Neuroprotective potential of synephrine against aluminium chloride (AlCl3) induced cognitive impairment & neuronal damage in rats

Alzheimer’s disease is a neurodegenerative disorder associated with cognitive decline, oxidative stress, and neuroinflammation. Synephrine, a naturally occurring alkaloid derived from traditional Chinese medicine (TCM) and commonly referred to as Zhi Shi, is proposed to exhibit potential neuroprotective properties. This study aims to evaluate the potential of synephrine against AlCl₃-induced cognitive impairment in Wistar rats, compared with donepezil as the standard treatment. Animal (Male Wistar rats) were divided into five groups: (1) Control, (2) Disease control (AlCl 3 , 175 mg/kg, p.o.), (3) Synephrine (40 mg/kg, p.o.) + AlCl 3 , (4) Synephrine (80 mg/kg, p.o.) + AlCl 3 , and (5) Donepezil (5 mg/kg, p.o.) + AlCl 3 . Treatment was administered for 28 days. Behavioral assessments included the Open Field Test (OFT), Novel Object Recognition Test (NORT), and Morris Water Maze (MWM). Biochemical evaluations included acetylcholinesterase (AChE) activity, oxidative stress markers (lipid peroxidation, catalase, superoxide dismutase, and glutathione), neuroinflammatory markers (TNF-α and IL-1β), and neuroplasticity markers (NF-κB and BDNF). The AlCl 3 treated group exhibited significant behavioral impairments, neuroinflammation, oxidative stress, and cholinergic dysfunction. Synephrine administration (especially at 80 mg/kg) significantly improved locomotion, exploratory behavior, and memory retention in the behavioral tests. It also reduced AChE activity, oxidative stress markers (lipid peroxidation), and neuroinflammatory cytokines (TNF-α, IL-1β), while enhancing antioxidant enzymes (SOD, catalase, GSH) and neuroplasticity markers (BDNF). The neuroprotective effects of synephrine were comparable to donepezil, suggesting its potential role in mitigating cognitive decline. To further elucidate the mechanism of synephrine in AChE inhibition, molecular docking studies were conducted. The docking analysis revealed that synephrine exhibited a binding affinity of -6.29 kcal/mol with AChE, forming hydrogen bonds with Thr83 and His447, and π-stacking interactions with Trp86, stabilizing the ligand within the active site. These interactions indicate that synephrine can effectively inhibit AChE, reinforcing its neuroprotective effects by modulating acetylcholine breakdown. The docking results provide mechanistic insights into synephrine's therapeutic potential for Alzheimer's disease and highlight its possible application in neurodegenerative disorder management. Synephrine demonstrated significant neuroprotective effects against AlCl₃-induced cognitive dysfunction, possibly through its antioxidant, anti-inflammatory, and cholinergic-modulating properties. The docking analysis further supports its potential role as an AChE inhibitor, which could contribute to its neuroprotective effects. These results point to synephrine's potential as a treatment for Alzheimer's disease. To establish its therapeutic usefulness and clarify its exact mode of action, additional research is required.