From anecdotal evidence of cannabinoids in multiple sclerosis to emerging new therapeutical approaches

The medicinal properties of extracts from Cannabis sativa have a long history, since there are reports, as early as 2600 BC, of its use in relieving cramps, rheumatic and menstrual pain. An accurate description of the psychotropic effects of cannabis dates back to 1848, from a commentary in the British Pharmacopoeia , which emphasized its analgesic and anti-spasmodic properties. Anecdotal reports have suggested that cannabinoids significantly relieve the symptoms of multiple sclerosis (MS), although a crucial point for their therapeutic application is the full assessment of their psychotropic effects. Several other plant cannabinoids, that have little or no psychoactive action, have been identified; their biosynthetic relationships have been established, and the possible contribution that they make to some of the proposed therapeutic actions of cannabis has been suggested. In particular, cannabidiol and the cannabinoic acids seem to be promising therapeutic tools, even though their sites of action are still not well understood [1]. The genetic selection of cannabis strains allowed the preparation of Sativex, a cannabis-based pharmaceutical product with exactly reproducible ratios of THC/cannabidiol, delivered as a sublingual spray. The results of a very recent clinical trial on patients with various neurological conditions (including MS), demonstrated that Sativex significantly reduced neurophatic pain, spasticity, muscle spasm and sleep disturbances [2]. These findings, together with insights from basic research and animal experiments, led to the conclusion that there is reasonable evidence for the therapeutic use of cannabinoids and their derivatives in the treatment of MS-related symptoms. Data suggests that cannabinoids have immunomodulatory and neuroprotective properties. Furthermore, the finding that the endocannabinoid system, endogenous ligands that can bind the cannabinoid receptors (CB), can regulate neurotransmission, led to many studies on the effect of these substances and their derivatives on several neurodegenerative diseases. In an animal model of MS, it has been demonstrated that both exogenous and endogenous cannabinoids, via the cannabinoid receptor CB1, alleviate spasticity and tremors [3,4]. Although CB1 agonism can inhibit spasticity, the experimental observation that CB1 receptor antagonists made spasticity transiently pounds do not bind directly to CB1 and, thus, have little inherent psychoactivity, as the limit of use of cannabinoids for therapeutic approaches is due to their CB1-mediated psychotropic effects. This finding implies that drugs based on endocannabinoids, with low potential for physical dependence, could be used in the treatment of spasticity. Recently, it has been reported that during central nervous system (CNS) inflammation, the endocannabinoid system is highly activated and the endocannabinoid an-andamide (AEA) protects neurons from inflammatory damage by CB(1/2) receptor-mediated rapid induction of mitogenactivated protein kinase phosphatase-1 (MKP-1) in microglial cell. The release of AEA in injured CNS tissue might represent a new mechanism of neuro-immune communication during CNS injury, which limits immune response after primary CNS damage [6]. Furthermore, evidence suggest that endocannabinoids have immunosuppressant and anti-inflammatory properties, they down-regulate the production of T helper 1 (Th1) cytokines, enhancing the production of T helper 2 (Th2) cytokines, since a polarization of T cell response towards a Th2 phenotype has been associated with therapeutic benefit in MS, while a shift towards Th1 has been associated with disease progression [7,8]. The anti-spastic effect of arvanil, a ‘chimeric’ ligand, which combines the structural features of the pungent ingredient of red peppers capsaicin (vanilloid receptor TRPV1 agonist), and of AEA (CB1 receptor agonist), have been reported. The anti-spastic effect of arvanil was more potent than capsaicin and CB1 receptor agonists, was unchanged in CB1 receptor gene-deficient mice or in wild type mice in the presence of both cannabinoid and vanilloid receptor antagonists, and therefore, was ascribed to the activation of non-CB1 nonTRPV1 receptors [9]. A recent publication by our laboratory reports that arvanil modulates human T lymphocyte proliferation and activation without induction of apoptosis through a cannabinoid and vanilloid receptor-independent mechanism. The inhibition of proliferation was confirmed in murine cells and was associated with reduced IFN-g production. Arvanil immunosuppressive properties were more efficient compared to anandamide and capsaicin. Furthermore, arvanil regulated the inflammatory