A sativex-like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.

BACKGROUND AND PURPOSE:

Sativex® is an oromucosal spray, containing equivalent amounts of Δ9 -tetrahydrocannabinol (Δ9 -THC) and cannabidiol (CBD)-botanical drug substance (BDS), and 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 (TMEV-IDD).

EXPERIMENTAL APPROACH:

A 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 RESULTS:

Sativex® improved motor activity -reduced CNS infiltrates, microglial activity, axonal damage- and restored myelin morphology. Similarly, we found weaker VCAM-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 dampened 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 Δ9 -THC-BDS produced weaker effects, acting through CB2 and primarily CB1 receptors.

CONCLUSIONS AND IMPLICATIONS:

The data support the therapeutic potential of Sativex® to slow MS progression and its relevance in CNS repair.
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