Search Results (118)

Alzheimer’s disease (AD) is the most common cause of dementia in older adults and is becoming a major public health crisis as life expectancy increases worldwide. A major contributor to this disease is a deficiency in melatonin signaling. We have recently synthesised a series of melatonin analogs containing donepezil fragments. These compounds have been tested both in silico and in vitro. In this study, a particularly potent compound, 3a, was evaluated in a hybrid rat model of melatonin deficiency and AD. Rats underwent pinealectomy followed one week later by bilateral intracerebroventricular infusion of Aβ_1-42 (1 µg/µL). A 14-day subchronic treatment with compound 3a was started simultaneously with the neurotoxin infusion. Melatonin was used as a reference drug, while a matched sham group received vehicle treatment. One week after the Aβ_1-42 infusion, the rats’ cognitive functions were assessed using two Y-maze protocols, object recognition and object location tests. Markers of oxidative stress, including hippocampal glutathione, superoxide dismutase, and malondialdehyde, were assessed by ELISA. Compound 3a effectively prevented cognitive impairment induced by the AD model, and its effects were comparable to those of melatonin. In addition, this melatonin analogue with a donepezil fragment reduced AD-associated oxidative stress and suppressed model-associated increased Aβ_1-42 levels in the hippocampus. Our findings suggest that melatonin analogs containing donepezil fragments are promising therapeutic options for targeting oxidative stress associated with AD. Full article

Background and Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative condition that significantly affects cognitive, emotional, and functional abilities in older adults. This study aimed to explore how demographic, clinical, and psychological factors influence the progression of cognitive decline in patients diagnosed with AD. Materials and Methods: A total of 101 patients were evaluated retrospectively and followed longitudinally at three different time points, using standardized instruments, including the MMSE, Reisberg’s GDS, clock-drawing test, MADRS, and Hamilton depression scale. Statistical methods included non-parametric tests, mixed-effect modeling, and Bayesian analysis. Results: Most patients were older women from rural areas, predominantly in moderate-to-severe stages of AD. Age showed a significant association with cognitive decline (p < 0.05), and depression—particularly in moderate and severe forms—was strongly linked to lower MMSE scores (p < 0.001). Over 70% of the participants had some degree of depression. The clock-drawing test highlighted visuospatial impairments, consistent with everyday functional loss. Although donepezil and memantine combinations appeared to be more frequently prescribed, no treatment showed a statistically significant advantage, and confidence interval overlaps suggest caution in interpreting differences between therapies. Longitudinal models confirmed a progressive and accelerated decline, with inter-individual variability becoming more pronounced in later stages. Although comorbidities, such as hypertension and diabetes, were frequent, they did not show a statistically significant effect on MMSE scores in this cohort. Conclusions: Age and depression appear to play central roles in the pace of cognitive deterioration in AD. Given the limited efficacy of most current therapies, these findings highlight the need for earlier intervention and a more personalized, integrated approach—combining cognitive care, psychiatric support, and comorbidity management—to better meet the needs of patients with AD. Full article

Background: Traditional fermented soybean foods, acting as potential synbiotics, may help mitigate cognitive impairment associated with amnesia. This study investigated the neuroprotective effects of four kanjang (Korean fermented soy sauce) varieties and their underlying mechanisms. Methods: Male Sprague Dawley rats (n = 70) were divided into seven groups: normal control, scopolamine control, positive control (1 mg/kg bw/day of donepezil), and four scopolamine-treated groups receiving different kanjang varieties (0.5% in high-fat diet). Based on their Bacillus content, the kanjang samples were categorized as traditionally made kanjang (TMK) with high Bacillus (SS-HB), TMK with medium Bacillus (SS-MB), TMK with low Bacillus (SS-LB), and factory-made kanjang (SS-FM). Results: Scopolamine administration disrupted energy, glucose, and water metabolism and impaired memory function (p < 0.05). All kanjang treatments improved insulin sensitivity, reduced inflammation, enhanced glucose tolerance, and decreased visceral fat. SS-MB, SS-HB, and SS-FM increased skeletal muscle mass. They maintained body water homeostasis by suppressing the renin–angiotensin–aldosterone system. Kanjang treatments improved memory function, with SS-FM showing the least significant effects. The treatments reduced neuronal cell death in the hippocampal CA1 region, decreased acetylcholinesterase activity, and increased brain-derived neurotrophic factor mRNA expression. Gut microbiota analysis revealed that kanjang treatments increased Lactobacillaceae and decreased Lachnospiraceae, with SS-HB and SS-LB specifically elevating Ligilactobacillus. Metagenomic analysis demonstrated enhanced glycolysis/gluconeogenesis pathways and enhanced butanoate metabolism while reducing lipopolysaccharide biosynthesis and pro-inflammatory signaling. SS-MB and SS-LB increased intestinal goblet cell counts and the serum butyrate concentration. Conclusions: These findings suggest that kanjang consumption, particularly SS-HB and SS-LB varieties, can ameliorate memory impairment in this murine model through multiple mechanisms: metabolic improvements, enhanced neurotrophic signaling, gut microbiota modulation, and reduced neuroinflammation via gut–brain axis activation. Human clinical trials are warranted to determine if these promising neuroprotective effects translate to clinical applications. Full article

Live Leuconostoc mesenteroides H40 has been reported to have probiotic properties; however, the effect of its live probiotic form on cognitive ability has not been reported. This study investigated modulatory effects of the probiotic L. mesenteroides H40 in an ICR mouse model (male) of cognitive disorders. Cognitive disorders were induced in mice by the addition of scopolamine (1 mg/kg/day) with donepezil (2 mg/kg/day) as a medicinal control. L. mesenteroides H40 significantly attenuated scopolamine-induced cognitive disorder in the novel object recognition and Y-maze tests in a concentration-dependent manner. L. mesenteroides H40 decreased amyloid β levels, but increased β-secretase levels. The mRNA expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 significantly decreased following L. mesenteroides H40 treatment. Additionally, TNF-α, IL-1β, and PGE2 protein expression was decreased. Acetylcholine, acetylcholinesterase, choline acetyltransferase, brain-derived neurotrophic factor (BDNF), and cAMP response element-binding protein (CREB) levels were increased in the brain tissues. The antioxidant effects of superoxide dismutase, catalase, and glutathione peroxidase were also alleviated. We demonstrated that L. mesenteroides H40 exhibits neuroprotective effects through anti-inflammatory, synaptic plasticity regulation, and antioxidant effects. Thus, the probiotic L. mesenteroides H40 could be used as a prophylactic functional food for cognitive disorders. Full article

Introduction—Aim: Agitation and aggression are common symptoms in people with Alzheimer’s disease and other dementias. This systematic review outlines the current evidence for the effect of antidementia treatments on agitation and aggression in patients with Alzheimer’s disease. Methods: The literature search was performed by manually checking articles published since 2000 in the following databases: PubMed, ResearchGate, and Google Scholar, following the PRISMA guidelines. Results: Nineteen double blinded placebo-controlled trials were included. Treatment with galantamine seems to provide more credible evidence for treating or preventing agitation/aggression. Studies on memantine often presented with an improvement of the neuropsychiatric inventory but not specifically on agitation/aggression. The trials on donepezil and rivastigmine either did not include enough information on agitation/aggression or did not provide compelling results. The incidence of agitation as an adverse event was not higher in antidementia treatments compared to placebo. Conclusions: Agitation and aggression are common symptoms of Alzheimer’s disease and have a significant impact on the patient, caregiver, and the broader healthcare system. The current literature lacks robust evidence on which of the antidementia treatments could be used to manage or prevent agitation and aggression in Alzheimer’s disease. In most included studies, no specific scores that assess those symptoms were used. Future research that specifically focuses on different disease phenotypes and behavioral profiles to enhance and facilitate the management of these symptoms is needed. Full article

Background/Objectives: Several genetic factors are related to the risk of Alzheimer’s disease (AD) and the response to cholinesterase inhibitors (ChEIs) (donepezil, galantamine, and rivastigmine) or memantine. However, findings have been controversial, and, to the best of our knowledge, admixed populations have not been previously evaluated. We aimed to determine the impact of genetic and non-genetic factors on the risk of AD and the short-term response to ChEIs and memantine in patients with AD from Mexico. Methods: This study included 117 patients from two specialty hospitals in Mexico City, Mexico. We evaluated cognitive performance via clinical evaluations and neuropsychological tests. Nineteen variants in ABCB1, ACHE, APOE, BCHE, CHAT, CYP2D6, CYP3A5, CHRNA7, NR1I2, and POR were assessed through TaqMan assays or PCR. Results: Minor alleles of the ABCB1 rs1045642, ACHE rs17884589, and CHAT rs2177370 and rs3793790 variants were associated with the risk of AD; meanwhile, CHRNA7 rs6494223 and CYP3A5 rs776746 were identified as low-risk variants in AD. BCHE rs1803274 was associated with worse cognitive functioning. None of the genetic and non-genetic factors studied were associated with the response to pharmacological treatment. Conclusions: We identified potential genetic variants related to the risk of AD; meanwhile, no factor was observed to impact the response to pharmacological therapy in patients with AD from Mexico. Full article

Alzheimer’s disease (AD), one of the neurodegenerative disorders, afflicts negatively across the whole world. Due to its complex etiology, no available treatments are disease-altering. This study aimed to explore isolated saponins profiles from Platycodon grandiflorum in the binding pockets of six target proteins of AD using computational and quantum chemistry simulations. Initially, saponin compounds were docked to AD enzymes, such as GSK-3β and synapsin I, II, and III. The subsequent research from MD simulations of the best three docked compounds (polygalacin D2, polygalacin D, and platycodin D) suggested that their profiles match with the binding of standard active drugs like ifenprodil and donepezil to the six enzymes. Moreover, analyzing DFT quantum calculations of top-scoring compounds fully unravels their electronic and quantum properties and potential in anti-AD. The subtle differences between polygalacin D and D2, and platycodin D, were studied at the level of theory DFT/B3LYP, showing that the electron-donating effect of the hydroxy ethyl group in platycodin D rendering this compound of moderate electrophilicity and reactivity. Polygalacin D2 diglucoside substituent in position-2 contributed to its best binding and intermolecular interactions more than polygalacin D and prosapogenin D, which acted as the negative decoy drug. Full article

Acetylcholinesterase (AChE) is a critical enzyme involved in neurotransmission by hydrolyzing acetylcholine at the synaptic cleft, making it a key target for drug discovery, particularly in the treatment of neurodegenerative disorders such as Alzheimer’s disease. Computational approaches, particularly molecular docking and molecular dynamics (MD) simulations, have become indispensable tools for identifying and optimizing AChE inhibitors by predicting ligand-binding affinities, interaction mechanisms, and conformational dynamics. This review serves as a comprehensive guide for future research on AChE using molecular docking and MD simulations. It compiles and analyzes studies conducted over the past five years, providing a critical evaluation of the most widely used computational tools, including AutoDock, AutoDock Vina, and GROMACS, which have significantly contributed to the advancement of AChE inhibitor screening. Furthermore, we identify PDB ID: 4EY7, the most frequently used AChE crystal structure in docking studies, and highlight Donepezil, a well-established reference molecule widely employed as a control in computational screening for novel inhibitors. By examining these key aspects, this review aims to enhance the accuracy and reliability of virtual screening approaches and guide researchers in selecting the most appropriate computational methodologies. The integration of docking and MD simulations not only improves hit identification and lead optimization but also provides deeper mechanistic insights into AChE–ligand interactions, contributing to the rational design of more effective AChE inhibitors. Full article

Alzheimer’s disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently associated with significant adverse effects. Faced with this challenge and in line with advances in the understanding of the pathophysiology of this neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge of the underlying pathophysiological mechanisms of the disease. Among the therapeutic alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target and eliminate toxic proteins implicated in AD. Additionally, the use of medicinal plants is examined, as their synergistic effects among components may confer neuroprotective properties. The modulation of the gut microbiota is also addressed as a peripheral strategy that could influence neuroinflammatory and degenerative processes in the brain. Furthermore, the therapeutic potential of emerging approaches, such as the use of microRNAs to regulate key cellular processes and nanotherapy, which enables precise drug delivery to the central nervous system, is analyzed. Despite promising advances in these strategies, the incidence of Alzheimer’s disease continues to rise. Therefore, it is proposed that achieving effective treatment in the future may require the integration of combined approaches, maximizing the synergistic effects of different therapeutic interventions. Full article

Alzheimer’s disease (AD) is a degenerative disorder characterized by progressive cognitive decline and memory loss. The few contemporary therapies may ease symptoms and/or slow down AD progression but cannot cure the disease. The orally administered AD drug donepezil hydrochloride enhances the availability of acetylcholine that supports cholinergic neurotransmission. In this paper, a generalized Hodgkin-Huxley model is proposed that uses Caputo fractional order temporal derivatives to link action potentials and viscoelasticity of cholinergic receptors. The model provides not only structurally dependent action potentials for health and AD but also a possible mechanism of donepezil effect on action potentials: the binding between the acetylcholine and the receptors preserves the structural fitness of these receptors. In addition, a generalized pharmacokinetic model of donepezil transport to the brain is proposed that incorporates controlled release modalities. Caputo fractional order temporal derivatives are used again to model anomalous drug release. Numerical simulations show how controlled release donepezil recovers the structural integrity of the receptors which further brings the abnormal action potentials due to AD to their healthy state. The results suggest that combining various drug release modalities and dosages may improve treatment effectiveness with donepezil. Full article

Gamma-glutamate is an important excitatory neurotransmitter in the central nervous system (CNS), which plays an important role in transmitting synapses, plasticity, and other brain activities. Nevertheless, alterations in the glutamatergic signaling pathway are now accepted as a central element in Alzheimer’s disease (AD) pathophysiology. One of the most prevalent types of dementia in older adults is AD, a progressive neurodegenerative illness brought on by a persistent decline in cognitive function. Since AD has been shown to be multifactorial, a variety of pharmaceutical targets may be used to treat the condition. N-methyl-D-aspartic acid receptor (NMDAR) antagonists and acetylcholinesterase inhibitors (AChEIs) are two drug classes that the Food and Drug Administration has authorized for the treatment of AD. The AChEIs approved to treat AD are galantamine, donepezil, and rivastigmine. However, memantine is the only non-competitive NMDAR antagonist that has been authorized for the treatment of AD. This review aims to outline the involvement of glutamate (GLU) at the molecular level and the signaling pathways that are associated with AD to demonstrate the drug target therapeutic potential of glutamate and its receptor. We will also consider the opinion of the leading authorities working in this area, the drawback of the existing therapeutic strategies, and the direction for the further investigation. Full article

Alzheimer’s disease (AD) is a complex/multifactorial brain disorder involving hundreds of defective genes, epigenetic aberrations, cerebrovascular alterations, and environmental risk factors. The onset of the neurodegenerative process is triggered decades before the first symptoms appear, probably due to a combination of genomic and epigenetic phenomena. Therefore, the primary objective of any effective treatment is to intercept the disease process in its presymptomatic phases. Since the approval of acetylcholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine) and Memantine, between 1993 and 2003, no new drug was approved by the FDA until the advent of immunotherapy with Aducanumab in 2021 and Lecanemab in 2023. Over the past decade, more than 10,000 new compounds with potential action on some pathogenic components of AD have been tested. The limitations of these anti-AD treatments have stimulated the search for multi-target (MT) drugs. In recent years, more than 1000 drugs with potential MT function have been studied in AD models. MT drugs aim to address the complex and multifactorial nature of the disease. This approach has the potential to offer more comprehensive benefits than single-target therapies, which may be limited in their effectiveness due to the intricate pathology of AD. A strategy still unexplored is the combination of epigenetic drugs with MT agents. Another option could be biotechnological products with pleiotropic action, among which nosustrophine-like compounds could represent an attractive, although not definitive, example. Full article

Alzheimer’s disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease’s progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer’s disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer’s disease treatment. Full article

Background: Alzheimer’s disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, ¹H NMR, and ¹³C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results: Compound 5 was the most potent inhibitor, with IC₅₀ values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of −10.21 kcal/mol to AChE and −13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5, 8, and 9, with Compound 5 showing the best activity. Conclusions: Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer’s disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors. Full article

Background and Objectives: Alzheimer’s disease is a global health concern, with a rising prevalence among the elderly. Current pharmacological treatments, including acetylcholinesterase inhibitors (AChEIs) and N-Methyl D-Aspartate (NMDA) receptor antagonists, are associated with adverse events (AEs), particularly in the context of polypharmacy. This study aimed to investigate the relationship between Alzheimer’s disease treatment combinations, the number of concomitant medications, and the occurrence of AEs. Materials and Methods: Data from the Japanese Adverse Drug Event Report database, spanning from April 2004 to June 2020, were analyzed. Patients aged 60 and older with Alzheimer’s disease treated with AChEIs (donepezil, galantamine, and rivastigmine) or the NMDA receptor antagonist memantine were included. Logistic regression models were employed to assess the association between AEs and Alzheimer’s disease drug combinations, as well as the number of concomitant medications. Results: Among 2653 patients, 47.7% were prescribed five or more drugs. The frequency of AEs was 6.4% for bradycardia, 4.6% for pneumonia, 3.6% for altered state of consciousness, 3.5% for seizures, 3.5% for decreased appetite, 3.5% for vomiting, 3.4% for loss of consciousness, 3.4% for fracture, 3.2% for cardiac failure, and 3.0% for falls. The combination of memantine with AChEIs was associated with a higher risk of bradycardia, whereas donepezil alone was linked to a reduced risk of fractures and falls. Polypharmacy was significantly correlated with an increased incidence of AEs, particularly altered state of consciousness, decreased appetite, vomiting, and falls. The adjusted odds ratios for using five or more drugs compared to no drugs was 10.45 for altered state of consciousness, 7.92 for decreased appetite, 4.74 for vomiting, and 5.95 for falls. Conclusions: In the treatment of Alzheimer’s disease, the occurrence of AEs is associated with the number of concurrent medications, independently of the known AEs of Alzheimer’s disease drugs and their combination patterns. Full article