Alzheimer disease (AD) is a progressive neurodegenerative disease, which is marked by cognitive impairments, cholinergic malfunctioning, and loss of synaptic capabilities. The current study aimed to investigate the neuroprotective effect of Synephrine in a model of amnesia induced by scopolamine in Wistar rats, combining in vivo, in vitro, and in silico experiments. The scopolamine (0.5 mg/kg) was used to cause cognitive impairment to male Wistar rats, and then they were treated with Synephrine (40 and 80mg/kg). The novel object recognition, spontaneous alternation, elevated plus maze, and rotarod tests were used to assess cognitive performance. Synephrine treatment enhanced recognition memory, exploratory behavior, and motor coordination dose-dependently, albeit the effect was not as high as that of donepezil. In vitro, Synephrine showed moderate acetylcholinesterase inhibition with an IC50 of 78.57 which would indicate partial recovery of cholinergic signaling. Rule of five analysis and bloodbrain barrier (BBB) prediction calculations by Lipinski showed good oral bioavailability and central nervous system (CNS) access. Stable interactions of Synephrine in the acetylcholinesterase active site (binding energy -8.57 kcal/mol) in terms of hydrogen bonding with catalytic residues and hydrophobic contacts in the gorge were identified through molecular docking. Simulations in the framework of molecular dynamics showed a lower root mean square fluctuation (RMSF) of all the essential catalytic and peripheral residues when ligands are bound, showing better structural stabilization. ADMET predictions indicated high intestinal absorption, moderate BBB penetration, and low toxicity, which is in favor of pharmacological viability. All these results reveal that Synephrine has moderate neuroprotective and cognitive-enhancing effects due to cholinergic modulation, anti-oxidative and anti-inflammatory effects, and structural stabilization of acetylcholinesterase, making it a prospective adjunct or replacement of traditional cholinesterase inhibitors in improving cognitive abnormalities in neurodegenerative disorders.
Tiwari et al. (Sun,) studied this question.