The Neuroprotective Potential of Multitarget Plant Extracts in Alzheimer’s Disease: Insights from In Silico Predictions and Behavioral Analysis in the 5xFAD Mouse Model

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline and pathological hallmarks such as amyloid-β plaques and neurofibrillary tangles. Despite current therapies, effective treatments remain elusive. Phytochemicals have emerged as promising neuroprotective agents, while transgenic models such as 5xFAD mice enable rigorous preclinical evaluation.

This study aimed to evaluate the pharmacokinetic properties, predicted molecular targets, and behavioral effects of seven phytochemical extracts derived from Rubus fruticosus (FT, FH, and LH), Abutilon pannosum (A2), Abutilon grandifolium (A1), Rheum palmatum (R), and Zingiber officinale (G), using a 5xFAD murine model expressing five AD mutations.

Pharmacokinetic parameters, including gastrointestinal absorption, blood–brain barrier (BBB) permeability, cytochrome P450 interactions, and P-glycoprotein efflux, were predicted using SwissADME and ADMETlab. Molecular interactions with AD-relevant targets, including β-secretase, acetylcholinesterase, GSK3β, Aβ, and tau, were assessed via SwissDock and SwissTargetPrediction.

In vivo, 5xFAD mice (n = 80) were divided into treatment groups (n = 10 per extract, administered at 50 mg/kg and 100 mg/kg) and controls (NaCl, n = 5; Galantamine, n = 5). Extracts were administered via oral gavage for seven consecutive days and one hour prior to behavioral testing. Cognitive and anxiety- and depression-related behaviors were assessed using the Y-Maze, Open Field, Novel Object Recognition, Elevated Plus Maze, Forced Swimming, and Radial Arm Maze tests.

Our results revealed extract-specific behavioral effects. Rubus fruticosus extracts exhibited an inverse dose-dependent profile, with lower doses yielding superior cognitive performance and improvements in anxiety- and depression-related behaviors, often outperforming Galantamine. FH and A2 showed classical dose-responsiveness, with enhanced cognition at higher doses and increased locomotor activity at lower ones.

These findings underscore the neurotherapeutic potential of selected plant extracts—especially Rubus, Abutilon, and Zingiber—and highlight the value of integrating in silico and behavioral methodologies in AD research. Future work will include biochemical, genetic, and histological analyses to validate these preliminary findings and further investigate underlying mechanisms.