Synthetic Derivates of Progesterone Ameliorate Scopolamine-Induced Cognitive Deficits in Animal Models: Antioxidant, Enzyme Inhibitory, Molecular Docking and Behavioral Correlates.

Abstract

Background: Alzheimer's disease (AD) is a neurological disorder characterized by cognitive decline and behavioral distrubance which are expected to significantly affect the patient's quality of life. Previous studies revealed the neuroprotective effects of progesterone. Furthermore, the aim of this study was to assess the neuroprotective potentials of new derivatives of progesterone (AN-1 to AN-5).

Methods: Following compound synthesis and structure elucidation, in vitro antioxidant (DPPH), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, as well as molecular docking studies, were performed, according to the standard procedures and the most potent compound was then subjected to more detailed behavioral studies, including the Y-Maze, Elevated Plus Maze (EPM), and open field tests in scopolamine-induced amnesic animals.

Results: In the DPPH assay, the AN-1 compound at 1000 μg/ml concentration exhibited 83.37 ± 2.03% inhibition of DPPH free radicals with an IC₅₀ value of 57.21 μM. Likewise, the compound AN-1 demonstrated 88.94 ± 1.20% inhibition against AChE and 86.78 ± 1.24% inhibition against BChE enzymes at 1000 μg/ml with IC₅₀ values of 56.52 and 43.33 μM, correspondingly. In behavioral studies, compound AN-1 demonstrated a significant decline in cognitive impairments and improved working memory as well as locomotor activities of the amnesic animals. Molecular docking studies also demonstrated that the compound AN-1 has promising inhibitory potentials against AChE and BChE enzymes by binding to their active site amino acid residues. The binding energies of AN-1 with both enzymes were -7.6 Kcal/mol for AChE and -8.1 Kcal/mol for BChE.

Conclusion: Based on our findings, it is concluded that the derivatives of progesterone exhibit neuroprotective potential, and further research is needed to extend their neuroprotective role in the treatment of AD.