1981 - Study ~ Biological activity of cannabichromene, its homologs and isomers.
2004- Study ~ Cannabinoids and neuroinflammation.
2007- Study ~ Cannabinoids and neuroprotection in motor-related disorders.
2007- Study ~ Cannabinoids for the treatment of inflammation.
2007- News ~ Pot Chemical May Curb Inflammation.
2008 - Study - Inflammation and aging: can endocannabinoids help
2008- Study ~ Anti-inflammatory cannabinoids in diet.
2008- Study ~ Cannabinoid CB2 receptors in human brain inflammation.
2008 - News -Marijuana reduces memory impairment
2008 - News -Why Cannabis Stems Inflammation
2009- Study ~ Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells.
2009- Study ~ Cannabinoids as novel anti-inflammatory drugs.
2009- News ~ How Hemp Seed Oil Can Help Your Arthritis.
2010- Study ~ Cannabinoids and Viral Infections.
2010 - News ~ Hemp Oil Benefits for Skin.
2011- Study ~ Gut feelings about the endocannabinoid system.
2011- News ~ New metabolic pathway for controlling brain inflammation.
E.A. Formukong, A.T. Evans, and F.J. Evans
Department of Pharmacognosy, The School of Pharmacy University of London,
29-39 Brunswick Square London, WC11N 1AX, England
Abstract---Two extracts of Cannabis sativa herb, one being cannabinoid--free (ethanol) and the other containing the cannabinoids (petroleum), were shown to inhibit PBQ- induced writhing in mouse when given orally and also to antagonize tetradecanoylphorbol acetate (TPA) -induced erythema of mouse skin when applied topically. With the exception of cannabinol (CBN) and delta-1-tetrahydrocannabinol (delta-1-THC), the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 mcg/kg. Delta-1-THC only became maximally effective in doses of 10 mg/kg.
This higher dose corresponded to that which induced catalepsy and is indicative of a central action. CBN produce a 40% inhibition of PBQ-induced writhing. Cannabidiol (CBD) was the most effective of the cannabinoids at doses of 100 mcg/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. The fact that delta-1-THC and CBN were the least effective in this test suggests a structural relationship between analgesic activity and antiinflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta-1-THC.
Various preparations of Cannabis sativa have been employed for their medicinal effects, including antipyretic, antirheumatic, antiallergic, and analgesic purposes. Extracts of Cannabis have been shown to possess analgesic activity, and delta-1-tetrahydrocannabinol (delta-1-THC), the psychoactive component of Cannabis has also been shown to possess this activity in various models. In addition, cannabinol (CBN) but not cannabidiol (CBD) was shown to exhibit analgesic activity in vivo.
It is possible that the antiinflammatory and antiasthmatic properties of this herb are mediated through effects on arachidonate metabolism. However, constituents of Cannabis are known to stimulate and inhibit prostaglandin (PG) release by influencing enzymes of this pathway.
A cannabinoid or an extract of Cannabis with little or no central effects could be of use therapeutically. In this paper, we have examined the antiinflammatory potential of two extracts of Cannabis, pure cannabinoids and olivetol (a cannabinoid biosynthetic precursor) in two models of inflammation, in an attempt to separate on a structural basis the peripheral from the central action of these phenolic drugs.
MATERIALS AND METHODS
The folowing were used: aspirin (Sigma Chemical Co., Poole, Dorset.), tripotassium citrate (analytical grade), all cannabinoids except CBG (Sigma), and CBG (Makor Chemicals, Jerusalem, Israel).
Preparation of Drugs: PBQ Test. Cannabinoids and cannabis extracts were suspended in a 1% ethanolic solution containing 2.5% w/v Tween. Aspirin was dissolved in a 40 mg/ml solution of tripotassium citrate.
Phenyl Benzoquinone Writhing (PBQ) and Preparation of PBQ Solution. A 0.04% solution of PBQ was prepared immediately before use by dissolving PBQ in warm ethanol and diluting with water at 40 degrees C bringing the ethanolic concentration to 5%. The bottle was stoppered, foil paper wrapped around it, and the solution maintained at 34 degrees C. Deterioration of the solution occurs if left exposed to light and air.
Administration of Drugs. Male CDI male (Charles River) weighing 18-20 g were starved overnight for the experiment. Animals were placed in a thermostatically controlled environment maintained at 34 degrees C. Mice were orally administered test drug 20 min before the intraperitoneal injection of PBQ (4 mg/kg). Five minutes after injection, a hand tally counter was used to record the number of stretching movements for each mouse in a 5-min period. Control animals were only administered the vehicle. Note less than five animals were used per dose.
Statistical Analysis. Results are expressed as mean percentage inhibition of control (+SEM) in the case of PBQ test. IC-50s were obtained from graphs relating probit percentage inhibition (ordinate) against log dose (abscissa). The IC-50 is that dose of drug which would inhibit PBQ-induced writhing by 50%.
Tetradecanoyl phorbol-acetate-induced (TPA) Erythema of Mouse Ear. In order to exclude the possibility of a central mechanism of action (see Discussion), compounds also were tested for their ability to inhibit TPA-induced erythema on mouse ears in 100% of the animals was chosen as the challenging dose for inhibition studies, measured 4 h after application.
Test drugs were dissolved in ethanol and 5 ul applied to the inner ear of the mouse 15 min before the application of 1 mcg TPA in 5 ul acetone. Only one dose of test dug was used for this experiment, 100 mcg/mcl ethanols, except trifluoperazine at 1 mg/5 ul. The other ear acted as a control.
The results were expressed as percentage inhibition, taken to mean the complete suppression of erythema in the test animals, as described in reference 19.
PBQ-Induced Writhing. CBD, CBG, olivetol, ethanolic extract, and petroleum spirit extract produced significant inhibition at doses up to 10 mg/kg (Figures 1-3). CBN was only marginally active.
Delta-1-THC was fully effective only at concentrations above 10 mg/kg Figure 2).
The ethanolic and petroleum extract, CBD, olivetol, CBG, and cannflavon were more potent than aspirin. The petroleum spirit extract was about four times more potent than the ethanolic extract, which was virtually equipotent with CBD. Cannflavon, isolated from the ethanolic extract was 14 times less potent than the ethanolic extract of the dried herb.
There was a decline in response following the administration of doses greater than 0.1 mg/kg of some substances. This is most evident in the bell shaped dose-response curve of the petroleum spirit extract. The activity of the ethanolic extract and CBD was also found to decrease slightly at higher dose levels.
TPA-Induced Erythema. In general, the ability of compounds to inhibit TPA-induced erythema correlated well with their potency in the PBQ-writhing test. Thus, CBN and delta-1-THC were the least active followed by CBG, CBD, and cannflavon. Again, the extracts were the most active (Table 3). Twenty-four hours after application, the ethanolic extract still produced 16% inhibition of TPA-induced erythema of the animals. All other substances were without activity after 24 h.
All substances were more active than trifluoperazine, 1 mg/5ul, a known phorbol ester antagonist both in vivo and in vitro (20).
The PBQ-induced writhing response is believed to be produced by the liberation of endogenous substance(s), notably metabolites of the arachidonic cascade. However, the PBQ test is not specific for weak analgesics such as the nonsteroidal antiinflammatory drugs, as it also detects centrally active analgesics.
Therefore, in the elucidation of the action of the cannabinoids as inflammatory drugs, it was necessary to perform more than one test. In this case, peripheral rather than central action was confirmed in the mouse ear erythema assay.
TPA-induced erythema was inhibited by the extracts cannflavon, cannabinoids, and olivetol. The activity of TPA has been shown to be dependent upon PG release in mouse epidermis and mouse peritoneal macrophages possibly via the initial stimulation of protein kinase C (for a review see reference. It has also been shown that compounds that show moderate to very potent antiinflammatory potential in standard in vivo inflammation models will also inhibit TPA-induced edema of the mouse ear, and phorbol-ester-induced erythema.
It is possible that the cannabinoids and their extracts are inhibiting both PBQ-induced writhing and TPA-induced erythema by effects on arachidonate release and metabolism. Cannabinoids and olivetol have been shown to inhibit PG mobilization and synthesis.
The noncannabinoid constituents of Cannabis, for example, cannflavon, have been shown to be mainly cyclooxygenase inhibitors. Cannabinoids, however, stimulate and inhibit phospholipase A2 (PLA2) activity, as well as inducing an inhibition of cyclooxygenase and lipoxygenase. The activity of Cannabis herb or resin is complex, in that activities can be demonstrated on at least three major enzymes of the arachidonate cascade.
The mechanism by which delta-1-THC inhibits PBQ-induced writhing may differ from that of the other substances. At concentrations greater than 10 mg/kg, delta-1-THC may be inhibiting PBQ-induced writhing by acting on central rather than peripheral functions.
It is possible that prostaglandins modulate certain inhibitory pathways in the brain, bringing about an increase in the pain threshold. This dose of delta-1-THC is capable of bringing about the cataleptic effect , which is a standard test for central involvement. Central analgesics have higher efficacies than peripheral ones, and this may explain the effectiveness of delta-1-THC.
The central involvement of delta-1-THC is perhaps the primary reason why delta-1-THC was recognized as an analgesic before other cannabinoids.
Our results suggest that the response of the ethanolic extract cannot be solely due to cannflavon. Other structurally related phenolic substances, known to be present in this complex extract, may account for the higher activity seen either due to cumulative or synergistic effects upon cyclooxygenase.
The activity of the petroleum ether extract is likely to be largely due to the presence of CBD and CBN. GLC analysis of the extract has shown that this extract contained 14.13% CBD, 9.08% CBN, and 6.68% delta-1-THC. On the basis of our results, it is possible to separate the centrally active cannabinoid delta-1-THC from peripherally active compounds of the herbal extracts. An attempt has been made to differentiate them structurally .
It can be seen that the olivetolic nucleus together with a free C-5 hydroxyl group are structural requirements for peripheral effects, involving both cyclooxygenase and lipoxygenase inhibition.
Substances possessing this structure possess antiinflammatory and analgesic activities without central hallucinogenic effects. Delta-1-THC and CBN, which are cyclized derivatives exhibiting no C-5 hydroxyl moiety, have little if any peripheral action.
The traditional use of Cannabis as an analgesic, antiasthmatic, and antirheumatic drug is well established. Our results would suggest that cultivation of Cannabis plants rich in CBD and other phenolic substances would be useful not only as fiber-producing plants but also for medicinal purposes in the treatment of certain inflammatory disorders.
Acknowledgments----We are grateful to the Medicinal Research Council and the Government of Cameroon for financial support.
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ScienceDaily (July 22, 2008) — Cannabis has long been accredited with anti-inflammatory properties. ETH Zurich researchers, however, have now discovered that it is not only the familiar psychoactive substances that are responsible for this; a compound we take in every day in vegetable nutriment also plays a significant role.
People not only rate cannabis sativa L. highly because of its intoxicating effects; it has also long been used as a medicinal plant. Although the plant has been scrutinized for years, surprising new aspects keep cropping up.
For example, researchers from ETH Zurich and Bonn University examined a component in the plant’s essential oil that until then had largely been ignored and found it to have remarkable phar- macological effects.
The findings open up interesting perspectives, especially for the prevention and treatment of inflammations.
Completely different molecule structure
The hemp plant contains over 450 different substances, only three of which are responsible for its intoxicating effect. They activate the two receptors in the body CB1 and CB2. Whilst the CB1 receptor in the central nervous system influences perception, the CB2 receptor in the tissue plays a crucial role in inhibiting inflammation. If the receptor is activated, the cell releases fewer pro-inflammatory signal substances, or cytokines. The scientists have now discovered that the substance beta-carophyllene, which composes between 12 and 35 percent of the cannabis plant’s essential oil, activates the CB2 receptor selectively.
Unlike the three psychoactive substances, however, beta-carophyllene does not latch onto the CB1 receptor and consequently does not trigger the intoxicating effect. “Due to the various effects of cannabis, we had suspected for quite some time that other substances could come into play besides the psychoactive ones”, explains Jürg Gertsch from the Institute of Pharmaceutical Sciences at ETH Zurich. “However, astonishingly we didn’t know what substances these were until now.”
Gertsch finds it remarkable that beta-carophyllene has a very different molecule structure to that of the classical cannabinoids. “This is presumably why no one realized that the substance can also activate the CB2 receptor.”
The scientists were not only able to prove that beta-carophyllene binds with the CB2 receptor in vitro but also in animal tests, where they treated mice that were suffering from an inflammatory swelling on their paws with orally administered doses of the substance. The swelling declined in up to 70 percent of the animals, even for deep doses. For mice lacking the gene for the CB2 receptor, however, the substance did not make an impact.
The results are encouraging for the prevention or treatment of ailments in which the CB2 receptor plays a positive role. However, Gertsch explains that we are still very much in the early stages on that score.
That said, the scientist can conceive that some day the compound will not only help heal certain forms of inflammation, but also be instrumental in treating chronic illnesses, such as liver cirrhosis, Morbus Crohn, osteoarthritis and arteriosclerosis.
In all of these diseases, the CB2 receptor and the associated endocannabinoid system play a crucial role.
The beauty is that beta-carophyllene is not only found in cannabis but also often in plants as a whole and we consume the substance in our diet.
The non-toxic compound, which incidentally has been used as a food additive for many years, can be found in spice plants like oregano, basil, cinnamon and black pepper. “Whether we have found a new link between the vegetable diet and the prevention of so-called lifestyle diseases in our study remains to be seen in future studies”, adds Gertsch.
Cannabis has long been recognized as a medicinal plant. Researchers from ETH Zurich and Bonn University have now established anti-inflammatory properties in hemp oil. (Credit: iStockphoto/Tatyana Ogryzko)
Napimoga MH, Benatti BB, Lima FO, Alves PM, Campos AC, Pena-Dos-Santos DR, Severino FP, Cunha FQ, Guimarães FS
Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. [Journal Article, Research Support, Non-U.S. Gov't]
Int Immunopharmacol 2009 Feb; 9(2):216-22.
Cannabidiol (CBD) is a cannabinoid component from Cannabis sativa that does not induce psychotomimetic effects and possess anti-inflammatory properties. In the present study we tested the effects of CBD in a periodontitis experimental model in rats.
We also investigated possible mechanisms underlying these effects. Periodontal disease was induced by a ligature placed around the mandible first molars of each animal. Male Wistar rats were divided into 3 groups: control animals; ligature-induced animals treated with vehicle and ligature-induced animals treated with CBD (5 mg/kg, daily). Thirty days after the induction of periodontal disease the animals were sacrificed and mandibles and gingival tissues removed for further analysis.
Morphometrical analysis of alveolar bone loss demonstrated that CBD-treated animals presented a decreased alveolar bone loss and a lower expression of the activator of nuclear factor-kappaB ligand RANKL/RANK. Moreover, gingival tissues from the CBD-treated group showed decreased neutrophil migration (MPO assay) associated with lower interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha production. These results indicate that CBD may be useful to control bone resorption during progression of experimental periodontitis in rats.
|GFAP||glial fibrillary acidic protein|
|iNOS||inducible nitric oxide synthase|
|IL-1β||interleukin 1 beta|
|ELISA||enzyme linked immunosorbent assay|
Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A
growing interest in the beneficial properties of manipulating the endocannabinoid system has lead to the possible involvement of CBr in the control of brain inflammation. In the present study we examined the effect of the CBr agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4benzoxazin-6-yl]-1-naphthalenyl-methanone mesylate (WIN-55212-2), on microglial activation and spatial memory performance, using a well characterized animal model of chronic brain inflammation produced by the infusion of lipopolysaccharide (LPS, 250 ng/hr for 3 weeks) into the 4th ventricle of young rats. WIN-55212-2 (0.5 or 1.0 mg/kg/day, i.p.) was administered for three weeks. During the third week of treatment, spatial memory ability was examined using the Morris water-maze task. We found that 0.5 and 1 mg/kg WIN-55212-2 reduced the number of LPS-activated microglia, while 1 mg/kg WIN-55212-2 potentiated the LPS-induced impairment of performance in the watermaze task. CB1 receptors were not expressed by microglia and astrocytes, suggesting an indirect effect of WIN on microglia activation and memory impairment. Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.
|aCSF||artificial cerebral spinal fluid|
|CB1||cannabinoid receptor 1|
|CB2||cannabinoid receptor 2|
|PBS||phosphate buffer saline|
|TBS||Tris buffer saline|
Cannabidiol (CBD) is the main non-psychotropic component of the glandular hairs of Cannabis sativa. It displays a plethora of actions including anticonvulsive, sedative, hypnotic, antipsychotic, antiinflammatory and neuroprotective properties. However, it is well established that CBD produces its biological effects without exerting significant intrinsic activity upon cannabinoid receptors. For this reason, CBD lacks the unwanted psychotropic effects characteristic of marijuana derivatives, so representing one of the bioactive constituents of Cannabis sativa with the highest potential for therapeutic use.The present review reports the pharmacological profile of CBD and summarizes results from preclinical and clinical studies utilizing CBD, alone or in combination with other phytocannabinoids, for the treatment of a number of CNS disorders. Copyright (c) 2008 John Wiley & Sons, Ltd.
, Zurier RB.
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St., Worcester, Massachusetts 01605, USA. email@example.com
This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation.
A possible mechanism for these actions is suggested involving increased production of eicosanoids that promote the resolution of inflammation. This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process.
The more research they do, the more evidence Ohio State University scientists find that specific elements of marijuana can be good for the aging brain by reducing inflammation there and possibly even stimulating the formation of new brain cells.
The research suggests that the development of a legal drug that contains certain properties similar to those in marijuana might help prevent or delay the onset of Alzheimer's disease. Though the exact cause of Alzheimer's remains unknown, chronic inflammation in the brain is believed to contribute to memory impairment.
Any new drug's properties would resemble those of tetrahydrocannabinol, or THC, the main psychoactive substance in the cannabis plant, but would not share its high-producing effects. THC joins nicotine, alcohol and caffeine as agents that, in moderation, have shown some protection against inflammation in the brain that might translate to better memory late in life.
"It's not that everything immoral is good for the brain. It's just that there are some substances that millions of people for thousands of years have used in billions of doses, and we're noticing there's a little signal above all the noise," said Gary Wenk, professor of psychology at Ohio State and principal investigator on the research.
Wenk's work has already shown that a THC-like synthetic drug can improve memory in animals. Now his team is trying to find out exactly how it works in the brain.
The most recent research on rats indicates that at least three receptors in the brain are activated by the synthetic drug, which is similar to marijuana. These receptors are proteins within the brain's endocannabinoid system, which is involved in memory as well as physiological processes associated with appetite, mood and pain response.
This research is also showing that receptors in this system can influence brain inflammation and the production of new neurons, or brain cells.
"When we're young, we reproduce neurons and our memory works fine. When we age, the process slows down, so we have a decrease in new cell formation in normal aging. You need those cells to come back and help form new memories, and we found that this THC-like agent can influence creation of those cells," said Yannick Marchalant, a study coauthor and research assistant professor of psychology at Ohio State.
Marchalant described the research in a poster presentation Wednesday (11/19) at the Society for Neuroscience meeting in Washington, D.C.
Knowing exactly how any of these compounds work in the brain can make it easier for drug designers to target specific systems with agents that will offer the most effective anti-aging benefits, said Wenk, who is also a professor of neuroscience and molecular virology, immunology and medical genetics.
"Could people smoke marijuana to prevent Alzheimer's disease if the disease is in their family? We're not saying that, but it might actually work. What we are saying is it appears that a safe, legal substance that mimics those important properties of marijuana can work on receptors in the brain to prevent memory impairments in aging. So that's really hopeful," Wenk said.
One thing is clear from the studies: Once memory impairment is evident, the treatment is not effective. Reducing inflammation and preserving or generating neurons must occur before the memory loss is obvious, Wenk said.
Marchalant led a study on old rats using the synthetic drug, called WIN-55212-2 (WIN), which is not used in humans because of its high potency to induce psychoactive effects.
The researchers used a pump under the skin to give the rats a constant dose of WIN for three weeks – a dose low enough to induce no psychoactive effects on the animals. A control group of rats received no intervention. In follow-up memory tests, in which rats were placed in a small swimming pool to determine how well they use visual cues to find a platform hidden under the surface of the water, the treated rats did better than the control rats in learning and remembering how to find the hidden platform.
"Old rats are not very good at that task. They can learn, but it takes them more time to find the platform. When we gave them the drug, it made them a little better at that task," Marchalant said.
In some rats, Marchalant combined the WIN with compounds that are known to block specific receptors, which then offers hints at which receptors WIN is activating. The results indicated the WIN lowered the rats' brain inflammation in the hippocampus by acting on what is called the TRPV1 receptor. The hippocampus is responsible for short-term memory.
With the same intervention technique, the researchers also determined that WIN acts on receptors known as CB1 and CB2, leading to the generation of new brain cells – a process known as neurogenesis. Those results led the scientists to speculate that the combination of lowered inflammation and neurogenesis is the reason the rats' memory improved after treatment with WIN.
The researchers are continuing to study the endocannabinoid system's role in regulating inflammation and neuron development. They are trying to zero in on the receptors that must be activated to produce the most benefits from any newly developed drug.
What they already know is THC alone isn't the answer.
"The end goal is not to recommend the use of THC in humans to reduce Alzheimer's," Marchalant said. "We need to find exactly which receptors are most crucial, and ideally lead to the development of drugs that specifically activate those receptors. We hope a compound can be found that can target both inflammation and neurogenesis, which would be the most efficient way to produce the best effects."
The National Institutes of Health supported this work.
November 20, 2008 sourced from Ohio State University - http://osu.edu/)