Dimeric bis (heptyl)-Cognitin Blocks Alzheimer's β-Amyloid Neurotoxicity Via the Inhibition of Aβ Fibrils Formation and Disaggregation of Preformed Fibrils
| Autor: | Yuan Ping Pang, Yifan Han, Ming Yuen Lee, Wei Cui, Rui Wang, Yuanjia Hu, Shing Hung Mak, Sheng Quan Hu, Gang Li |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Amyloid Cell Survival Drug Evaluation Preclinical Morris water navigation task Rats Sprague-Dawley chemistry.chemical_compound Alzheimer Disease Cell Line Tumor Physiology (medical) medicine Animals Humans Pharmacology (medical) Senile plaques Maze Learning Pharmacology Memory Disorders Amyloid beta-Peptides Dose-Response Relationship Drug Chemistry Neurotoxicity Original Articles medicine.disease Acetylcholinesterase Peptide Fragments Disease Models Animal Psychiatry and Mental health Neuroprotective Agents Biochemistry Tacrine Biophysics Thioflavin Reactive Oxygen Species Intracellular medicine.drug |
| Zdroj: | CNS Neuroscience & Therapeutics. 21:953-961 |
| ISSN: | 1755-5930 |
| DOI: | 10.1111/cns.12472 |
| Popis: | Summary Aims Fibrillar aggregates of β-amyloid protein (Aβ) are the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit Aβ fibrils formation, disaggregate preformed Aβ fibrils as well as reduce their associated neurotoxicity might have therapeutic values for treating AD. In this study, the inhibitory effects of bis (heptyl)-cognitin (B7C), a multifunctional dimer derived from tacrine, on aggregation and neurotoxicity of Aβ1-40 were evaluated both in vitro and in vivo. Methods Thioflavin T fluorescence assay was carried out to evaluate Aβ aggregation, MTT and Hoechst-staining assays were performed to investigate Aβ-associated neurotoxicity. Fluorescent probe DCFH-DA was used to estimate the accumulation of intracellular reactive oxygen stress (ROS). Morris water maze was applied to determine learning and memory deficits induced by intracerebroventricular infusion of Aβ in rats. Results B7C (0.1–10 μM), but not tacrine, effectively inhibited Aβ fibrils formation and disaggregated preformed Aβ fibrils following co-incubation of B7C and Aβ monomers or preformed fibrils, respectively. In addition, B7C markedly reduced Aβ fibrils-associated neurotoxicity in SH-SY5Y cell line, as evidenced by the increase in cell survival, the decrease in Hoechst-stained nuclei and in intracellular ROS. Most encouragingly, B7C (0.1 and 0.2 mg/kg), 10 times more potently than tacrine (1 and 2 mg/kg), inhibited memory impairments after intracerebroventricular infusion of Aβ in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with upregulation of choline acetyltransferase activity and downregulation of acetylcholinesterase activity. Conclusion These findings provide not only novel molecular insight into the potential application of B7C in treating AD, but also an effective approach for screening anti-AD agents. |
| Databáze: | OpenAIRE |
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