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Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the presence of amyloid-ß (Aß) plaques and tau-containing neurofibrillary tangles, leading to cognitive and physical decline. Representing the majority of dementia cases, AD poses a significant burden on healthcare systems globally, with onset typically occurring after the age of 65. While most cases are sporadic, about 10% exhibit autosomal forms associated with specific gene mutations. Neurofibrillary tangles and Aß plaques formed by misfolded tau proteins and Aß peptides contribute to neuronal damage and cognitive impairment. Currently, approved drugs, such as acetylcholinesterase inhibitors and N-methyl D-aspartate receptor agonists, offer only partial symptomatic relief without altering disease progression. A promising development is using lecanemab, a humanized IgG1 monoclonal antibody, as an immune therapeutic approach. Lecanemab demonstrates selectivity for polymorphic Aß variants and binds to large soluble Aß aggregates, providing a potential avenue for targeted treatment. This shift in understanding the role of the adaptive immune response in AD pathogenesis opens new possibilities for therapeutic interventions aiming to address the disease's intricate mechanisms. This review aims to summarize recent advancements in understanding Alzheimer's disease pathology and innovative therapeutic approaches, providing valuable insights for both researchers and clinicians.
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BACKGROUND: The study investigated the effect of co-administration of curcumin and donepezil on several markers of cognitive function (such as spatial memory, astrocyte activation, cholinesterase expressions) in the brain cortex and hippocampus of scopolamine-treated rats. METHOD AND RESULTS: For seven consecutive days, a pre-treatment of curcumin (50 mg/kg) and/or donepezil (2.5 mg/kg) was administered. On the seventh day, scopolamine (1 mg/kg) was administered to elicit cognitive impairment, 30 min before memory test was conducted. This was followed by evaluating changes in spatial memory, cholinesterase, and adenosine deaminase (ADA) activities, as well as nitric oxide (NO) level were determined. Additionally, RT-qPCR for glial fibrillary acidic protein (GFAP) and cholinesterase gene expressions was performed in the brain cortex and hippocampus. Also, GFAP immunohistochemistry of the brain tissues for neuronal injury were performed in the brain cortex and hippocampus. In comparison to the control group, rats given scopolamine had impaired memory, higher levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ADA activities, as well as elevated markers of oxidative stress. In addition to enhanced GFAP immunoreactivity, there was also overexpression of the GFAP and BChE genes in the brain tissues. The combination of curcumin and donepezil was, however, observed to better ameliorate these impairments in comparison to the donepezil-administered rat group. CONCLUSION: Hence, this evidence provides more mechanisms to support the hypothesis that the concurrent administration of curcumin and donepezil mitigates markers of cognitive dysfunction in scopolamine-treated rat model.
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Acetilcolinesterasa , Astrocitos , Curcumina , Donepezilo , Proteína Ácida Fibrilar de la Glía , Hipocampo , Escopolamina , Memoria Espacial , Animales , Donepezilo/farmacología , Curcumina/farmacología , Curcumina/administración & dosificación , Escopolamina/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratas , Masculino , Memoria Espacial/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/genética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratas Wistar , Estrés Oxidativo/efectos de los fármacos , Colinesterasas/metabolismo , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/genética , Óxido Nítrico/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/administración & dosificaciónRESUMEN
Alzheimer's disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer's disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer's treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a-j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.
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Antioxidantes , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Quinazolinas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Butirilcolinesterasa/metabolismo , Butirilcolinesterasa/química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Quinazolinas/farmacología , Quinazolinas/química , Quinazolinas/síntesis química , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Humanos , Relación Estructura-Actividad , Dominio Catalítico , Animales , Cinética , ElectrophorusRESUMEN
Cholinesterase inhibitors (ChEIs) insecticide poisoning is a serious global health concern that results in hundreds of thousands of fatalities each year. Although inhibition of the cholinesterase enzyme is the main mechanism of ChEI poisoning, oxidative stress is considered the mechanism underlying the related complications. The study aimed to assess the oxidative status of the patients with ChEI insecticide poisoning and the role of L-carnitine as adjuvant therapy in their management. Human studies on the efficacy and safety of L-carnitine in treating insecticide poisoning are limited despite its growing research interest as a safe antioxidant. This prospective study was conducted on eighty patients with acute ChEIs insecticide poisoning admitted to Alexandria Poison Center, Alexandria Main University Hospital, Egypt. Patients were allocated into two equal groups randomly. The L-carnitine (LC) group received the conventional treatment (atropine & toxogonin) and LC and the standard treatment (ST) group received the standard treatment only. Outcome measures were fatality rate, the total administered dose of atropine & toxogonin, length of hospital stay, and the requirement for ICU admission or mechanical ventilation. The study results revealed that malondialdehyde (MDA) significantly decreased in the LC group. Cholinesterase enzyme levels increased significantly after treatment in the LC group than in the ST group. The LC group needed lower dosages of atropine and toxogonin than the ST group. Also, the LC group showed no need for ICU admission or mechanical ventilation. The study concluded that LC can be considered a promising adjuvant antioxidant treatment in acute ChEIs pesticide poisoning.
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A family of new compounds with sulfonamide and amide functional groups as potential Alzheimer's disease drugs were prepared by multistep synthesis. Thermal stability measurements recorded the initial decomposition in the range of 200-220°C, close above the melting point. The final compounds were tested for their ability to inhibit acetylcholinesterase and butyrylcholinesterase, and the in vitro dissolution behavior of selected compounds was studied through both lipophilic and hydrophilic matrix tablets. All nine tested derivatives were even more active in inhibiting acetylcholinesterase than the clinically used rivastigmine. Regression analysis of the obtained dissolution profiles was performed, and the effects of the pH and the release mechanism were determined. Some substances showed remarkable biological activity and became a subject of interest for further extensive study.
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BACKGROUND: A large proportion of nursing home (NH) residents suffer from dementia and effects of conventional anti-dementia drugs on their health is poorly known. We aimed to investigate the associations between exposure to anti-dementia drugs and mortality among NH residents. METHODS: This retrospective longitudinal observational study involved 329 French NH and the residents admitted in these facilities since 2014 and having major neurocognitive disorder. From their electronic health records, we obtained their age, sex, level of dependency, Charlson comorbidity index, and Mini mental examination score at admission. Exposure to anti-dementia drugs was determined using their prescription into 4 categories: none, exposure to acetylcholinesterase inhibitors (AChEI) alone, exposure to memantine alone, exposure to AChEI and memantine. Survival until the end of 2019 was studied in the entire cohort by Cox proportional hazards. To alleviate bias related to prescription of anti-dementia drugs, we formed propensity-score matched cohorts for each type of anti-dementia drug exposure, and studied survival by the same method. RESULTS: We studied 25,358 NH residents with major neurocognitive disorder. Their age at admission was 87.1 + 7.1 years and 69.8% of them were women. Exposure to anti-dementia drugs occurred in 2,550 (10.1%) for AChEI alone, in 2,055 (8.1%) for memantine alone, in 460 (0.2%) for AChEI plus memantine, whereas 20,293 (80.0%) had no exposure to anti-dementia drugs. Adjusted hazard ratios for mortality were significantly reduced for these three groups exposed to anti-dementia drugs, as compared to reference group: HR: 0.826, 95%CI 0.769 to 0.888 for AChEI; 0.857, 95%CI 0.795 to 0.923 for memantine; 0.742, 95%CI 0.640 to 0.861 for AChEI plus memantine. Results were consistent in propensity-score matched cohorts. CONCLUSION: The use of conventional anti-dementia drugs is associated with a lower mortality in nursing home residents with dementia and should be widely used in this population.
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Inhibidores de la Colinesterasa , Demencia , Memantina , Casas de Salud , Humanos , Memantina/uso terapéutico , Casas de Salud/estadística & datos numéricos , Femenino , Masculino , Demencia/tratamiento farmacológico , Demencia/mortalidad , Estudios Longitudinales , Anciano de 80 o más Años , Inhibidores de la Colinesterasa/uso terapéutico , Estudios Retrospectivos , Anciano , Hogares para Ancianos/estadística & datos numéricos , Francia/epidemiologíaRESUMEN
In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19â µmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56â ng/g) after dosing 30â min. Its half-life in the serum is 331â min (5.52â h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24â hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.
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Barrera Hematoencefálica , Inhibidores de la Colinesterasa , Cinamatos , Animales , Humanos , Masculino , Ratones , Acetilcolinesterasa/metabolismo , Aminas/química , Aminas/farmacología , Barrera Hematoencefálica/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacocinética , Inhibidores de la Colinesterasa/metabolismo , Cinamatos/química , Cinamatos/farmacología , Cinamatos/farmacocinética , Descubrimiento de Drogas , Estructura Molecular , Relación Estructura-Actividad , Pirrolidinas/química , Pirrolidinas/farmacología , Morfolinas/química , Morfolinas/farmacología , Piperidinas/química , Piperidinas/farmacologíaRESUMEN
In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified.
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Acetilcolinesterasa , Secretasas de la Proteína Precursora del Amiloide , Butirilcolinesterasa , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Humanos , Relación Estructura-Actividad , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Acetamidas/síntesis química , Acetamidas/farmacología , Acetamidas/química , Piperazinas/farmacología , Piperazinas/química , Piperazinas/síntesis químicaRESUMEN
INTRODUCTION: Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically administered orally, which can be difficult for people with AD and their caregivers. AREAS COVERED: In this drug profile and narrative review, the authors trace the development of the new FDA-approved transdermal donepezil. The authors discuss the studies showing its bioequivalence with the oral formulation, including two double-blinded placebo controlled non-inferiority trials. The authors also compare the patch to the only other transdermal cholinesterase inhibitor on the market, rivastigmine, and highlight the potential advantages and disadvantages between these two treatments. EXPERT OPINION: While the patch is bio-equivalent, it is rather large and may not be affordable for some patients. In addition, there is no high dose (e.g. 23 mg) equivalent. Nevertheless, transdermal donepezil will be useful for people with AD and their caregivers, given its effectiveness and potential convenience.
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Administración Cutánea , Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Donepezilo , Humanos , Donepezilo/administración & dosificación , Donepezilo/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/uso terapéutico , Parche Transdérmico , Rivastigmina/administración & dosificación , Rivastigmina/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aß) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aß plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed. As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.
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Dementia is a major public health concern due to its increasing prevalence, substantial caregiver burden, and high financial costs. Currently, the anti-dementia drugs aim only at a symptomatic effect. The subject of prescribing these drugs in advanced stages is a matter of considerable debate, with different countries making distinct recommendations. In this review article, we analyzed the evidence regarding cognitive and functional outcomes, adverse events, health-related costs, and caregiver burden in patients with advanced Alzheimer disease (AD) and mixed dementia. We included 35 studies. Most studies are heterogeneous, focus exclusively on AD, and show small benefits in terms of cognitive and functional scales. The overall evidence seems to suggest a benefit in introducing or maintaining anti-dementia drugs in patients with advanced dementia, but clinical meaningfulness is difficult to ascertain. The issue of costs and caregiver burden is significantly underexplored in this field but also seems to favor treatment continuation, despite a reduced overall effect. The decision of introducing or withdrawing anti-dementia drugs in advanced stages of dementia should be individualized. Future studies with homogeneous designs and outcomes are warranted.
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Myasthenia gravis is an autoimmune disease of the neuromuscular junction caused by autoantibodies directed against the acetylcholine receptors. It presents with skeletal muscle weakness, often initially presenting with ocular symptoms such as ptosis and diplopia. When myasthenia gravis is isolated to only ocular symptoms, it is referred to as ocular myasthenia gravis (OMG). Here, we present an atypical initial presentation of OMG in a 68-year-old male patient presenting with isolated abducens nerve palsy at the initial onset. With this case report, we highlight the importance of a thorough history and clinical assessment necessary for a timely diagnosis of OMG in patients who present with isolated abducens nerve palsy.
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Current drugs for Alzheimer's Disease (AD), such as cholinesterase inhibitors (ChEIs), exert only symptomatic activity. Different psychometric tools are needed to assess cognitive and non-cognitive dimensions during pharmacological treatment. In this pilot study, we monitored 33 mild-AD patients treated with ChEIs. Specifically, we evaluated the effects of 6 months (Group 1 = 17 patients) and 9 months (Group 2 = 16 patients) of ChEIs administration on cognition with the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Frontal Assessment Battery (FAB), while depressive symptoms were measured with the Hamilton Depression Rating Scale (HDRS). After 6 months (Group 1), a significant decrease in MoCA performance was detected. After 9 months (Group 2), a significant decrease in MMSE, MoCA, and FAB performance was observed. ChEIs did not modify depressive symptoms. Overall, our data suggest MoCA is a potentially useful tool for evaluating the effectiveness of ChEIs.
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Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Humanos , Inhibidores de la Colinesterasa/uso terapéutico , Proyectos Piloto , Enfermedad de Alzheimer/tratamiento farmacológico , Pruebas de Estado Mental y Demencia , Resultado del TratamientoRESUMEN
Triazoles and triazolium salts are very common subunits in the structures of various drugs. Medicaments with a characteristic 1,2,3-triazole core are also being developed to treat neurodegenerative disorders associated with cholinesterase enzyme activity. Several naphtho- and thienobenzo-triazoles from our previous research emerged as being particularly promising in that sense. For this reason, in this research, new naphtho- and thienobenzo-triazoles 23-34, as well as 1,2,3-triazolium salts 44-51, were synthesized and tested. Triazolium salts 44-46 showed excellent activity while salts 47 and 49 showed very good inhibition toward both butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes. In contrast, neutral photoproducts were shown to be selective towards BChE but with very good inhibition potential as molecules 24-27. The representative of newly prepared compounds, 45 and 50, were stable in aqueous solution and revealed intriguing fluorimetric properties, characterized by a strong Stokes shift of >160 nm. Despite their condensed polycyclic structure shaped similarly to well-known DNA-intercalator ethidium bromide, the studied compounds did not show any interaction with ds-DNA, likely due to the unfavorable steric hindrance of substituents. However, the studied dyes bind proteins, particularly showing very diverse inhibition properties toward AChE and BChE. In contrast, neutral photoproducts were shown to be selective towards a certain enzyme but with moderate inhibition potential. The molecular docking of the best-performing candidates to cholinesterases' active sites identified cation-π interactions as the most responsible for the stability of the enzyme-ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the compounds synthesized have been performed.
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Butirilcolinesterasa , Inhibidores de la Colinesterasa , Inhibidores de la Colinesterasa/farmacología , Acetilcolinesterasa , Simulación del Acoplamiento Molecular , Sales (Química) , Complejos Multienzimáticos , Triazoles/farmacologíaRESUMEN
INTRODUCTION: There is limited knowledge about early-onset dementia (EOD) on fracture risk. METHODS: Individuals ages 50 to 64 were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (2012 to 2019). The association between EOD and fractures and the association between cholinesterase inhibitors for EOD and fractures were evaluated using logistic regression analyses. RESULTS: We identified 13,614 EOD patients and 9,144,560 cognitively healthy individuals. The analysis revealed that EOD was associated with an increased risk of hip fractures (adjusted odds ratio, 95% confidence interval: 8.79, 7.37-10.48), vertebral fractures (1.73, 1.48-2.01), and major osteoporotic fractures (2.05, 1.83-2.30) over 3 years. The use of cholinesterase inhibitors was significantly associated with a reduction in hip fractures among EOD patients (0.28, 0.11-0.69). DISCUSSION: EOD patients have a higher risk of osteoporotic fractures than cognitively healthy individuals. The use of cholinesterase inhibitors may reduce the risk of hip fracture among EOD patients. HIGHLIGHTS: It is unknown whether early-onset dementia (EOD) increases the risk of fractures. We identified 13,614 individuals with EOD using a nationwide administrative database. Patients with EOD have a higher risk of hip, vertebral, and major osteoporotic fractures. The use of cholinesterase inhibitors may reduce hip fracture among patients with EOD.
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Demencia , Fracturas de Cadera , Fracturas Osteoporóticas , Humanos , Femenino , Masculino , Demencia/epidemiología , Fracturas de Cadera/epidemiología , Persona de Mediana Edad , Japón/epidemiología , Fracturas Osteoporóticas/epidemiología , Inhibidores de la Colinesterasa/uso terapéutico , Factores de Riesgo , Edad de Inicio , Bases de Datos FactualesRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease affecting mental ability and neurocognitive functions. Cholinesterase enzymes affect concentration of acetylcholine in the brain, leading to dementia. Thus, there is an urgent need to develop novel dual cholinesterase inhibitors as possible anti-AD drugs. Herein, we have designed and synthesized a novel series of 9H-carbazole-4H-chromenes 4(a-l) through a one-pot three-component reaction of salicylaldehydes (1), hydroxycarbazole (2) and N-methyl-1-(methylthio)-2-nitroethenamine (3) using triethylamine as a catalyst in ethanol. Synthetic transformation involves the formation of two C-C bonds and one C-O bond in a single step to obtain desired analogs. The rapid one-pot reaction does not require chromatographic purification, proceeds under mild conditions, and exhibits good tolerance toward various functional groups with high synthetic yields. Synthesized compounds were screened for cytotoxicity using MTT assay in BV-2 microglial cells. These compounds were then in-vitro screened against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes. Most of these ligands have shown dual cholinesterase inhibitory activity compared to the standard drug. In-vitro results showed that the compounds 4a and 4d have promising anticholinesterase response against both cholinesterase enzymes (4a, AChE IC50: 5.76 µM, BuChE IC50: 48.98 µM; 4d, AChE IC50: 3.58 µM, BuChE IC50: 42.73 µM). In-vitro results were validated by molecular docking and dynamic simulation at 100 ns. Molecular docking and molecular dynamics simulation study strongly supported structural features present in these analogs. Together, these analogs could be exploited to develop dual anti-cholinesterase candidates to treat AD in combination with other drugs.
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In clinical trials for Alzheimer's disease (AD), hydromethylthionine mesylate (HMTM) showed reduced efficacy when administered as an add-on to symptomatic treatments, while it produced a significant improvement of cognitive function when taken as monotherapy. Interference of cholinesterase inhibition with HMTM was observed also in a tau transgenic mouse model, where rivastigmine reduced the pharmacological activity of HMTM at multiple brain levels including hippocampal acetylcholine release, synaptosomal glutamate release and mitochondrial activity. Here, we examined the effect of HMTM, given alone or in combination with the acetylcholinesterase inhibitor, rivastigmine, at the level of expression of selected pre-synaptic proteins (syntaxin-1; SNAP-25, VAMP-2, synaptophysin-1, synapsin-1, α-synuclein) in brain tissue harvested from tau-transgenic Line 1 (L1) and wild-type mice using immunohistochemistry. L1 mice overexpress the tau-core unit that induces tau aggregation and results in an AD-like phenotype. Synaptic proteins were lower in hippocampus and cortex but greater in basal forebrain regions in L1 compared to wild-type mice. HMTM partially normalised the expression pattern of several of these proteins in basal forebrain. This effect was diminished when HMTM was administered in combination with rivastigmine, where mean protein expression seemed supressed. This was further confirmed by group-based correlation network analyses where important levels of co-expression correlations in basal forebrain regions were lost in L1 mice and partially re-established when HMTM was given alone but not in combination with rivastigmine. These data indicate a reduction in pharmacological activity of HMTM when given as an add-on therapy, a result that is consistent with the responses observed in the clinic. Attenuation of the therapeutic effects of HMTM by cholinergic treatments may have important implications for other potential AD therapies.
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Inhibidores de la Colinesterasa , Modelos Animales de Enfermedad , Ratones Transgénicos , Rivastigmina , Tauopatías , Animales , Tauopatías/tratamiento farmacológico , Tauopatías/metabolismo , Inhibidores de la Colinesterasa/farmacología , Rivastigmina/farmacología , Ratones , Proteínas tau/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Masculino , Azul de Metileno/análogos & derivadosRESUMEN
Alzheimer's disease (AD) has few effective treatment options and continues to be a major global health concern. AD is a neurodegenerative disease that typically affects elderly people. Alkaloids have potential sources for novel drug discovery due to their diverse chemical structures and pharmacological activities. Alkaloids, natural products with heterocyclic nitrogen-containing structures, are considered potential treatments for AD. This review explores the neuroprotective properties of alkaloids in AD, focusing on their ability to regulate pathways such as amyloid-beta aggregation, oxidative stress, synaptic dysfunction, tau hyperphosphorylation, and neuroinflammation. The FDA has approved alkaloids such as acetylcholinesterase inhibitors like galantamine and rivastigmine. This article explores AD's origins, current market medications, and clinical applications of alkaloids in AD therapy. This review explores the development of alkaloid-based drugs for AD, focusing on pharmacokinetics, blood-brain barrier penetration, and potential adverse effects. Future research should focus on the clinical evaluation of promising alkaloids, developing recently discovered alkaloids, and the ongoing search for novel alkaloids for medical treatment. A pharmaceutical option containing an alkaloid may potentially slow down the progression of AD while enhancing its symptoms. This review highlights the potential of alkaloids as valuable drug leads in treating AD, providing a comprehensive understanding of their mechanisms of action and therapeutic implications.
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Alcaloides , Enfermedad de Alzheimer , Fármacos Neuroprotectores , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Alcaloides/farmacología , Alcaloides/uso terapéutico , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Estrés Oxidativo/efectos de los fármacosRESUMEN
An enhanced, sustainable, and efficient method for synthesizing tacrine, achieving a 98% yield, has been developed by replacing volatile organic compounds with more eco-friendly solvents such as deep eutectic solvent (DESs). The optimized protocol scales easily to 3 g of substrate without yield loss and extends successfully to tacrine derivatives with reduced hepatotoxicity. Particularly notable is the synthesis of novel triazole-based derivatives, yielding 90-95%, by integrating an in situ preparation of aryl azides in DESs with N-propargyl-substituted tacrine derivatives. Quantitative metrics validate the green aspects of the reported drug development processes.
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Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting elderly individuals, characterized by progressive cognitive decline leading to dementia. This review examines the challenges posed by anatomical and biochemical barriers such as the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and p-glycoproteins in delivering effective therapeutic agents to the central nervous system (CNS) for AD treatment. This article outlines the fundamental role of acetylcholinesterase inhibitors (AChEIs) and NMDA(N-Methyl-D-Aspartate) receptor antagonists in conventional AD therapy and highlights their limitations in terms of brain-specific delivery. It delves into the intricacies of BBB and pglycoprotein-mediated efflux mechanisms that impede drug transport to the CNS. The review further discusses cutting-edge nanomedicine-based strategies, detailing their composition and mechanisms that enable effective bypassing of BBB and enhancing drug accumulation in brain tissues. Conventional therapies, namely AChEIs and NMDA receptor antagonists, have shown limited efficacy and are hindered by suboptimal brain penetration. The advent of nanotechnology-driven therapeutic delivery systems offers promising strategies to enhance CNS targeting and bioavailability, thereby addressing the shortcomings of conventional treatments. Various nanomedicines, encompassing polymeric and metallic nanoparticles (MNPs), solid lipid nanoparticles (SLNs), liposomes, micelles, dendrimers, nanoemulsions, and carbon nanotubes, have been investigated for their potential in delivering anti-AD agents like AChEIs, polyphenols, curcumin, and resveratrol. These nanocarriers exhibit the ability to traverse the BBB and deliver therapeutic payloads to the brain, thereby holding immense potential for effective AD treatment and early diagnostic approaches. Notably, nanocarriers loaded with AChEIs have shown promising results in preclinical studies, exhibiting improved therapeutic efficacy and sustained release profiles. This review underscores the urgency of innovative drug delivery approaches to overcome barriers in AD therapy. Nanomedicine-based solutions offer a promising avenue for achieving effective CNS targeting, enabling enhanced bioavailability and sustained therapeutic effects. As ongoing research continues to elucidate the complexities of CNS drug delivery, these advancements hold great potential for revolutionizing AD treatment and diagnosis.