Abstract Details

Title BG-12 (Dimethyl Fumarate) Pharmacodynamic Responses Have Distinct Temporal Profiles and Are Dose-Dependent

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 146

Objective

Background BACKGROUND: Dimethyl fumarate is an oral therapeutic in development for the treatment of multiple sclerosis. Previous studies have demonstrated that primary pharmacodynamic responses to dimethyl fumarate treatment are mediated through activation of the nuclear factor (erythroid-derived 2)-like 2(Nrf2) pathway, an intrinsic cellular defense system that protects against various forms of oxidative, inflammatory and xenobiotic stress. Characterization of pharmacodynamic responses is essential for understanding the potential contribution of Nrf2 activation to biological and clinical effects of dimethyl fumarate.

Design/Methods DESIGN/METHODS: Naive C57BL/6 mice given dimethyl fumarate via oral gavage at 100 mg/kg were sacrificed at 0, 2, 4, 6, 8, 12, 16, 24 and 36 hours after dosing. Liver, spleen, kidney, jejunum, cortex, hippocampus, striatum, cerebellum and whole blood were collected and analyzed by RT-PCR. Single ascending doses of dimethyl fumarate (50, 100, 200, 400 and 600 mg/kg) were administered and the same tissues were harvested at 6 hours and profiled.

Results RESULTS: Dimethyl fumarate induced gene expression within the examined tissues, with differentiation in the onset and duration of the response observed between genes and tissue type. Transcriptional changes were observed in both the central nervous system (CNS) and peripheral tissues. Transcriptional changes peaked 4-8 hours after dosing, and then gradually decreased to baseline by 12 hours for most genes in most tissues. The magnitude of the response was found to be dose-dependent.

Conclusions CONCLUSIONS: These data confirm dimethyl fumarate-dependent activation of Nrf2-dependent genes in the CNS and periphery. Induction was transient and responses were dose-dependent. There were observations of tissue-specific gene expression, indicating additional levels of transcriptional regulation. Preclinical data indicate that activation of Nrf2 has a role in mediating the efficacy of dimethyl fumarate in animal models, and the transient nature of the response suggests that the pathway is amenable to repeated daily stimulation.

Authors/Disclosures
Melanie Shackett PRESENTER	No disclosure on file
	No disclosure on file
Mi-young Jung	No disclosure on file
Sarah Ryan	No disclosure on file
	No disclosure on file
Pradeep Bista (Biogen Idec)	No disclosure on file
	No disclosure on file
	No disclosure on file
Robert H. Scannevin, PhD	No disclosure on file

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