ABSTRACT
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.
Subject(s)
Cognition Disorders/drug therapy , Cognition Disorders/pathology , Immunosuppressive Agents/therapeutic use , Methotrexate/therapeutic use , Myelin Sheath/metabolism , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Channelrhodopsins/genetics , Channelrhodopsins/metabolism , Cognition Disorders/genetics , Disease Models, Animal , Humans , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myelin Sheath/pathology , Myelin Sheath/ultrastructure , Oligodendrocyte Precursor Cells/drug effects , Organic Chemicals/therapeutic use , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Recognition, Psychology/drug effects , Signal Transduction/drug effects , Signal Transduction/genetics , Urea/analogs & derivatives , Urea/metabolismABSTRACT
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.
