Cannabinoids as neuroprotectants and modulators of the processing of amyloid precursor protein (APP)

Projektdetails:

Projektbeschreibung

The use of Cannabis for the treatment of neurological problems has a long history and only in the last decade several advancements have been reached regarding potential mechanisms of its beneficial effects. In fact, Cannabis has been used for the treatment of various neurological problems in the past including epilepsy and motor disorders and very recently the range of neurological symptoms have been extended to disorders such as Multiple Sclerosis. Due to the expression of cannabinoid receptors in the central nervous system, the effect of Cannabis and cannabinoid compounds on the course and prevention of neurodegenerative processes have also been investigated. lndeed, various reports have underlined a neuroprotective function of cannabinoids in vitro and in vivo.

The main research topics of the key personnel in this particular research project is the investigation of Alzheimer Disease (AD)-associated oxidative apoptosis and necrosis (Christian Behl) and the elucidation of cannabinoid receptor (CB1) function in the central nervous system (Beat Lutz).

Abschlussbericht

ln summary, our results clearly show that the neuroprotective activity of phenolic cannabinoid compounds is not dependent on the expression or activity of the cannabinoid receptor CB1. These results are highly interesting since cannabinoid structures may define a new class of neuroprotective antioxidant compounds which have access to the brain and which may be used as blue pint for a future rational antioxidant drug design. In addition, when studying the potential role of cannabinoids in the treatment of neurological disorders, besides the cannabinoid-related psychoactive effects, also antioxidant activities of these compounds need to be considered.

These effects are - as shown here in our study - completely in dependent of cannabinoid receptors and may affect also brain regions lacking CB1 expression. These results have been presented at different national and international Neuroscience meetings, such as the Göttinger Neurobiologientagung 2001 and the Neuroscience Meeting in San Diego 2001. In addition our results are now in press in the Journal of Neurochemistry and will be published very soon.

In parallel of the study of the neuroprotective rolee of cannabinoid compounds and their activity as powerful antioxidant structures, potential interactions of cannabinoids with certain intracellular signalling pathways have been initiated and are still on their way. One highly interesting finding which is also derived from our AFl-funded research project is a more detailed study of the compound AM404 which has been described as inhibitor for an ,,anandamide transporter". lndeed, AM404 has been frequently proposed as a pharmaceutical drug already for the treatment of various neurological disorders. Here, we found that AM404 shares intracellular activities with 17-beta estradiol which may be related to the phenolic structure of AM404.  AM4O4 activates estrogen receptors and induces the transcription of estrogen-regulated genes as investigated by using estrogen response vectors linked to luciferase reporter genes. ln addition, AM404 just like 17-beta-estradiol activates phosphorylation of mitogen-activated protein kinase signalling. On the other hand, 4M404 does not interact with other signalling mechanisms such as NF-kappaB or CRE-dependent activation of transcription, underlining that the effects of AM404 at the estrogen receptor and the mitogen activated protein kinase system is specific.

These studies are still ongoing and we do not have a clear picture of the actual impact of our finding so far. Nevertheless, it shows already that a compound such as 4M404 has to be considered also as a compound which may activate certain signalling pathways when a potential pharmaceutical use of AM404 or derived compound is considered. This appears to us very important, especially in the light of the discussion of the activation of estrogen receptors in certain tissues and their beneficial and untoward effects.

Wissenschaftliche Publikationen auf Basis des geförderten Projekts

Marsicano, G., Moosmann,B., Hermann, H., Lutz, B., Behl, C. (2002). Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem., 80(3):448-56.