Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like D 9 -tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB1 and CB2 receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB2 receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB2 receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB2 receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB2 receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB2 receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. LINKED ARTICLES

Our results demonstrated changes in endocannabinoid signaling, in particular a marked up-regulation of CB2 receptors, in SOD1(G93A) transgenic mice, and provide support that Sativex(®) may serve as a novel disease-modifying therapy in ALS.

BACKGROUND AND PURPOSE Sativex® is an oromucosal spray, containing equivalent amounts of Δ 9-tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS). In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler's murine encephalomyelitis virus-induced demyelinating disease model of MS. EXPERIMENTAL APPROACHA Sativex-like combination of phytocannabinoids and each phytocannabinoid alone were administered to mice once they had established MS-like symptoms. Motor activity and the putative targets of these cannabinoids were assessed to evaluate therapeutic efficacy. The accumulation of chondroitin sulfate proteoglycans (CSPGs) and astrogliosis were assessed in the spinal cord and the effect of Sativex on CSPGs production was evaluated in astrocyte cultures. KEY RESULTSSativex improved motor activity -reduced CNS infiltrates, microglial activity, axonal damage -and restored myelin morphology. Similarly, we found weaker vascular cell adhesion molecule-1 staining and IL-1β gene expression but an up-regulation of arginase-1. The astrogliosis and accumulation of CSPGs in the spinal cord in vehicle-infected animals were decreased by Sativex, as was the synthesis and release of CSPGs by astrocytes in culture. We found that CBD-BDS alone alleviated motor deterioration to a similar extent as Sativex, acting through PPARγ receptors whereas Δ 9 -THC-BDS produced weaker effects, acting through CB2 and primarily CB1 receptors. CONCLUSIONS AND IMPLICATIONSThe data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair. -tetrahydrocannabinol-botanical drug substance; Arg-1, arginase-1; CBD-BDS, cannabidiol-botanical drug substance; CSPGs, chondroitin sulfate proteoglycans; ECM, extracellular matrix; GAG chains, glycosaminoglycan chains; OPCs, oligodendrocyte precursor cells; TMEV-IDD, Theiler's murine encephalomyelitis virus-induced demyelinating disease; VCAM-1, vascular cell adhesion molecule-1; Sativex, Sativex-like combination of phytocannabinoids; XT-I, xylosyltransferase-I Abbreviations

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The cannabinoid signaling system participates in the control of cell homeostasis in the CNS, which explains why, in different neurodegenerative diseases including multiple sclerosis (MS), alterations in this system have been found to serve both as a pathogenic factor (malfunctioning of this system has been found at early phases of these diseases) and as a therapeutic target (the management of this system has beneficial effects). MS is an autoimmune disease that affects the CNS and it is characterized by inflammation, demyelination, remyelination, gliosis and axonal damage. Although it has been considered mainly as an inflammatory disorder, recent studies have recognized the importance of axonal loss both in the progression of the disorder and in the appearance of neurological disability, even in early stages of the disease. In recent years, several laboratories have addressed the therapeutic potential of cannabinoids in MS, given the experience reported by some MS patients who self-medicated with marijuana. Most of these studies focused on the alleviation of symptoms (spasticity, tremor, anxiety and pain) or on the inflammatory component of the disease. However, recent data also revealed the important neuroprotective action that could be exerted by cannabinoids in this disorder. The present review will be precisely centered on this neuroprotective potential, which is based mainly on antioxidant, anti-inflammatory and anti-excitotoxic properties, exerted through the activation of CB1 or CB2 receptors or other unknown mechanisms.

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