Tag Archives: anti-inflammatory

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

Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain.

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Abstract

“Cannabinoids suppress behavioural responses to noxious stimulation and suppress nociceptive transmission through activation of CB1 and CB2 receptor subtypes. CB1 receptors are expressed at high levels in the central nervous system (CNS), whereas CB2 receptors are found predominantly, but not exclusively, outside the CNS. CB2 receptors are also upregulated in the CNS and dorsal root ganglia by pathological pain states. Here, we review behavioural, neurochemical and electrophysiological data, which identify cannabinoid CB2 receptors as a therapeutic target for treating pathological pain states with limited centrally, mediated side effects. The development of CB2-selective agonists (with minimal affinity for CB1) as well as mutant mice lacking CB2 receptors has provided pharmacological and genetic tools required to evaluate the effectiveness of CB2 agonists in suppressing persistent pain states. This review will examine the efficacy of cannabinoid CB2-selective agonists in suppressing acute, inflammatory and neuropathic nociception following systemic and local routes of administration. Data derived from behavioural, neurochemical and neurophysiological approaches are discussed to better understand the relationship between antinociceptive effects induced by CB2-selective agonists in behavioural studies and neural mechanisms of pain suppression. Finally, the therapeutic potential and possible limitations of CB2-based pharmacotherapies for pathological pain states induced by tissue and nerve injury are discussed.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219541/

Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis.

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“Background and Purpose:

Effects of locally administered agonists and antagonists for cannabinoid CB1 and CB2 receptors on mechanical and thermal hypersensitivity were compared after the establishment of chronic inflammation.

Conclusions and Implications:

Cannabinoids act locally through distinct CB1 and CB2 mechanisms to suppress mechanical hypersensitivity after the establishment of chronic inflammation, at doses that produced modest changes in thermal hyperalgesia. Additive antihyperalgesic effects were observed following prophylactic co-administration of the CB1– and CB2-selective agonists. Our results suggest that peripheral cannabinoid antihyperalgesic actions may be exploited for treatment of inflammatory pain states.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042894/

Targeting cannabinoid agonists for inflammatory and neuropathic pain.

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Abstract

“The cannabinoid receptors CB(1) and CB(2) are class A G-protein-coupled receptors. It is well known that cannabinoid receptor agonists produce relief of pain in a variety of animal models by interacting with cannabinoid receptors. CB(1) receptors are located centrally and peripherally, whereas CB(2) receptors are expressed primarily on immune cells and tissues. A large body of preclinical data supports the hypothesis that either CB(2)-selective agonists or CB(1) agonists acting at peripheral sites, or with limited CNS exposure, will inhibit pain and neuroinflammation without side effects within the CNS. There has been a growing interest in developing cannabinoid agonists. Many new cannabinoid ligands have been synthesized and studied covering a wide variety of novel structural scaffolds. This review focuses on the present development of cannabinoid agonists with an emphasis on selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists for treatment of inflammatory and neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/17594182

Targeting CB2 receptors and the endocannabinoid system for the treatment of pain.

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Abstract

“The endocannabinoid system consists of the cannabinoid (CB) receptors, CB(1) and CB(2), the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB(1) receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB(2) receptor agonists. Selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB(2) receptors were originally described as being restricted to cells of immune origin, but there is evidence for their expression in human primary sensory neurons, and increased levels of CB(2) receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB(2) receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of mu-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment strategy, while minimizing the potential for NSAID-induced gastrointestinal and cardiovascular disturbances. Other potential “partners” for endocannabinoid modulatory agents include alpha(2)-adrenoceptor modulators, peroxisome proliferator-activated receptor alpha agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.”

http://www.ncbi.nlm.nih.gov/pubmed/19150370

Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors.

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“BACKGROUND:

Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia.”

“CONCLUSIONS:

Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/14508331

Attenuation of Experimental Autoimmune Hepatitis by Exogenous and Endogenous Cannabinoids: Involvement of Regulatory T Cells

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“The endocannabinoid system plays a protective role in various inflammatory diseases, and it is considered an attractive therapeutic target.”

“The aim of the present study was to determine the immunomodulatory effect of THC in the murine model of ConA-induced hepatitis. We demonstrate that a single injection of THC significantly ameliorates ConA-induced T-cell-mediated liver injury by up-regulating Forkhead helix transcription factor p3 (Foxp3)+ regulatory T cells and down-regulating inflammatory cytokines. Using select cannabinoid receptor agonists and antagonists, we demonstrate that THC mediates immune modulation in this model by signaling through both CB1 and CB2 receptors. We also demonstrate that anandamide, an endocannabinoid can effectively attenuate the disease.”

“There is growing interest in recent years to target cannabinoid receptors for treating liver diseases. In the current study, CB1 or CB2 activation alone had no anti-inflammatory effect on hepatitis. However, cannabinoids that bind to both CB1 and CB2 receptors (THC, CP55,940, WIN55212, and anandamide) effectively attenuated hepatitis. That CB1/CB2 mixed agonists could suppress the disease but not the coadministered CB1 and CB2 agonists indicates that both the cannabinoid receptors need to be activated simultaneously to produce the observed effect and that the different pharmacokinetics of the two coadministered agonists may not allow this to happen. Signaling through both the receptors is important because blocking either CB1 or CB2 could reverse the effect of THC.”

“Taken together, our data suggest that exogenous cannabinoids such as THC upon binding to CB1 and CB2 receptors on immune cells, induce apoptosis in effector T cells, up-regulate Treg function, and suppress inflammatory cytokines there by preventing ConA-induced activated T-cell-mediated liver injury. The observation that the anandamide treatment ameliorates ConA-induced hepatitis, together with FAAH deficiency or inhibition leading to increased resistance to the disease, strongly suggests that the endocannabinoid system serves to attenuate the inflammatory response in ConA-induced acute hepatitis. These findings raise the promising potential of developing novel pharmacological treatments for T-cell-mediated liver diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828293/

Use of cannabinoids as a novel therapeutic modality against autoimmune hepatitis.

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Abstract

“Autoimmune hepatitis is a severe immune mediated chronic liver disease with a prevalence range between 50 and 200 cases per million in Western Europe and North America and mortality rates of up to 80% in untreated patients. The induction of CB1 and CB2 cannabinoid receptors during liver injury and the potential involvement of endocannabinoids in the regulation of this process have sparked significant interest in further evaluating the role of cannabinoid systems during hepatic disease. Cannabinoids have been shown to possess significant immunosuppressive and anti-inflammatory properties. Cannabinoid abuse has been shown to exacerbate liver fibrogenesis in patients with chronic hepatitis C infection involving CB1 receptor. Nonetheless, CB2 receptor activation may play a protective role during chronic liver diseases. Thus, differential targeting of cannabinoid receptors may provide novel therapeutic modality against autoimmune hepatitis. In this review, we summarize current knowledge on the role of endocannabinoids and exocannabinoids in the regulation of autoimmune hepatitis.”

http://www.ncbi.nlm.nih.gov/pubmed/19647124