Alzheimer's disease (AD) is a neurodegenerative condition that accounts for approximately 65% of all dementia cases worldwide. Donepezil (DNP) is an acetylcholinesterase inhibitor that is widely prescribed for AD patients. However, extensive first-pass metabolism and the presence of the blood-brain barrier (BBB) significantly restrict its therapeutic efficacy. To address these challenges, two nanocarrier systems were developed: biodegradable polycaprolactone (PCL) and polyvinyl alcohol (PVA)-based polymeric nanoparticles, and dipalmitoylphosphatidylcholine (DPPC)-based liposomes. DNP-loaded PCL/PVA double emulsion nanoparticles and DPPC liposomes were prepared and characterized based on their particle sizes, uniformity, zeta potential, entrapment efficiency, Fourier transform infrared spectroscopy (FTIR), and in vitro drug release kinetics. Their safety profiles and cellular uptake potential were evaluated using the trypan blue exclusion assay and qualitative and quantitative cellular uptake assays with the human endothelial-like ECV-304 and neuronal PC-12 cell lines. The mean particle sizes of polymeric nanoparticles and liposomes were 175.97 ± 11.72 nm and 115.18 ± 4.63 nm, respectively, with low polydispersity indices (<0.3) and negative zeta potentials. FTIR analysis confirmed the absence of chemical interactions between DNP and formulation components. In addition, both nanocarrier systems demonstrated favorable biocompatibility, with cell viability exceeding 80%. Liposomes exhibited a more controlled drug release profile over 48 hours compared to polymeric nanoparticles. In contrast, both formulations exhibited significantly higher cellular uptake compared to their respective controls, with polymeric nanoparticles showing significantly higher cellular uptake than liposomes in ECV-304 cells (27.41 ± 2.38%, p < 0.05), demonstrating that carrier composition is a key determinant of nanoparticle-cell interactions independent of targeting ligands or surface modifications. This suggests that polymeric nanoparticles enhance in vitro cellular uptake in endothelial-like cells, warranting further in vivo investigation for their brain delivery potential.

Alzheimer's disease (AD) is a degenerative neurological disorder characterized by a deterioration in cognitive abilities, especially memory and learning. The main aim of this study is to evaluate the effects of our agents on oxidative stress, neuroinflammation, cognitive function, and behavioral performance in an LPS-induced AD animal model and comprehensive in vitro and in vivo assays. The synthesized compounds, namely 4b, 5b, 6, 8a-d, and 11a-c, revealed acetylcholinesterase inhibitory activity (3.50-5.91 nM) superior to that of the reference drug donepezil (6.33 nM). The IC50 value of 11a the most active candidate was 3.50 nM against hAChE, with a significant reduction in amyloid-β accumulation by 70% compared to LPS-treated groups, it also reduced neuronal damage, as evidenced by histopathological analysis. Compared to LPS treated groups, 11a decreased brain GFAP, NLRP3, NF-κB, APOE and MDA by 76%, 65%, 48%, 75%, and 59% respectively while increasing GSH by 81%. Molecular docking simulation, along with 100 ns molecular dynamics (MD) simulations conducted on the AChE-ligand complexes, demonstrated favorable conformations of ligand-protein complex throughout the simulations, predicting a dual binding to the CAS and PAS regions of the enzyme which is consistent with kinetic studies against hAChE. Moreover, the chemical stability and reactivity of the drug-target complex were evaluated using global and local reactive descriptors. These findings suggested that compound 11a possessed promising potential as a multi-target lead compound for the development of anti-Alzheimer treatments based on cholinergic, amyloidogenic, and neuroinflammation, through GFAP/NF-κB/APOE/NLRP3 signaling axis.

A new set of quinazolin-4-one-based chalcones was prepared from 3-(4-acetylphenyl)-2- methylquinazolin-4(3H)-one (1) via a base-catalyzed Claisen-Schmidt condensation with substituted aromatic aldehydes. Synthesis was conducted using either a conventional NaOH/EtOH protocol or a solvent-minimized mechanochemical grinding approach. The grinding method delivered chalcones 3a-j and 5 in improved yields (85-94%) within 15-25 min, compared with 65-72% over 12-20 h for the solution method. Product structures were verified by spectroscopic and elemental analyses. The anti-Alzheimer's potential was investigated through molecular docking of the complete series to propose binding modes and prioritize candidates, followed by in vitro evaluation of the five top-ranked compounds (3e, 3f, 5, 3i, and 3 h) for AChE and BuChE inhibition relative to donepezil. In vitro assays revealed the following IC50 values for the compounds against AChE and BuChE: 3e (0.751 ± 0.023 µg/mL for AChE, 0.108 ± 0.003 µg/mL for BuChE), 3f (1.283 ± 0.039 µg/mL for AChE, 0.383 ± 0.01 µg/mL for BuChE), and 5 (2.148 ± 0.066 µg/mL for AChE, 1.212 ± 0.04 µg/mL for BuChE). These values suggest that 3e was the most promising dual inhibitor, outperforming donepezil in both AChE and BuChE inhibition. Docking outcomes agreed with the experimental trends, supporting this scaffold as a promising platform for dual cholinesterase inhibition. In silico ADMET assessment further indicated drug-like characteristics with predicted high oral bioavailability, supporting further lead optimization for Alzheimer's disease therapy.

Alzheimer's disease (AD) is the fourth leading cause of death among elderly people worldwide. It has a complex pathogenesis, making multitarget-directed ligands (MTDLs) a key therapeutic strategy. This study evaluated pregnane glycosides isolated from Caralluma species (Apocynaceae) as potential cholinesterase inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes for AD treatment. In silico molecular docking against AChE (PDB: 4EY7) and BuChE (PDB: 8CGO) identified caratuberside E and awdelioside B as top AChE binders (-11.09 and -11.49 kcal mol[-1], outperforming the cocrystal inhibitor at -9.52 kcal mol[-1]). For BuChE, caratuberside G and penicilloside C showed superior scores (-10.94 and -11.55 kcal mol[-1] vs. -8.89 kcal mol[-1] for the cocrystal). These results were validated by 200 ns molecular dynamics simulations (stable RMSD values) and MM-GBSA binding free-energy calculations, confirming strong interactions and favourable energetics. In vitro assays (using donepezil as reference) demonstrated potent inhibition: caratuberside E was most active against AChE (IC50 = 0.69 ± 0.07 µM), followed by awdelioside B (IC50 = 18.99 ± 0.06 µM); caratuberside G (IC50 = 1.59 ± 0.16 µM) and penicilloside C (IC50 = 12.38 ± 0.51 µM) excelled against BuChE. Collectively, these pregnane glycosides from Caralluma show promise as selective cholinesterase inhibitors and potential MTDLs for AD therapy.

Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous reaction characterized by rapidly progressive epidermal necrosis within hours to days, extensive skin detachment, and high mortality. Rarely, patients present with TEN-like eruptions that evolve slowly, over days to weeks, and have skin changes mostly confined to photodistributed areas, with possible mucosal involvement. The latter scenario is compatible with TEN-like lupus erythematosus. We report a 65-year-old man without prior lupus history who developed a widespread, photodistributed erythematous patchy eruption within 24 h of initiating donepezil for Parkinsonism-associated aphasia. The erythema rapidly progressed to erosions, bullae, and detachment involving 81% total body surface area (TBSA) and a Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) of 2. Initial differential diagnoses included TEN/Stevens Johnson Syndrome (SJS), bullous pemphigoid, generalized bullous fixed drug eruption, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and reactive infectious mucocutaneous eruption (RIME). Histopathology revealed interface dermatitis with diffuse basilar apoptosis, focal full-thickness epidermal necrosis and robust dermal mucin deposits. Direct immunofluorescence study was negative. Serologies showed strongly positive anti-Ro/SSA and ANA titers. COVID-19 testing was positive. The constellation of clinical, pathologic and laboratory features supported a diagnosis of TEN-like subcutaneous lupus erythematosus (SCLE), likely triggered by donepezil and complicated by a concurrent COVID-19 infection. To our knowledge, this is a novel case of TEN-like SCLE associated with donepezil initiation.

Memory decline, particularly in neurodegenerative disorders such as Alzheimer's disease, represents a critical global public health challenge, with projections exceeding 150 million cases by 2050. Current therapeutic options remain limited: while drugs like donepezil and memantine offer symptomatic relief, and newer agents like lecanemab show modest effects on slowing progression, no disease-modifying cures exist. This underscores the urgent need to refine preclinical models bridging discovery and clinical translation. This review evaluates animal and human models of memory decline associated with aging, arguing that optimal model selection depends on aligning design with research phase objectives rather than pursuing a singular "best" model. For animal models, mechanism-focused approaches clarify individual pathways but often oversimplify multifactorial neurodegeneration; phenotypically integrative models mimic complex pathologies yet risk distorting natural disease courses via non-physiologically transgenic overexpressions; translation-enhanced models leverage human genetics or neuroanatomical homologies to improve validity, albeit with higher cost and ethical complexity, suiting late-stage validation. Human models (clinical cohorts, in vitro systems like 3D organoids, and computational tools) provide direct clinical relevance but require cross-system validation to address limitations like invasiveness or scalability. Given the marked heterogeneity of memory decline across individuals, future breakthroughs hinge on multisystem collaborative validation-iteratively cross-checking findings across cell, animal, and human models to bridge mechanistic insights and clinical applicability, thereby accelerating the development of personalized interventions. This review is based on a systematic literature search of PubMed, Web of Science, Google Scholar and Scopus databases for articles published between March 1951 to January 2026, focusing on animal and human models of memory decline and Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline. This study aimed to develop and optimize an intranasal nanostructured lipid carrier (NLC) system co-loaded with Donepezil Hydrochloride (DPZ) and Caesalpinia bonduc seed extract (CBSE) to enhance therapeutic outcomes. LC-MS/MS profiling identified a CBSE bioactive compound with 93.16% structural similarity to neostigmine, suggesting synergistic cholinergic activity. NLCs were prepared using high-pressure homogenization and ultrasonication, optimized using Design of Experiments (DoE). The optimized NLCs exhibited an average particle size of 144.3 ± 1.78 nm, polydispersity index of 0.245 ± 0.025, and a zeta potential of -42.13 ± 2.14 mV, indicating uniformity and stability. TEM confirmed spherical morphology and particle size. The formulation showed high entrapment efficiency (67.27 ± 2.32%) with drug loading (16.81 ± 3.59%) and sustained drug release (72.43 ± 4.78%) over 5 h, following Zero-Order kinetics with Super Case II transport. Ex vivo nasal permeation studies showed significantly higher permeability (p < 0.05) than control, while histological analysis confirmed nasal mucosal safety. In vivo behavioral studies on AD-induced rats demonstrated significantly improved memory and cognition (p < 0.05) following nasal NLC administration. The DPZ-CBSE NLCs present a promising, safe, and non-invasive strategy for effective AD management.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive neuronal loss, cognitive impairment, oxidative stress, neuroinflammation, and aggregation of abnormal proteins, including amyloid precursor protein (APP), amyloid-beta (Aβ), and hyper phosphorylated Tau (p-Tau). Developing therapies that simultaneously target multiple pathogenic pathways remains a major therapeutic challenge. Lawsone (LW), a naturally occurring naphthoquinone derived from the leaf of henna plant (Lawsonia inermis), was investigated for its therapeutic potential in AD. Computational studies were performed to evaluate binding affinities and stability of the compound against key AD-related molecular targets. Sprague-Dawley rats were randomly assigned to five groups: vehicle control, Scopolamine (SCP), donepezil (DNZ), and two groups treated with LW at doses of 2.5 and 5 mg/kg. Morris water Maze and Y Maze tests were employed to validate the behavioral performance. Oxidative stress markers were measured biochemically, tissue histopathology was evaluated using hematoxylin-eosin and Congo red staining. Expression of the proinflamatory markers, nuclear factor kappa β (NF-κβ), c-Jun N terminal kinase (c-JNK), Tumor necrosis factor-α (TNF-α) and Alzheimer's associated proteins APP, Aβ1-42, and p-Tau were assessed through real time polymerase chain reaction (qPCR), enzyme linked immunosorbent assay (ELISA). Computational evaluation showed strong binding to NF-κβ, c-JNK, acetylcholinestrase (AChE), butyrylcholinestrase (BuChE) and TNF-α, supporting its multi-target potential. LW demonstrated neuropharmacological efficacy through preservation of neuronal structure, suppression of Aβ pathology, enhancement of cognitive function, restoration of antioxidant defenses, downregulation of proinflamatory, amyloidogenic, and tauopathic markers. These findings featured its potential as a multi target therapeutic agent for the management of AD.