A NOVEL SMALL MOLECULE PROMOTOR OF REMYELINATION (P3.2-066)

Objective: To examine the efficacy of Anacardic acid (AA) as a novel small molecule agent for remyelination Background: Currently there are no approved agents which are available to repair demyelinating lesions. Axons devoid of myelin ultimately become atrophic and die leading to permanent neurologic deficits. Design/Methods: Oligodendrocyte cultures were prepared from 6 day old rat pups. Purified populations of oligodendrocyte precursor cells (OPC) were cultured with AA and the expression of MBP, PLP and MOG was examined. We also examined the efficacy of AA in inducing Sox10 and Purα known transcription elements which regulate myelin gene expression. We used the Cuprizone model of gliotoxic demyelination to examine the effect of AA in promoting remyelination. Results: AA enhanced the expression of MBP over that seen in controls in OPC using both western blot and qRT-PCR assays. In addition, using q RT-PCR there was a > 3 fold increase in mRNA for Mbp, Plp and Mog along with increase in mRNA expression of the transcriptional elements Purα and Sox 10 which regulate MBP expression by AA suggesting a rapid induction of myelin genes. AA also induced IL-33, a known trophic factor for axons. When AA was given to animals fed with cuprizone, AA treated mice showed a 18% increase in expression of MBP over vehicle treated controls (p, Conclusions: Our studies show that AA a naturally occurring small molecule is able to induce myelin genes and promote remyelination in vivo. Induction of myelin genes appeared to be mediated as a direct effect on OPC and indirectly through the activation IL-33. Since the cashew fruit and nuts from which AA is isolated has been used as a nutrient and a diet supplement it is unlikely to be toxic and will form a basis for its use as a novel therapeutic agent to promote remyelination. Disclosure: Dr. Natarajan has nothing to disclose. Dr. Rose has nothing to disclose. Dr. Sriram has received research support from EMD Serono.