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Brain's own cannabis compound protects against inflammation

4-Jan-2006: Some clinical studies have indicated that marijuana or its active cannabinoid ingredient alleviates symptoms of the inflammatory disease multiple sclerosis (MS). Also, researchers have found that the brain's natural "endocannabinoids" are released after brain injury and are believed to alleviate neuronal damage. However, scientists have not understood how such substances act within the brain's own immune system.

Now, experiments by Oliver Ullrich and colleagues have pinpointed how one of the brain's endocannabinoids protects neurons from inflammation after such damage. They say their studies could lead to new drugs to treat the inflammation and brain degeneration from MS or other such disorders.

In an article in the January 5, 2006, issue of Neuron, the researchers reported experiments showing how the endocannabinoid anandamide (AEA) protects brain cells from inflammation. Such a role in the brain's immune system is distinct from cannabinoids' effects on neuronal signaling that produce the behavioral effects of marijuana.

When Ullrich and colleagues analyzed brain tissue from people with MS, they found elevated levels of AEA, compared to healthy tissue. And in studies with mouse brain slices, they found that inducing damage with a brain-cell-exciting chemical, called NMDA, caused an invasion of the brain's immune cells, called microglia, and an increase in AEA levels.

Importantly, they found that adding AEA to such damaged brain tissue abolished inflammatory damage to the brain cells, but did not reduce the primary "excitotoxic" damage from the chemical. They found similar effects of AEA when they damaged the brain tissue by depriving it of oxygen and glucose.

The researchers also found that when they used a drug to block the receptors on microglial cells by which AEA effects the cells, inflammatory damage was increased.

The researchers also explored the mechanism by which AEA prevents inflammatory damage. They found that, when AEA plugs into its receptors on activated microglial cells, it basically activates a specific molecular signaling pathway that suppresses the production of inflammation-causing nitric oxide, which would otherwise cause brain injury.

The researchers concluded that the release of AEA in injured brain tissue might act as a "gatekeeper" and an important "negative-feedback loop within the CNS [central nervous system] immune system needed to reduce the extent of the inflammatory response and to limit neurodegenerative immune reactions after primary brain damage.

"Moreover, endocannabinoid signaling strongly suppresses attack of microglial cells on nondamaged neurons," they wrote, "suggesting also a physiological function of the endocannabinoid system in maintaining a protective and healthy CNS microenvironment."

They also concluded that "the endocannabinoid system represents a local messenger system between the nervous and immune system and is obviously involved in the control of immune activation and neuroprotection. Therefore, elucidating the pathology of the endocannabinoid system during neuroinflammation and neurodegeneration might open new avenues of therapeutic interventions in the future."

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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press

The researchers included Eva Eljaschewitsch, Christian Mawrin, Peter M. Schmidt, Regine Schneider-Stock and Oliver Ullrich of the Otto-von-Guericke-University Magdeburg in Magdeburg, Germany; Anke Witting of the University of Washington in Seattle, WA; Thomas Lee, Heide Hoertnagl and Robert Nitsch of the CharitŽ University Hospital Berlin in Berlin, Germany; Susanne Wolf of the Max-Delbrueck-Center of Molecular Medicine in Berlin, Germany; Cedric S. Raine of the Albert Einstein College of Medicine in New York, NY. This work was supported by the Research Network N2 of the State Saxony-Anhalt of Germany (O.U.) and a grant from the Deutsche Forschungsgemeinschaft to R.N., O.U., and R.S.S. and National Institutes of Health grants (NS 08952 and NS 11920) to C.S.R.

Eljaschewitsch et al.: "The Endogenous Cannabinoid Anandamide (AEA) Protects Neurons during CNS Inflammation by Induction of MKP-1 in Microglial Cells." Publishing in Neuron 49, 67ö79, January 5, 2006 DOI 10.1016/j.neuron.2005.11.027 www.neuron.org


Cannabinoids produced in the human body have an anti-inflammatory effect

http://www.eurekalert.org/pub_releases/2007-06/uob-cpi060507.php

7-Jun-2007: Cannabinoids produced in the human body have an anti-inflammatory effect Constituents of hashish and marijuana may help to fight inflammation and allergies

Endocannabinoids seem to play an important role in regulating inflammation processes. Scientists from the University of Bonn have discovered this in experiments on mice. Their results will be published in the distinguished scientific journal 'Science' on Friday, 8 June. The study may also have implications for therapy. In animal experiments, a solution with an important component made from cannabis reduced allergic reactions of the skin.

Extracts of the hemp plant cannabis are traditionally used as a popular remedy against inflammation. At the beginning of the last century this natural remedy was even available at every chemist’s. But due to the intoxicating effect of the component THC (tetrahydrocannabinol) the plant was taken off the chemist’s shelves in the 1930s.

THC acts on the cannabinoid receptors, of which there are two types, CB1 and CB2. Both receptors are made such that THC can attach itself to them. In the brain this causes the intoxicating effect of hashish, cannabis and marijuana. But why does the body have CB1 and CB2 anyway" For two decades it has been known that the human body also produces its own cannabinoids. Like THC they can attach themselves to the receptors. The brain scientist Professor Andreas Zimmer from the Bonn Institute of Molecular Psychiatry is investigating what the function of this endocannabinoid system is. ‘Mice without CB1 receptors show psychological abnormalities,’ he explains. ‘By contrast, CB2 regulates the growth of bones, for example.’

Coincidence

However, according to these most recent results, endocannabinoids also seem to play an important part in regulating inflammation processes. As is often the case with important discoveries, coincidence was involved. In scientific experiments mice are given an ear clip, so that researchers can tell them apart.‘ In most cases the mice can handle this without problems,’ Dr. Meliha Karsak, a member of Professor Zimmer’s team, explains. ‘With our mice this was different. The skin around the ear clips became inflamed.’ There are genetically modified strains of mice in which both cannabinoid receptors are dysfunctional.‘ And it was in precisely these strains that the inflammation occurred,' she explains.

Together with the Bonn dermatologists Dr. Evelyn Gaffal and Professor Thomas Tüting the researchers investigated these findings. Skin rash can be caused by allergens in laboratory mice. 'However, normally these rashes are only minor,' Dr. Gaffal emphasises. 'However, strains of mice in which the cannabinoid receptors are missing react much more intensely. We observed something similar when we blocked the receptors with medication.'

Step on the brakes

When inflammation occurs the endocannabinoids act like someone stepping on the brakes. They prevent the body from doing too much of a good thing and the immune reaction from getting out of control. This is consistent with the fact that at the beginning of the infection the endocannabinoid concentration increased in the mice. 'Apart from that there are strains of mice in which the breakdown of these active substances produced by the body is malfunction-ing,' Evelyn Gaffal says. 'They have an increased endocannabinoid concen-tration in their skin. In our experiments these animals also showed a less marked allergic reaction.'

The results open up new options for the treatment of skin allergies and inflammation. Firstly, drugs which prevent the breakdown of endocannabin-oids look promising. But the old household remedy cannabis could also make a comeback as an ointment. In the experiment on mice this approach has already been successful. 'If we dabbed THC solution on to the animals' skin shortly before and after applying the allergen, a lot less swelling occurred than normal,' Professor Thomas Tüting explains. 'THC attaches itself to cannabin-oid receptors and activates them. In this way the active substance reduces the allergic reaction.' Incidentally, ointment like this would probably not have an intoxicating effect, for this the amount of THC contained would be much too small.

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Contact: Professor Andreas Zimmer
neuro@uni-bonn.de
49-022-868-85300
University of Bonn

Contact:
Professor Thomas Tüting
Dermatological Clinic at the Bonn University Clinic
Tel.: ++49-(0)228-287-16231
E-mail: Thomas.Tû - ting@ukb.uni-bonn.de