1. Supporting central nervous system neuroprotection and remyelination by specific TLR4 antagonism
- Author
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Comunidad de Madrid, Ministerio de Economía y Competitividad (España), AptaTargets, Universidad de Castilla La Mancha, Fernández-Gómez, Beatriz, Marchena, Miguel A., Piñeiro, David, Laó, Yolanda, Valencia, Gloria, Nocera, Sonia, Benítez-Fernández, Rocío, Gómez-Martín, Paula, Castaño-León, Ana M., Lagares, Alfonso, Hernández-Jiménez, Macarena, Castro, Fernando de, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), AptaTargets, Universidad de Castilla La Mancha, Fernández-Gómez, Beatriz, Marchena, Miguel A., Piñeiro, David, Laó, Yolanda, Valencia, Gloria, Nocera, Sonia, Benítez-Fernández, Rocío, Gómez-Martín, Paula, Castaño-León, Ana M., Lagares, Alfonso, Hernández-Jiménez, Macarena, and Castro, Fernando de
- Abstract
ApTOLL is an aptamer specifically designed to antagonize toll-like receptor 4 (TLR4), which is involved in the innate immunity that promotes inflammatory responses in several diseases, including multiple sclerosis (MS). MS is a chronic, immune, demyelinating and neurodegenerative disease of the central nervous system that represents the second most important cause of neurological disability in young adults. The drugs currently available to treat this disease are immunomodulators and, to date, there are no therapeutic remyelinating drugs available to manage MS. In this study, we show that TLR4 is located in post-mortem cortical lesions of MS patients and as a result, we evaluated the effect of its inhibition by ApTOLL in two different animal models of MS, that of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. ApTOLL administration ameliorated the clinical symptomatology of the affected mice, which was associated with better preservation and restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals. This revealed not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL which was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs). In summary, the molecular nature of ApTOLL and its mechanism of action strongly supports its further study and use in novel strategies to treat MS and eventually, other demyelinating diseases.
- Published
- 2023