Novel PPAR-γ agonists as potential neuroprotective agents against Alzheimer's disease: rational design, synthesis<i>, in silico</i> evaluation, PPAR-γ binding assay and transactivation and expression studies
Duraipandi Devi Priya, Umme Hani, Nazima Haider, Sirajunisa Talath, Dhivya Shanmugarajan, Prabitha Prabhakaran, P. Archana, B. R. Prashantha Kumar
Abstract
values of 8.607, 9.242, and 5.974 μM, respectively, in TR-FRET binding assay. These compounds were cell proliferative and non-cytotoxic in a neuroblastoma cell line (SH-SY5Y). They also demonstrated dose-dependent PPAR-γ activation in transactivation assay. Their neuroprotective effect was studied based on their anti-inflammatory and anti-oxidant potential by reducing the levels of proinflammatory markers (TNF-α, IL-6 and IL-1β) and ROS in Aβ-induced SH-SY5Y neuroblastoma cells using a flow cytometry method. The synthesized compounds also showed interactions in molecular docking study with the PPAR-γ receptor and demonstrated good stability in MD simulation. Our results highlight that through activation of PPAR-γ, the compounds 4a, 4h and 4j offer neuroprotective effects by reducing neuroinflammation and oxidative stress, and hence, they may be considered lead molecules for treating AD.