Tag Archives: anti-inflammatory

Cannabinoids: novel therapies for arthritis?

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“A key feature of osteoarthritis and rheumatoid arthritis is the loss of articular cartilage.

Cartilage breakdown is mediated by complex interactions of proinflammatory cytokines, such as IL-1, inflammatory mediators, including nitric oxide and prostaglandin E(2), and proteases, including matrix metalloproteinases and aggrecanases, such as ADAMTS-4 and -5.

Cannabinoids have been shown to reduce joint damage in animal models of arthritis.

They have also been shown to prevent IL-1-induced matrix breakdown of collagen and proteoglycan, indicating that cannabinoids may mediate chondroprotective effects.

Cannabinoids produce their effects via several cannabinoid receptors and it is important to identify the key cannabinoids and their receptors that are involved in chondroprotection.

This review aims to outline the current and future prospects of cannabinoids as anti-arthritic therapeutics, in terms of their ability to prevent cartilage breakdown.”

http://www.ncbi.nlm.nih.gov/pubmed/22530636

Cannabinoid receptor 2 modulates susceptibility to experimental cerebral malaria through a CCL17-dependent mechanism.

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“Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain-barrier and a strong inflammation in the brain.

We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM).

Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2-/-) mice inoculated with Plasmodium berghei ANKA-erythrocytes exhibited enhanced survival and a diminished blood-brain-barrier disruption.

Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice.

Hematopoietic-derived immune cells were responsible for the enhanced protection in bone-marrow-chimeric (BM)-Cnr2-/- mice. Mixed BM-chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b+ cell population, containing macrophages and neutrophils, expanded in the Cnr2-/- spleen after infection and expressed macrophage mannose receptors, arginase-1 activity and IL-10.

Also in the Cnr2-/-brain CD11b+ cells that expressed selected anti-inflammatory markers accumulated and expression of inflammatory mediators IFN-γ and TNF-α was reduced.

Finally, the M2-macrophage chemokine CCL17 was identified as essential factor for enhanced survival in the absence of CB2, since CCL17 x Cnr2 double-deficient mice were fully susceptible to ECM.

Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM.”

http://www.ncbi.nlm.nih.gov/pubmed/27474745

The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer’s disease.

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“Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by progressive loss of cognition. Over 35 million individuals currently have AD worldwide. Unfortunately, current therapies are limited to very modest symptomatic relief.

The brains of AD patients are characterized by the deposition of amyloid-β and hyperphosphorylated forms of tau protein. AD brains also show neurodegeneration and high levels of oxidative stress and inflammation.

The phytocannabinoid cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-β production and tau hyperphosphorylation in vitro.

CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD, especially as it lacks psychoactive or cognition-impairing properties.

CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy.

Thus, this review will present a brief introduction to AD biology and current treatment options before outlining comprehensively CBD biology and pharmacology, followed by in-vitro and in-vivo evidence for the therapeutic potential of CBD. We will also discuss the role of the endocannabinioid system in AD before commenting on the potential future of CBD for AD therapy (including safety aspects).”

http://www.ncbi.nlm.nih.gov/pubmed/27471947

Cannabinoids in pain and inflammation.

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“Cannabinoids exhibit medicinal properties including analgesic, anti-inflammatory and immunosuppressive properties. This paper reviews some of the recent findings in the study of cannabinoids in pain and inflammation. Some of the effects of cannabinoids are receptor mediated and others are receptor independent. Endocannabinoids naturally reduce pain and are cerebroprotective. Natural and synthetic cannabinoids have the potential to reduce nociception, reverse the development of allodynia and hyperalgesia, reduce inflammation and inflammatory pain and protect from secondary tissue damage in traumatic head injury.”

http://www.ncbi.nlm.nih.gov/pubmed/15265314

Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism.

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“We examined the neuroprotective mechanism of cannabidiol, non-psychoactive component of marijuana, on the infarction in a 4 h mouse middle cerebral artery (MCA) occlusion model in comparison with Delta(9)-tetrahydrocannabinol (Delta(9)-THC).

Both pre- and post-ischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection, whereas only pre-ischemic treatment with Delta(9)-THC reduced the infarction.

Unlike Delta(9)-THC, cannabidiol did not affect the excess release of glutamate in the cortex after occlusion.

Cannabidiol suppressed the decrease in cerebral blood flow by the failure of cerebral microcirculation after reperfusion and inhibited MPO activity in neutrophils.

Furthermore, the number of MPO-immunopositive cells was reduced in the ipsilateral hemisphere in cannabidiol-treated group.

Cannabidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB(1) receptor-independent mechanism, suggesting that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/17437545

Deficient Adolescent Social Behavior Following Early-Life Inflammation is Ameliorated by Augmentation of Anandamide Signaling.

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“Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function.

The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence.

We investigate the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS.

These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.”

http://www.ncbi.nlm.nih.gov/pubmed/27453335

Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia.

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“Activation of opioid and cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia.

In this study, we examined whether combinations of opioid and cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness.

Our findings showed that MOR and CB1 agonists directed at the inflamed site effectively attenuate mechanical hyperalgesia when administered individually, but exert opposing effects when administered together.

The antagonistic interactions between the two classes of drugs at the inflamed site suggest distinct mechanisms unique to peripheral nociceptors or inflamed tissue, and therefore require further studies to investigate whether the therapeutic utility of the combined drug treatments in chronic pain conditions can be optimized.”

http://www.ncbi.nlm.nih.gov/pubmed/27450703

Discovery of novel Tetrahydrobenzo[b]thiophene and pyrrole based scaffolds as potent and selective CB2 receptor ligands: The structural elements controlling binding affinity, selectivity and functionality.

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“CB2-based therapeutics show strong potential in the treatment of diverse diseases such as inflammation, multiple sclerosis, pain, immune-related disorders, osteoporosis and cancer, without eliciting the typical neurobehavioral side effects of CB1 ligands.

For this reason, research activities are currently directed towards the development of CB2 selective ligands. Herein, the synthesis of novel heterocyclic-based CB2 selective compounds is reported.

The present findings thus pave the way to the design and optimization of heterocyclic-based scaffolds with lipophilic carboxamide and/or retroamide substituent that can be exploited as potential CB2 receptor activity modulators.”

http://www.ncbi.nlm.nih.gov/pubmed/27448919

Cannabinoid Modulation of Cutaneous Aδ Nociceptors During Inflammation

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“Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB1 and CB2).

These results suggest that attenuation of mechanically evoked responses of Aδ nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB1 receptors during inflammation.

Several studies have demonstrated that locally administered cannabinoids produce antinociception in animal models of both acute and persistent pain through peripheral mechanisms.

Taken together, our data suggest that peripherally acting cannabinoids could be a potential therapeutic treatment for chronic inflammatory pain.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585399/

 

Cannabinoid receptors in microglia of the central nervous system: immune functional relevance.

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“Microglia, resident macrophages of the brain, function as immune effector and accessory cells. Paradoxically, they not only play a role in host defense and tissue repair but also have been implicated in a variety of neuropathological processes.

Microglia, in addition to exhibiting phenotypic markers for macrophages, express CB1 and CB2 cannabinoid receptors. Recent studies suggest the existence of a third, yet-to-be cloned, non-CB1, non-CB2 cannabinoid receptor.

These receptors appear to be functionally relevant within defined windows of microglial activation state and have been implicated as linked to cannabinoid modulation of chemokine and cytokine expression.

The recognition that microglia express cannabinoid receptors and that their activation results in modulation of select cellular activities suggests that they may be amenable to therapeutic manipulation for ablating untoward inflammatory responses in the central nervous system.”  http://www.ncbi.nlm.nih.gov/pubmed/16204639

http://www.jleukbio.org/content/78/6/1192.long