Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.667108
Title: Characterisation of fatty acid amide hydrolase as a potential therapeutic target in Multiple Sclerosis
Author: Graves, Ryan Stanley
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2013
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Abstract:
Multiple sclerosis (MS) is a demyelinating neurodegenerative disease that typically has a relapsing-remitting pattern of progression superimposed on a gradual worsening of disease symptoms. Experimental autoimmune encephalomyelitis (EAE) is a model of MS where animals develop relapses, demyelination and accumulate neurological deficits. Studies using the EAE model have provided evidence that cannabinoids are beneficial in reducing disease symptoms and may impact long term neurodegeneration, but side-effects of exogenous cannabinoid receptor agonists may limit their potential as therapeutic agents for MS. Targeting enzymes involved in degradation of endocannabinoids such as the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH) may be an attractive alternative strategy. Using experimental allergic encephalomyelitis (EAE) as a mouse model of MS, two complementary approaches were used to assess FAAH as a potential therapeutic target. The FAAH deficient (ABH.FAAH-/-) developed similar paralytic relapsing disease of similar severity of disease compared to the wild-type, but showed a poorer recovery following the acute phase. However, following a relapsing-remitting disease course, the FAAH deficient mice showed a substantial improvement in clinical score, improved motor control, and lost less neurofilament compared to wild-type mice. These findings indicate that fatty acid amides may be neuroprotective in EAE. Secondly, a selective FAAH inhibitor (PF-3845; 10 mg/kg) was used to treat mice during the relapse phase of the disease course. Treatment with PF-3845 caused an elevation of anandamide in the CNS. This treatment resulted in a small reduction in neurofilament loss, but no reduction in clinical score or improvement in motor control was observed compared to the vehicle treated group. To investigate at a cellular level how FAAH might affect disease progression in the EAE model, immunohistochemistry was used to analyse FAAH expression in the CNS. Employing novel antibodies to FAAH in combination with neuronal and glial cell markers, it was found that, in addition to previously reported neuronal expression of FAAH, FAAH is highly expressed 3 in oligodendrocytes, but not in other glial cell types. Thus, genetic deletion or pharmacological inhibition of FAAH may affect both neuronal activity and oligodendroglial function (e.g. myelination). The role of FAAH in oligodendrocytes was investigated in vitro. An oligodendrocyte precursor cell (OPC) monoculture was used to monitor differentiation, and a co-culture comprising neurons and OPCs was used to monitor myelination. During the differentiation of OPCs, FAAH expression was detected in the entire oligodendroglia lineage, but with high expression only in mature myelin basic protein (MBP) expressing cells. Treatment with the FAAH inhibitor PF-3845 (0.1 μM to 1 μM) increased differentiation of OPCs into mature oligodendrocytes. However, the same treatment of co-cultures had no effect on the myelination of neurites. In conclusion, this study has: i) obtained evidence that genetic deletion of FAAH is neuroprotective in a mouse model of MS and ii) provided new insights on FAAH expression in the CNS. Further investigation of FAAH, in particular its role(s) in oligodendrocytes, will be required to fully unlock the therapeutic potential of FAAH inhibition in the treatment of MS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.667108  DOI: Not available
Keywords: Biochemistry ; Experimental autoimmune encephalomyelitis ; Fatty acid amide hydrolase ; FAAH ; Cannabinoids
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