Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation
The development of neuroprotective therapies is a sought-after goal. By screening combinatorial chemical libraries using in vitro assays, we identified the small molecule BN201 that promotes the survival of cultured neural cells when subjected to oxidative stress or when deprived of trophic factors. Moreover, BN201 promotes neuronal differentiation, the differentiation of precursor cells to mature oligodendrocytes in vitro, and the myelination of new axons. BN201 modulates several kinases participating in the insulin growth factor 1 pathway including serum–glucocorticoid kinase and midkine, inducing the phosphorylation of NDRG1 and the translocation of the transcription factor Foxo3 to the cytoplasm. In vivo, BN201 prevents axonal and neuronal loss, and it promotes remyelination in models of multiple sclerosis, chemically induced demyelination, and glaucoma. In summary, we provide a new promising strategy to promote neuroaxonal survival and remyelination, potentially preventing disability in brain diseases.
Key WordsNeuroprotection neuroinflammation neurodegenerative diseases multiple sclerosis glaucoma
We would like to thank Prof Stephen L Hauser, David Pearce, and Ari Green from University of California, San Francisco; Joaquim Trias and Craig Smith for their scientific advice; and Mr. Mark Sefton for the review of the language of the manuscript.
VC, BM, BFD, RV, GV, IZ, JMF, NLS, MT, EG, and PV performed the experiments; PV, JMF, EG, JD, LS, and AM designed and supervised the research; JM, GM, and AM synthesized the libraries and the specific small chemicals; JMF and NLS developed the in vitro assays; MT and EG performed the blood–brain barrier assays; VC, BM, BFD, RV, GV, IZ, and PV performed the EAE experiments and evaluated CNS inflammatory infiltration; LS performed the Th17 passive transfer EAE model; VC and RV carried out the experiments with the glaucoma model; RV and PV performed the lysolecithin optic neuropathy model; JD, DL, and KLW performed the in vitro remyelination assays; BM, VC, JMF, EG, AM, and PV analyzed the data; PV prepared the manuscript, which was revised by JMF, EG, and AM; and the statistical analysis was performed by BM, RV, IZ, and PV.
This work was supported by the Fundación Ramon Areces, Madrid, Spain, and the Instituto de Salud Carlos III, Madrid Spain (RD07/0060 and PI12/01823) to PV and AM and by an unrestricted grant from Bionure SL, Barcelona, Spain.
Compliance with Ethical Standards
PV and AM hold a patent covering the composition of matter and uses of BN201. PV is founder and hold stocks in Bionure SL, which has licensed the patent rights to BN201, serves in its scientific advisory board, and had received compensation for such service. MM is an employee of Bionure SL. LS has shares of Bionure SL stock and has received consulting fees.
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