Cognitive-enhancing effect of Cordia dichotoma fruit on scopolamine-induced cognitive impairment in rats: metabolite profiling, in vivo, and in silico investigations

Abstract

Many plants are reported to enhance cognition in amnesic-animal models. The metabolite profile of Cordia dichotoma fruit methanolic extract (CDFME) was characterized by LC-QTOF-MS/MS, and its total phenolics content (TPC) and total flavonoids content (TFC) were determined. In parallel, its cognitive-enhancing effect on scopolamine (SCOP)-induced AD in rats was evaluated. The TPC and TFC were 44.75 ± 1.84 mg gallic acid equiv. g⁻¹ sample and 5.66 ± 0.67 mg rutin equiv. g⁻¹ sample, respectively. In total, 81 metabolites were identified, including phenolic acids, lignans, coumarins, amino acids, fatty acids, and their derivatives, fatty acid amides, polar lipids, terpenoids, and others. The most abundant metabolites identified were quinic acid, caffeoyl-4′-hydroxyphenyllactate, rosmarinic acid, and oleamide. CDFME (200 mg kg⁻¹) was found to significantly enhance recognition memory in the novel object recognition test. Furthermore, it nearly corrected acetylcholinesterase (AChE), acetylcholine, noradrenaline, and dopamine hippocampal levels, which changed due to SCOP. Further in silico validation of the in vivo results was conducted, focusing on the most abundant metabolites. Molecular docking showed that rosmarinic acid, caffeoyl-4′-hydroxyphenyllactate, sebestenoid C, and sagerinic acid exhibited the greatest affinity for receptor binding against AChE. However, molecular dynamics and mechanics calculations clarified that the complex of caffeoyl-4′-hydroxyphenyllactate with AChE was the most stable one. This study represents the first comprehensive metabolite profiling of CDFME to assess its cognition-enhancing effect both in vivo and in silico. These results demonstrate that CDFME protects against SCOP-induced cognitive impairment. Thus, additional preclinical and clinical studies on CDFME may provide an attractive approach in pharmacotherapy and AD prophylaxis.