cortodoxone and Alzheimer-Disease

Insomnia, depression, and Alzheimer's disease are all neurodegenerative diseases and are associated with the levels of steroid hormones. To investigate the internal connection and difference of steroid hormones among these three diseases and distinguish them from the perspective of biomarkers, an easy, quick, and efficient high-performance liquid chromatography with tandem mass spectrometry method was established and validated to determine six steroid hormones simultaneously in rat serum. The separation was accomplished on a SHIM-PACK XR-ODS chromatographic column with 0.1% v/v formic acid and methanol as the mobile phase and the detection was performed with electrospray ionization source in the positive ion mode. Based on the concentrations of steroid hormones, all the groups could be distinguished obviously from each other by using partial least square discriminant analysis. Meanwhile, 11-deoxycortisol, corticosterone, and cortisol were identified as potential biomarkers and 100% of samples were classified correctly by Bayes' discriminant function. These biomarkers were further screened by one-way analysis of variance and cortisol was significantly different among all these groups. Bayes' discriminant function was also built by cortisol and the classification accuracy was 87.2%. This workflow including determination of steroid hormones and discrimination among three neurological diseases would provide a basis for further clinical studies.

Topics: Alzheimer Disease; Animals; Bayes Theorem; Biomarkers; Calibration; Chromatography, High Pressure Liquid; Corticosterone; Cortodoxone; Depression; Diagnosis, Differential; Hormones; Hydrocortisone; Least-Squares Analysis; Male; Rats; Rats, Wistar; Reproducibility of Results; Sleep Initiation and Maintenance Disorders; Spectrometry, Mass, Electrospray Ionization; Steroids; Tandem Mass Spectrometry

Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment.

Topics: Alzheimer Disease; Animals; Antioxidants; Biphenyl Compounds; Blood-Brain Barrier; Cell Survival; Chemical and Drug Induced Liver Injury; Cholinesterase Inhibitors; Chromans; Drug Design; In Vitro Techniques; Kinetics; Male; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; PC12 Cells; Picrates; Rats; Swine; Tacrine