Jackson, S.J.; (2004) Cannabinoids and neuroprotection in mouse models of demyelination. Doctoral thesis , University of London.

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Abstract

The symptoms of multiple sclerosis (MS), an immune-mediated, degenerative disease of the central nervous system (CNS), are thought to be due to demyelination and axonal damage leading to impairment of neurotransmission. In a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis (CREAE), cannabinoid compounds have been shown to protect axons and improve disease severity. In this study, CREAE and rotation-mediated CNS aggregate cell cultures were used to examine the role of cannabinoid receptor 1 (CB1R) in endocannabinoid-mediated modulation of demyelination and neurodegeneration. The aggregate cell culture system was developed and characterised in mouse to exploit CB1R knockout (CB1R-KO) animals. CREAE was induced in CB1R-KO mice and wildtype counterparts, and CNS aggregate cell cultures derived from the same mouse strains were demyelinated with interferon gamma. CREAE animals were assessed for functional deficit by clinical scoring and in an open field activity chamber. CREAE spinal cords and aggregate samples were assessed for myelin content and axonal damage by measurement of myelin basic protein and neurofilament. Axonal vulnerability was assessed using a monoclonal antibody (SMI-32) against a dephosphorylated neurofilament epitope and caspase 3 expression and activation were measured to gauge cell death. Neurofilament loss following demyelination was increased in CB1R-KO animals and cultures when compared with wildtypes while myelin levels did not differ between the two strains. This indicates that the presence of CB1R may be partially responsible for restricting damage to axons in inflammation, but has a less marked effect on myelination or remyelination. Neurofilament loss correlated with functional deficit, suggesting that axonal or neuronal loss was responsible for neurodegeneration in CREAE. SMI-32 immunoreactivity was also increased, indicating axonal vulnerability or damage through alteration of neurofilament phosphorylation state. Increased activation of caspase 3 in knockout animals and cultures was evident, but not accompanied by increased procaspase 3 expression, signifying higher caspase activation rates. Caspases may therefore be involved in the death of neurons or axonal compromise in these two models. Manipulation of the cannabinoid pathway by exogenous agonist-mediated CB1R activation or indirect upregulation of endogenous ligands could slow disease progression in demyelinating diseases such as multiple sclerosis, indicating a potential therapeutic benefit.

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