Abstract Details

Title BG-12 (Dimethyl Fumarate) Is Neuroprotective in the Murine Cuprizone/Rapamycin Model of Demyelination and Neurodegeneration

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 184

Objective

Background BACKGROUND: BG-12 (dimethyl fumarate) is in development for the treatment of multiple sclerosis (MS). A growing body of preclinical and clinical evidence suggests dimethyl fumarate may be neuroprotective against pathogenic stimuli. The cuprizone demyelination model has been used to investigate modulation of remyelination, and adding rapamycin results in more robust and consistent demyelination. This modified model produces significant axonal transection and neuronal degeneration, consistent with MS plaque pathology.

Design/Methods DESIGN/METHODS: C57BL/6J male 8-week-old mice were fed chow containing 0.3% cuprizone (w/w), and received rapamycin daily (intraperitoneally 10 mg/kg) and concurrent dimethyl fumarate (100 mg/kg) or vehicle by daily oral gavage. After 6 weeks of treatment, the corpus callosum (CC) was analyzed by immunohistochemistry with antibodies against non-phosphorylated neurofilament H (SMI32) and PDGFRa, and stained with paraphenylenediamine. CC blocks were also subjected to 3D electron microscopy to evaluate myelin integrity (myelin thickness, g-ratio, internodal length).

Results RESULTS: Dimethyl fumarate-treated animals exhibited significantly less SMI32+ axonal ovoids (p<0.001 vs vehicle) and significantly more myelinated axons (p<0.01 vs vehicle) in the CC as compared to vehicle. Dimethyl fumarate-treated animals also exhibited significantly less expansion of PDGFRa+ oligodendrocyte precursor cells in the CC, and evidenced modulation of myelin characteristics with significant improvements in myelin thickness, g-ratio and internodal length relative to vehicle controls.

Conclusions CONCLUSIONS: These data suggest that dimethyl fumarate reduces transection/degeneration of acutely demyelinated axons and increases the number of myelinated axons. 3D electron microscopy data indicates that all animals receiving cuprizone/rapamycin were completely demyelinated over the study duration. The beneficial effects on myelin characteristics suggest dimethyl fumarate may have promoted the differentiation of oligodendrocyte precursor cells, or established an environment more permissive for endogenous remyelination. The preservation of neuronal histology in the face of an MS-relevant demyelinating insult further supports the neuroprotective properties of dimethyl fumarate.

Authors/Disclosures
Robert H. Scannevin, PhD PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Bruce D. Trapp, PhD (Cleveland Clinic)	Dr. Trapp has received personal compensation for serving as an employee of Renovo Neural Inc.. The institution of Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Therini Bio, Inc.. Dr. Trapp has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Trapp has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Disarm Therapeutics. Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Kantonsspital Aarau AG. Dr. Trapp has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for triMS.online. The institution of Dr. Trapp has received research support from Genzyme Corporation. The institution of Dr. Trapp has received research support from ALS Association. The institution of Dr. Trapp has received research support from National Institute of Neurological Disorders and Stroke.
	No disclosure on file
Krzysztof W. Selmaj (University of Warmia and Mazury)	Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astra. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Astra. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS. Krzysztof W. Selmaj has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck.

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