RESUMO
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/patologia , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Bainha de Mielina/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Transtornos Cognitivos/genética , Modelos Animais de Doenças , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Bainha de Mielina/patologia , Bainha de Mielina/ultraestrutura , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Compostos Orgânicos/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ureia/análogos & derivados , Ureia/metabolismoRESUMO
Skin protection and control of its microbial pathogens are highly important demands; natural biological agents are the ideals for that. Collagen (Cg) was extracted and characterized from skin and scales of Nile tilapia fish (Oreochromis niloticus), chitosan (Cts) was extracted from shrimp shells and extract of oak (Quercus infectoria) galls (OGE) was prepared. The antimicrobial potentialities of extracted agents, Cts and OGE, were qualitatively proved against skin pathogens, Staphylococcus aureus and Candida albicans, including both antibiotic sensitive and resistant strains, neither Cg nor negative control exhibited antimicrobial actions toward examined strain. The entire agents were loaded onto cotton fabrics and evaluated for antimicrobial actions and durability. Loaded textiles with the combined extracts' composite were the most effectual followed by individual treatments with OGE and Cts, respectively. Treated textiles upheld most of their antimicrobial activity after 2 laundering cycles toward all microbial pathogens. This invention could be consequently applied for production of skin protectant and hygienic fabrics.