Parkinson's disease is characterized by the selective death of dopaminergic neurons in the midbrain and accumulation of amyloid fibrils composed of α-synuclein (αSyn). Current treatment involves approaches that compensate the death of dopaminergic neurons by increasing the dopamine levels in remaining cells. However, dopamine can interact with αSyn and produce oligomeric species which were reported to be toxic in many models. We studied formation of dopamine-induced αSyn oligomers and their effect on the αSyn aggregation. Using the Thioflavin T kinetic assay, we have shown that small oligomers efficiently inhibit αSyn fibrillization by binding to fibril ends and blocking the elongation. Moreover, all the fractions of oligomer species proved to be nontoxic in the differentiated SH-SY5Y cell model and showed negligible neurotoxicity on isolated rat synaptosomes. The observed inhibition is an important insight in understanding of dopamine-enhancing therapy on Parkinson's disease progression and explains the absence of pathology enhancement.
- MeSH
- alfa-synuklein metabolismus MeSH
- amyloid metabolismus MeSH
- dopamin chemie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- neuroblastom * MeSH
- Parkinsonova nemoc * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Changes in cholesterol concentration in the plasma membrane of presynaptic nerve terminals nonspecifically modulate glutamate transport and homeostasis in the central nervous system. Reduction of the cholesterol content in isolated rat brain nerve terminals (synaptosomes) using cholesterol-depleting agents decreases the glutamate uptake and increases the extracellular level of glutamate in nerve terminals. Extraction of cholesterol from the plasma membrane and its further removal from the synaptosomes by external magnetic field can be achieved by means of magnetic nanoparticles with immobilized cholesterol-depleting agent such as O-methyl-β-cyclodextrin (MCD). A simple approach is developed for preparation of maghemite (γ-Fe2O3) nanoparticles containing chemically bonded MCD. The method is based on preparation of a silanization agent containing MCD. It is synthesized by the reaction of triethoxy(3-isocyanatopropyl)silane with MCD. Base-catalyzed silanization of superparamagnetic γ-Fe2O3 provides a relatively stable colloid product containing 48μmol of MCDg(-1). MCD-modified γ-Fe2O3 nanoparticles decrease the initial rate of the uptake and accumulation of l-[(14)C]glutamate and increase the extracellular l-[(14)C]glutamate level in the preparation of nerve terminals. The effect of MCD-immobilized nanoparticles is the same as that of MCD solution; moreover, magnetic manipulation of the nanoparticles enables removal of bonded cholesterol.
- MeSH
- beta-cyklodextriny chemie farmakologie MeSH
- biologický transport účinky léků MeSH
- buněčná membrána účinky léků metabolismus MeSH
- cholesterol izolace a purifikace metabolismus farmakologie MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- kyselina glutamová metabolismus MeSH
- magnetické nanočástice chemie MeSH
- membránové potenciály účinky léků MeSH
- mozek účinky léků metabolismus MeSH
- potkani Wistar MeSH
- presynaptické terminály účinky léků metabolismus MeSH
- radioizotopy uhlíku MeSH
- silany chemie MeSH
- synaptozomy účinky léků metabolismus MeSH
- železité sloučeniny chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
