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 turbulence and is anticipated to badly affect the patient's quality of life. Previous studies revealed the neuroprotective effects of progesterone, so this study aimed to appraise the neuroprotective potentials of new derivatives of progesterone (AN-1 to AN-5).

Methods: Subsequent to compound synthesis and structure elucidation, the in-vitro antioxidant (DPPH), acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory and molecular docking studies were performed following standard procedures. The most potent compound was subjected to more detailed behavioral studies, including 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 and an IC50 value of 24.81 μg/ml. 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 24.51 and 18.79 μg/ml, 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 sites. 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.