Ameliorative role of Polyscias fruticosa leaf extract in aluminum chloride-induced neurotoxicity flies possibly mediated by N-methyl-D-aspartate receptor antagonistic and anticholinesterase active compounds

Abstract

Polyscias fruticosa leaves have been used in traditional medicine to aid in the therapy of brain and nerve-related disorders, including dementia. However, the evidences for the effects and mechanisms of P. fruticosa leaf extract (PFLE) and its constituents in improving dementia remain unclear. This study aims to evaluate the ameliorative effect of PFLE in aluminum chloride-induced neurotoxicity Drosophila melanogaster model. Simultaneously, the dementia-improving mechanisms of PFLE's compounds were explored by computational pharmacological analysis. Results showed that D. melanogaster exposed to 1.0, 2.0, and 4.0 mg/mL PFLE or 0.1 mg/mL donepezil hydrochloride had significant improvements in lifespan, memory, motor behavior, and oxidative stress markers, including decreased malondialdehyde level and increased glutathione level in flies' homogenates. Also, PFLE had acetylcholinesterase inhibitory ability with an IC₅₀ value of 266.10 µg/mL. Applying the UHPLC-Q-TOF-MS/MS technique, 36 compounds were identified in the PFLE. Among these, 25 compounds, including acid amines, flavonoids, saponins, choline, piperine, and vitamin B1, have been demonstrated potential for supporting the treatment of Alzheimer's disease (AD). Interestingly, molecular docking study indicated that many of the compounds are agents of prominent targets in dementia treatment including N-methyl-D-aspartate (NMDA) receptor and cholinesterase, in which polyscioside A-E are the main components of the PFLE that may be responsible for the NMDA receptor antagonistic and anticholinesterase activities. These compounds have favorable physiochemical properties and drug-likeliness. This study suggested the potential of the PFLE and its compounds in the prophylactic and treatment of neurodegenerative pathologies, including AD, and laid the foundation for further studies.

Keywords: N-Methyl-d-aspartate (NMDA) receptor antagonists; Polyscias fruticosa leaves; Aluminum chloride (AlCl3); Alzheimer’s disease; Anti-cholinesterase; Neurotoxicity.