which could significantly contribute to the therapeutic effects, it cannot be excluded that the synergism observed might be achieved also in the absence of the cytochrome P450 inhibition.”

http://www.ncbi.nlm.nih.gov/pubmed/18618522

The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications.

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“Prostate cancer is a global public health problem, and it is the most common cancer in American men and the second cause for cancer-related death. Experimental evidence shows that prostate tissue possesses cannabinoid receptors and their stimulation results in anti-androgenic effects.”

“Cannabis is a bushy plant with palmate leaves and clusters of small green flowers, and it grows wild in regions of tropical weather and can attain up to 3 m height. The genus Cannabis is complemented by sativa which translates to useful. Cannabis has indeed been used throughout history for a variety of purposes, including the production of fiber for paper and textile manufacture. However, its current popularity lies in its use as a recreational drug with psychoactive properties. The plant contains many chemical compounds that have different pharmacological properties, varying in quantity and quality depending on the strain, culture, and storage conditions.”

“The frequently held view of cannabis and its related products as drugs of abuse have slowed progress in the development of studies designed to take advantage of the properties of cannabinoid derivatives for therapeutic purposes…”

“Delta-9-THC is the substance with the greatest psychoactive potency of the natural cannabinoids and exhibits the greatest analgesic activity. Cannabidiol (CBD), another major constituent of the Cannabis sativa plant, has the same therapeutic effects of THC (analgesic, anti-inflammatory, and others), but with a different pharmacologic profile…”

“It is our conclusion that it would be of interest to conduct clinical trials involving medicinal cannabis or other cannabinoid agonists, comparing clinical markers such as PSA with controls, especially in men with bone metastatic prostate cancer, whom would not only benefit from the possible anti-androgenic effects of cannabinoids but also from analgesia of bone pain, improving quality of life, while reducing narcotic consumption and preventing opioid dependence.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339795/

Cannabinoid Receptor as a Novel Target for the Treatment of Prostate Cancer

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“Because prostate cancer has become the most common cancer diagnosed in men, developing novel targets and mechanism-based agents for its treatment has become a challenging issue. In recent years cannabinoids, the active components of Cannabis sativa Linnaeus (marijuana) and their derivatives have drawn renewed attention because of their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects, and tumor regression . Cannabinoids have been shown to induce apoptosis in gliomas, PC-12 pheochromocytoma, CHP 100 neuroblastoma, and hippocampal neurons in vitro, and most interestingly, regression of C6-cell gliomas in vivo. Further interest in cannabinoid research came from the discovery of specific cannabinoid systems and the cloning of specific cannabinoid receptors. These diversified effects of cannabinoids are now known to be mediated by the activation of specific G protein-coupled receptors that are normally bound by a family of endogenous ligands, the endocannabinoids. Two different cannabinoid receptors have been characterized and cloned from mammalian tissues: the “central” CB1 receptor, and the “peripheral” CB2 receptor.”

“In the present study, we show for the first time that expression levels of both cannabinoid receptors, CB1 and CB2, are higher in human prostate cancer cells than in normal cells. Importantly, we also show that WIN-55,212-2 (CB1/CB2 agonist) treatment with androgen-responsive LNCaP cells results in a dose- and time-dependent inhibition of cell growth with a concomitant induction of apoptosis, decrease in protein and mRNA expression of androgen receptor and prostate-specific antigen (PSA), decrease in secreted PSA levels, protein expression of proliferating cell nuclear antigen (PCNA), and vascular endothelial growth factor (VEGF). We suggest that cannabinoid receptor agonists may be useful in the treatment of human prostate cancer.”

“…non–habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.”

“We conclude that cannabinoids should be considered as agents for the management of prostate cancer.”

.http://cancerres.aacrjournals.org/content/65/5/1635.long

Cannabinoid Receptor Agonist-induced Apoptosis of Human Prostate Cancer Cells LNCaP Proceeds through Sustained Activation of ERK1/2 Leading to G1 Cell Cycle Arrest

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“Prostate cancer (CaP)2 ranks as the most common noncutaneous malignancy and the second leading cause of cancer-related deaths in American males, with similar trends in many Western countries…The major cause of mortality from this disease is metastasis of hormone refractory cancer cells that fail to respond to hormone ablation therapy. Because surgery and current treatment options have proven to be inadequate in treating and controlling CaP, the search for novel targets and mechanism-based agents for prevention and treatment of this disease has become a priority.”

“In recent years, cannabinoids the active components of Cannabis sativa linnaeus (marijuana) and their derivatives are drawing renewed attention because of their diverse pharmacological activities such as cell growth inhibition, anti-inflammatory effects, and tumor regression. Further interest in cannabinoid research came from the discovery of the cannabinoid system and the cloning of specific cannabinoid receptors. Two cannabinoid receptors have been identified: the “central” CB1 and the “peripheral” CB2 receptor. In a recent study, we have shown that WIN 55,212-2 a mixed CB1/CB2 receptor agonist imparts cell growth inhibitory effects in LNCaP cells via an induction of apoptosis. An important observation of this study was that WIN 55,212-2 treatment did not result in apoptosis of the normal prostate epithelial cell at similar doses.”

“Cannabinoids and their derivatives are drawing considerable attention in the treatment of cancer because of their diverse activities such as cell growth inhibition, anti-inflammatory effects, and tumor regression. Accumulated evidence indicates that cannabinoid receptor(s) could be an important target for the treatment of cancer. We have earlier shown that WIN-55,212-2 induced apoptosis of prostate cancer LNCaP cells is mediated through CB1 and CB2 receptors and suggested that these receptors could be an important targets for the treatment of prostate cancer…”

“Hence, we conclude that cannabinoid receptor agonist should be considered as an effective agent for the treatment of prostate cancer. If our hypothesis is supported by in vivo experiments, the long term implications of our study could be to develop nonhabit-forming cannabinoid agonist (s) for the management of prostate cancer.”

http://www.jbc.org/content/281/51/39480.long

Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease.

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Abstract

“Cannabinoids have been reported to provide neuroprotection in acute and chronic neurodegeneration. In this study, we examined whether they are also effective against the toxicity caused by 6-hydroxydopamine, both in vivo and in vitro, which may be relevant to Parkinson’s disease (PD). First, we evaluated whether the administration of cannabinoids in vivo reduces the neurodegeneration produced by a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. As expected, 2 weeks after the application of this toxin, a significant depletion of dopamine contents and a reduction of tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in tyrosine hydroxylase-mRNA levels in the substantia nigra. None of these events occurred in the contralateral structures. Daily administration of delta9-tetrahydrocannabinol (delta9-THC) during these 2 weeks produced a significant waning in the magnitude of these reductions, whereas it failed to affect dopaminergic parameters in the contralateral structures. This effect of delta9-THC appeared to be irreversible since interruption of the daily administration of this cannabinoid after the 2-week period did not lead to the re-initiation of the 6-hydroxydopamine-induced neurodegeneration. In addition, the fact that the same neuroprotective effect was also produced by cannabidiol (CBD), another plant-derived cannabinoid with negligible affinity for cannabinoid CB1 receptors, suggests that the antioxidant properties of both compounds, which are cannabinoid receptor-independent, might be involved in these in vivo effects, although an alternative might be that the neuroprotection exerted by both compounds might be due to their anti-inflammatory potential. As a second objective, we examined whether cannabinoids also provide neuroprotection against the in vitro toxicity of 6-hydroxydopamine. We found that the non-selective cannabinoid agonist HU-210 increased cell survival in cultures of mouse cerebellar granule cells exposed to this toxin. However, this effect was significantly lesser when the cannabinoid was directly added to neuronal cultures than when these cultures were exposed to conditioned medium obtained from mixed glial cell cultures treated with HU-210, suggesting that the cannabinoid exerted its major protective effect by regulating glial influence to neurons. In summary, our results support the view of a potential neuroprotective action of cannabinoids against the in vivo and in vitro toxicity of 6-hydroxydopamine, which might be relevant for PD. Our data indicated that these neuroprotective effects might be due, among others, to the antioxidant properties of certain plant-derived cannabinoids, or exerted through the capability of cannabinoid agonists to modulate glial function, or produced by a combination of both mechanisms.”

http://www.ncbi.nlm.nih.gov/pubmed/15837565

The therapeutic potential of the cannabinoids in neuroprotection.

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Abstract

“After thousands of years of interest the last few decades have seen a huge increase in our knowledge of the cannabinoids and their mode of action. Their potential as medical therapeutics has long been known. However, very real concerns over their safety and efficacy have lead to caution and suspicion when applying the legislature of modern medicine to these compounds. The ability of this diverse family of compounds to modulate neurotransmission and act as anti-inflammatory and antioxidative agents has prompted researchers to investigate their potential as neuroprotective agents. Indeed, various cannabinoids rescue dying neurones in experimental forms of acute neuronal injury, such as cerebral ischaemia and traumatic brain injury. Cannabinoids also provide symptomatic relief in experimental models of chronic neurodegenerative diseases, such as multiple sclerosis and Huntington’s disease. This preclinical evidence has provided the impetus for the launch of a number of clinical trials in various conditions of neurodegeneration and neuronal injury using compounds derived from the cannabis plant. Our understanding of cannabinoid neurobiology, however, must improve if we are to effectively exploit this system and take advantage of the numerous characteristics that make this group of compounds potential neuroprotective agents.”

http://www.ncbi.nlm.nih.gov/pubmed/12387700

Cannabinoids and neuroprotection.

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Abstract

“Cannabinoid compounds are endowed with pharmacological properties that make them interesting candidates for therapeutic development. These properties have been known since antiquity. However, in the last decade extremely important advances in the understanding of the physiology, pharmacology, and molecular biology of the cannabinoid system have given this field of research fresh impetus and have renewed the interest in the possible clinical exploitation of these compounds. In the present review we summarize the effects elicited, at the cellular level, by cannabinoids acting through receptor-dependent and receptor-independent mechanisms. These data suggest different ways by which cannabinoids may act as neuroprotective agents (prevention of excitotoxicity by inhibition of glutamate release, antioxidant effects, anti-inflammatory actions, etc.). The experimental evidence supporting these hypotheses are presented and discussed with regard to both preclinical and clinical studies in disease states such as cerebral ischemia, brain trauma, and Multiple Sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/11831553

Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells.

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“The active components of Cannabis sativa L., Cannabinoids, traditionally used in the field of cancer for alleviation of pain, nausea, wasting and improvement of well-being have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory activity and induction of tumor regression. Here we used several experimental approaches, which identified delta-9-tetrahydrocannabinol (Delta(9)-THC) as an essential mediator of cannabinoid antitumoral action.”

“CONCLUSIONS:

Delta(9)-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Delta(9)-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors.”

http://www.ncbi.nlm.nih.gov/pubmed/17934890

A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss

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“CB2 agonists not only produce antinociceptive and anti-inflammatory effects, but also have been shown to increase bone density.”

“Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance bone destruction in a murine model of bone cancer. In contrast, CB(2) selective agonists have been shown to reduce bone loss associated with a model of osteoporosis. Here we tested whether a CB(2) agonist administered over a 7day period inhibits bone cancer-induced pain as well as attenuates cancer-induced bone degradation.”

“Based on the antihyperalgesic effects of CB2 agonists, the lack of potential CNS-induced side effects and their propensity to stimulated bone growth, we addressed whether the sustained selective CB2 agonists…  has the potential to alleviate bone cancer-induced pain while maintaining bone integrity in a murine model of bone cancer”.

“These findings suggest a novel therapy for cancer-induced bone pain, bone loss and bone fracture while lacking many unwanted side effects seen with current treatments for bone cancer pain.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871326/

 

Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators.

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“Cannabinoids-endocannaboids are possible preventatives of common diseases including cancers. Cannabinoid receptors (CB(½), TRPV1) are central components of the system. Many disease-ameliorating effects of cannabinoids-endocannabinoids are receptor mediated, but many are not, indicating non-CBR signaling pathways.

Cannabinoids-endocannabinoids are anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic in most cancers, in vitro and in vivo in animals.

They signal through p38, MAPK, JUN, PI3, AKT, ceramide, caspases, MMPs, PPARs, VEGF, NF-κB, p8, CHOP, TRB3 and pro-apoptotic oncogenes (p53,p21 waf1/cip1) to induce cell cycle arrest, autophagy, apoptosis and tumour inhibition. Paradoxically they are pro-proliferative and anti-apoptotic in some cancers. Differences in receptor expression and concentrations of cannabinoids in cancer and immune cells can elicit anti- or pro-cancer effects through different signal cascades (p38MAPK or PI3/AKT).

Similarities between effects of cannabinoids-endocannabinoids, omega-3 LCPUFA and CLAs/CLnAs as anti-inflammatory, antiangiogenic, anti-invasive anti-cancer agents indicate common signaling pathways.

Evidence in vivo and in vitro shows EPA and DHA can form endocannabinoids that: (i) are ligands for CB(½) receptors and possibly TRPV-1, (ii) have non-receptor mediated bioactivity, (iii) induce cell cycle arrest, (iii) increase autophagy and apoptosis, and (iv) augment chemotherapeutic actions in vitro. They can also form bioactive, eicosanoid-like products that appear to be non-CBR ligands but have effects on PPARs and NF-kB transcription factors. The use of cannabinoids in cancer treatment is currently limited to chemo- and radio-therapy-associated nausea and cancer-associated pain apart from one trial on brain tumours in patients. Further clinical studies are urgently required to determine the true potential of these intriguing, low toxicity compounds in cancer therapy. Particularly in view of their synergistic effects with chemotherapeutic agents similar to that observed for n-3 LCPUFA.”  https://www.ncbi.nlm.nih.gov/pubmed/23103355

http://www.sciencedirect.com/science/article/pii/S0163782712000537