RESUMO
BACKGROUND: Serum homocysteine (Hcy) level is considered to be an important biomarker for Alzheimer's disease (AD); however, the status of Hcy in brain tissue, and the association between brain and serum levels of Hcy in AD patients remain unclear. OBJECTIVE: We aimed to examine whether the changes of three thiols are consistent in serum of AD patients and the brain of APP/PS1 mice, and to verify the effectiveness of Hcy as a biomarker for early AD detection. METHODS: The levels of Hcy, cysteine (Cys), and glutathione (GSH) in Aß1-42-treated PC12 cells, the brain and hippocampus of APP/PS1 mouse, and the serum of AD patients were evaluated using ethyl (E)-3-(9-chloro-11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f] pyrido [3,2,1 -ij] quinolin-10-yl)-2-cyanoacrylate (Probe 1) and ELISA assay or LC-MS. RESULTS: Measurement by Probe 1 revealed a significant increase in Hcy level, and a decrease in Cys and GSH levels in Aß1-42-treated PC12 cells and the serum of AD patients. The hippocampus and whole brain of APP/PS1 mice also showed a significant increase in Hcy level alongside the accumulation of age-related AD symptoms. The upregulation of Hcy and the downregulation of Cys and GSH were reversed in the Aß1-42-treated PC12 cells and the brain of APP/PS1 mice when supplemented with VB6. CONCLUSION: Changes in Hcy, Cys, and GSH levels in the brain of APP/PS1 mice and Aß1-42-treated PC12 cells were observed in situ with a new fluorescent probe, which were consistent with the abnormal changes in Hcy, Cys, and GSH levels in the serum of AD patients. VB6 supplementation was successful in ameliorating abnormal increases in Hcy levels.
Assuntos
Doença de Alzheimer , Encéfalo/metabolismo , Homocisteína , Compostos de Sulfidrila , Vitamina B 6/farmacologia , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Cisteína/metabolismo , Regulação para Baixo , Diagnóstico Precoce , Feminino , Corantes Fluorescentes , Glutationa/metabolismo , Homocisteína/sangue , Homocisteína/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células PC12 , Ratos , Espectrometria de Fluorescência/métodos , Compostos de Sulfidrila/classificação , Compostos de Sulfidrila/metabolismo , Regulação para Cima , Complexo Vitamínico B/farmacologiaRESUMO
The comparative molecular field analysis steric field of a single "topomeric" conformer is introduced as a molecular diversity descriptor particularly useful for combinatorial chemistry involving variations around a fixed "core". Using this new descriptor, 736 commercially available thiols are divided into 231 bioisosteric clusters, whose compositions agree at least as well with medicinal chemical experience and intuition as do clusters derived from Tanimoto differences between 2D fragment occurrences. However, in practice topomeric steric fields complement 2D fingerprints, being the two most frequently useful descriptors yet found for neighborhood-based design of combinatorial libraries.