Alzheimer’s disease (AD) is a multifactorial disorder characterized by exponential loss of memory and cognitive deficit involving several disease modifying targets (amyloid beta, beta-secretase, monoaminoxidase-B, and cholinesterase). The present study explores multi-target directed ligand approach using secondary metabolite reserpine (RES) and ajmalicine (AJM) obtained from Rauwolfia serpentina roots. Novel LCMS and HPLC methods were developed for identification and quantification of reserpine and ajmalicine. In vitro enzyme inhibition assays were performed to evaluate anti-cholinesterase, β-site amyloid cleaving enzyme (BACE-1) inhibition and monoamine oxidase-B (MAO-B) inhibition, further analyzed with in silico analysis. Anti-amyloidogenic potential was studied using anti-aggregation studies along with TEM and circular dichroism (CD) analysis. In vitro neuroprotective potential against Aβ toxicity and anti-oxidative stress was demonstrated using PC12 cell cultures. Reserpine is a more potent dual cholinesterase inhibitor than ajmalicine (IC50 values of 1.7 μM (AChE) and 2.8 μM (BuChE)). The anti-aggregation activity of reserpine (68%) was more than ajmalicine (56%). Both compounds demonstrated neuroprotective activity against Aβ42 (92%) and H2O2 (93%) induced toxicity in PC12 cells against controls. Phytocompounds also inhibited MAO-B and BACE-1 enzymes in concentration dependent manner. Molecular docking studies indicated the strong binding of compounds to the catalytic site of targets. This novel study demonstrated that reserpine and ajmalicine as a multi-target directed ligand that have disease modifying potential for amelioration of AD.
Background; Tamoxifen, is a first-generation selective estrogen receptor modulator which is widely used for adjuvant breast cancer therapy. Tamoxifen metabolites completely bind to estrogen receptor on tumors as well as other tissues and target a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. But these Selective Estrogen Receptor Modulators (SERMs) are classified as Prohibited substances according to the list of forbidden substances in sports by the World Anti-Doping Agency (WADA) In sports male athletes use tamoxifen in fighting against increase of estrogen level in the body, breast swelling, gynecomastia and fat forming a pear-silhouette very successfully. Aim; In the present study Tamoxifen was investigated carefully by administering to a Healthy volunteer. Material and Method; Urine samples are collected at different hours from 1 st day to 5 th day and analyzed by GC-MS. Result; It was found that Tamoxifen is rapidly metabolized in to their metabolite 3-hydrohy-4-methoxy Tamoxifen. Urinary extracts were analyzed by Gas Chromatography-Mass spectrometric Detector by using Selective ion modulator (SIM) and targeted GC-MS techniques with accurate mass. By the GC-MS study it is observed that 3-hydroxy-4-methoxy Tamoxifen metabolite gives two neutral loss m/z value at 58 & 72, but m/z value 58 shows more abundance than 72m/z value, hence it was selected as the marker m/z value to check the presence of metabolite in urine. Conclusion; After oral administration, Tamoxifen metabolite can be detected in to their maximum period up to 5 days.
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