Therapeutic effectiveness of Donepezil hydrochloride in combination with butylphthalide for post-stroke cognitive impairment.

OBJECTIVE: To study the therapeutic effectiveness of donepezil hydrochloride (DPZ) in combination with butylphthalide (BP) for the treatment of post-stroke cognitive impairment (PSCI). METHODS: In this retrospective study, the clinical data of 125 PSCI patients treated at the First Affiliated Hospital of Harbin Medical University from December 2019 to December 2023 were collected and analyzed. The patients were grouped into a joint group (n=75, receiving DPZ + BP) and a control group (n=50, receiving DPZ alone) according to their treatment regimen. Inter-group comparisons were then carried out from the perspectives of therapeutic effectiveness, safety (constipation, abdominal distension and pain, and gastrointestinal reactions), cognitive function (Montreal Cognitive Assessment Scale [MoCA], Chinese Stroke Scale [CSS]), Activities of Daily Living Scale (ADL), and serum biochemical indexes (neuron-specific enolase [NSE], high-sensitivity C-reactive protein [hs-CRP], nitric oxide [NO], and malondialdehyde [MDA]). In addition, a univariate analysis was carried out to identify factors affecting therapeutic effectiveness in PSCI patients. RESULTS: The joint group showed significantly better therapeutic effectiveness compared to the control group (P<0.05). There was a significant correlation between the type of stroke, treatment method, and therapeutic effectiveness in PSCI patients (P<0.05). There was no significant difference in the total incidence of adverse reactions (P>0.05). After the treatment, compared to the control group, the joint group demonstrated significant improvements in MoCA and ADL scores (all P<0.05) and reductions in CSS scores and levels of NSE, hs-CRP, NO, and MDA (all P<0.05). CONCLUSIONS: DPZ in combination with BP is highly effective for the treatment of PSCI. It positively affects cognitive function and ADL, alleviates neurological deficits, and reduces abnormal serum biochemical indices without increasing the risk of adverse reaction.

Alzheimer's disease and its treatment-yesterday, today, and tomorrow.

Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-ß (Aß) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aß monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aß will benefit the majority of subjects with AD that the anti-Aß MABs are unlikely to be the "magic bullet". A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

Obsessive-compulsive disorder induced by donepezil in a patient with Alzheimer's disease.

Background: Donepezil, an acetylcholinesterase inhibitor commonly used to treat Alzheimer's disease (AD), is generally well tolerated. There have been no previous reports on donepezil-induced obsessive-compulsive disorder (OCD). Case Presentation: The patient, a retired man in his 70s diagnosed with AD, displayed OCD symptoms following donepezil initiation, exacerbating post-stroke-specifically, a cerebral infarction in the right posterior limb of the internal capsule. Remarkably, the symptoms abated upon discontinuation of donepezil. Conclusion: Caution should be exercised when using donepezil in patients with a history of stroke.

Treating Diphenhydramine Overdose: A Literature Review of Currently Available Treatment Methods.

From 2019 to 2020, antihistamines were found in 15% of all US drug overdose deaths, often co-administered with fentanyl, with 3.6% of overdose deaths due to antihistamines alone. The most common antihistamine found in all these reported deaths is diphenhydramine, a ubiquitous, over-the-counter and clinically important medication. Currently, there is no antidote for diphenhydramine overdose. This review summarizes the adverse health effects and current emergency medicine treatments for diphenhydramine. Several emergency medicine case reports are reviewed, and the efficacy and outcomes of a variety of treatments are compared. The treatments reviewed include the more traditional antihistamine overdose therapeutics physostigmine and sodium bicarbonate, as well as newer ones such as donepezil, dexmedetomidine, and lipid emulsion therapy. We conclude that more study is needed to determine the ideal therapeutic approach to treating antihistamine overdoses.

Donepezil protects against cyclophosphamide-induced premature ovarian failure in mice: A focus on proinflammatory cytokines and NLRP3/TLR-4/NF-κB interplay.

BACKGROUND AND AIM: Cyclophosphamide (CP) chemotherapy is a significant iatrogenic component of premature ovarian failure (POF). The aim of this work was to evaluate the potential protective effects of donepezil, a centrally acting acetylcholinesterase (AChE) inhibitor, on CP-induced POF in mice. METHODS: 40 female Swiss albino mice were split into 5 equal groups: group 1 (control), group 2 (CP-POF); induced by intraperitoneal injection of CP on 8th day of the experiment, and group (3-5); mice received oral donepezil daily (1, 2, or 4 mg/kg, respectively) 8 days before CP injection. Mice were euthanized after 24 h of CP injection, and blood samples were collected to assay serum anti-Mullerian hormone (AMH) levels. Ovarian tissues were dissected, and the right ovary was processed for further assays of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interlukin-6 (IL-6), nucleotide-binding domain-like receptor family, the Pyrin domain-containing 3 (NLRP3) inflammasome, and Toll-like receptor 4 (TLR-4), while the left one was processed for histopathological and immunohistochemical examination of nuclear factor-Kappa beta (NF-κB) and caspase-3. RESULTS: Donepezil, in a dose-dependent manner particularly (4 mg/kg), has an inhibitory action on NO (40 ± 2.85 vs. 28.20 ± 2.23, P < 0.001), proinflammatory cytokines (P < 0.001), the TLR-4/ NF-κB / NLRP3 inflammasome pathway (P < 0.001), and apoptosis (P < 0.001), with a significant elevation in the AMH levels (4.57 ± 1.08 vs. 8.57 ± 0.97, P < 0.001) versus CP-POF group. CONCLUSION: Donepezil may be a potential protective agent against CP-induced POF in mice, but further research is needed to fully understand its therapeutic function experimentally and clinically.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

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Association of CHAT Gene Polymorphism rs3793790 and rs2177370 with Donepezil Response and the Risk of Alzheimer's Disease Continuum.

Background: Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer's disease continuum (ADC). Objective: This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC. Material and Methods: According to 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) standard, amyloid ß-protein positive (Aß+) and negative (Aß-) patients were recruited according to the Aß-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aß+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aß+ and 73 Aß- patients using a logistic regression analysis. Results: The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64-28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28-4.95). Conclusion: The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.

A green micelle-enhanced first derivative synchronous fluorescence approach for determination of donepezil HCl and trazodone HCl in their pure state, pharmaceutical dosage form and spiked human plasma.

The study's objective is to establish an eco-friendly, sensitive and economical quantitative methodology for the concurrent analysis of donepezil HCl (DPZ) and trazodone HCl (TRZ) in raw materials, tablets and human plasma. The first derivative synchronous fluorescence spectroscopic (FDSFS) technique was applied at constant wavelength difference (∆λ = 120) for assessment of DPZ and TRZ at each other's zero-crossing point at 279 nm and 297 nm, respectively. The submitted technique was validated in accordance with ICH Q2 R1 guidelines and the linearity of the standard calibration curve was observed over the concentration range of 10-500 ng/ml for DPZ and 20-1,000 ng/ml for TRZ. The detection limits (LOD) were found to be 2.65 and 5.4 ng/ml, and the limits of quantitation (LOQ) were 8.05 and 16.3 ng/ml for DPZ and TRZ, respectively. This technique was used further to quantify the studied medications in their laboratory-prepared mixtures, commercial tablets and spiked plasma samples. The results obtained were not significantly different from those acquired from the comparison methods, indicating the high accuracy and precision of the proposed method. Furthermore, the ecological friendliness of the suggested method was evaluated and proven to be excellent using Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE) evaluation tools.

Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3ß for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3ß (GSK-3ß) and Acetylcholinesterase (AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it. OBJECTIVES: To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3ß and AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3ß and AChE. METHODS: In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger. RESULTS: Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3ß and AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3ß and AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules. CONCLUSION: Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3ß and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.

Relationship between donepezil and fracture risk in patients with dementia with Lewy bodies.

AIM: Patients with dementia with Lewy bodies (DLB) are at a high risk for falls and fractures. Although cholinesterase inhibitors reportedly are effective in suppressing the progression of cognitive symptoms in DLB patients, their effects on fracture risk remain unclarified. This study aimed to evaluate the association between donepezil use and hip fracture risk in older patients with DLB. METHODS: Using the Japanese insurance claim database, we collected the data of patients aged ≥65 years with DLB from April 2012 to March 2019. After propensity score matching, we compared the fracture rate over 3 years between DLB patients receiving donepezil and those not receiving antidementia drugs. RESULTS: Altogether, 24 022 239 individuals aged ≥65 years were newly registered from April 2012 to March 2016 and had verifiable information from 6 months before to 3 years after the registration. We identified 6634 pure-DLB patients and analyzed the data of 1182 propensity score-matched pairs. The characteristics, including age, sex, fracture history, osteoporosis, and bone mineral density test rate, of the two groups were well balanced by propensity score matching. The incidence rate of hip fracture was significantly lower in DLB patients receiving donepezil than in those not receiving antidementia drugs (0.60 vs. 1.44/100 person-years, P < 0.001), whereas that of vertebral fractures was the same. CONCLUSIONS: Donepezil administration in Japanese people aged ≥65 years with DLB was significantly associated with a decreased risk of hip fracture. Donepezil may provide new benefits to DLB patients. Geriatr Gerontol Int 2024; ••: ••-••.

Donepezil ameliorates gut barrier disruption in doxorubicin-treated rats.

An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into three groups. Each group was treated with either vehicle as a control, doxorubicin, or doxorubicin-cotreated with donepezil. Heart rate variability was assessed to reflect the impact of doxorubicin and donepezil. Then, animals were euthanized, and the ileum and its contents were collected in each case to investigate the gut barrier and gut microbiota, respectively. The microbiota-derived endotoxin, trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) in the serum were determined. An increase in the sympathetic tone, endotoxins, and TMAO levels with disruption of the gut barrier and a decrease in SCFAs levels were observed in doxorubicin-treated rats. Gut microbiota of doxorubicin-treated rats was significantly different from that of the control group. Donepezil treatment significantly decreased the sympathetic tone, restored the gut barrier, and reduced endotoxin and TMAO levels in doxorubicin-treated rats. Nonetheless, donepezil administration did not alter the gut microbiota profile and levels of SCFAs in doxorubicin-treated rats. Doxorubicin impaired the autonomic balance and the gut barrier, and induced gut dysbiosis, resulting in gut toxicity. Donepezil partially improved the doxorubicin-induced gut toxicity through balancing the autonomic disturbance.

Circadian ABCG2 Expression Influences the Brain Uptake of Donepezil across the Blood-Cerebrospinal Fluid Barrier.

Donepezil (DNPZ) is a cholinesterase inhibitor used for the management of Alzheimer's disease (AD) and is dependent on membrane transporters such as ABCG2 to actively cross brain barriers and reach its target site of action in the brain. Located in the brain ventricles, the choroid plexus (CP) forms an interface between the cerebrospinal fluid (CSF) and the bloodstream, known as the blood-CSF barrier (BCSFB). Historically, the BCSFB has received little attention as a potential pathway for drug delivery to the central nervous system (CNS). Nonetheless, this barrier is presently viewed as a dynamic transport interface that limits the traffic of molecules into and out of the CNS through the presence of membrane transporters, with parallel activity with the BBB. The localization and expression of drug transporters in brain barriers represent a huge obstacle for drug delivery to the brain and a major challenge for the development of therapeutic approaches to CNS disorders. The widespread interest in understanding how circadian clocks modulate many processes that define drug delivery in order to predict the variability in drug safety and efficacy is the next bridge to improve effective treatment. In this context, this study aims at characterizing the circadian expression of ABCG2 and DNPZ circadian transport profile using an in vitro model of the BCSFB. We found that ABCG2 displays a circadian pattern and DNPZ is transported in a circadian way across this barrier. This study will strongly impact on the capacity to modulate the BCSFB in order to control the penetration of DNPZ into the brain and improve therapeutic strategies for the treatment of AD according to the time of the day.

The donepezil transdermal system for the treatment of patients with mild, moderate, or severe Alzheimer's disease: a critical review.

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.

Optimizing Neuroprotective Nano-structured Lipid Carriers for Transdermal Delivery through Artificial Neural Network.

BACKGROUND: Dementia associated with Alzheimer's disease (AD) is a neurological disorder. AD is a progressive neurodegenerative condition that predominantly impacts the elderly population, although it can also manifest in younger people through the impairment of cognitive functions, such as memory, cognition, and behaviour. Donepezil HCl and Memantine HCl are encapsulated in Nanostructured Lipid Carriers (NLCs) to prolong systemic circulation and minimize the systemic side effects. OBJECTIVE: This work explores the use of data mining tools to optimize the formulation of NLCs comprising of Donepezil HCl and Memantine HCl for transdermal drug delivery. Neuroprotective drugs and excipients are utilized for protecting the nervous system against damage or degeneration. METHOD: The NLCs were formulated using a high-speed homogenization technique followed by ultrasonication. NLCs were optimized using Box Behnken Design (BBD) in Design Expert Software and artificial neural network (ANN) in IBM SPSS statistics. The independent variables included the ratio of solid lipid to liquid lipid, the percentage of surfactant, and the revolutions per minute (RPM) of the high-speed homogenizer. RESULTS: The NLCs that were formulated had a mean particle size ranging from 67.0±0.45 to 142.4±0.52nm. Both drugs have a %EE range over 75%, and Zeta potential was determined to be - 26±0.36mV. CryoSEM was used to do the structural study. The permeation study showed the prolonged release of the formulation. CONCLUSION: The results indicate that NLCs have the potential to be a carrier for transporting medications to deeper layers of the skin and reaching systemic circulation, making them a suitable formulation for the management of Dementia. Both ANN and BBD techniques are effective tools for systematically developing and optimizing NLC formulation.

The increased effective connectivity from left middle occipital gyrus to right medial septum/diagonal bands in AD patients after donepezil intervention.

Introduction: Donepezil enhances the function of cholinergic nerves by increasing the concentration of acetylcholine, thereby improving clinical symptoms in patients with Alzheimer's disease (AD). However, the neural mechanisms of how donepezil modulates the effective connectivity (EC) network of cholinergic system in AD patients remain unknown. We speculated that the effective network of the cholinergic system changes in AD patients after donepezil intervention. Methods: We employed resting-state functional magnetic resonance imaging and Granger causality analysis approach to explore changes in the effective connectivity network of the basal forebrain in AD patients before and after donepezil intervention. This study included 32 participants, including 16 healthy controls (HCs) and 16 AD patients. In a 3T MRI scanner, the 16 AD patients were scanned before and after the donepezil intervention. To compare EC differences between the three groups of participants, ANOVA and post-hoc t-tests analysis were employed. Results: Compared to baseline status, AD patients after donepezil intervention had an increased EC from left middle occipital gyrus to right medial septum/diagonal bands. Compared to HCs, AD patients after donepezil intervention had an increased EC from right inferior frontal gyrus/orbit part to right medial septum/diagonal bands, AD patients before donepezil intervention had a reduced EC from right precuneus to right medial septum/diagonal bands. A significant positive correlation was found between EC values in right precuneus and Mini-Mental State Examination in pre-intervention AD patients (r = 0.7338, p = 0.0012). Discussion: Our study showed that effective connectivity of brain regions associated with the default mode network in the cholinergic pathway was enhanced after donepezil intervention. The results of this study will help us to better understand the neural mechanisms of donepezil intervention in AD and to find clinical targets for intervention.

Predicting the efficacy of donepezil intervention in Alzheimer's disease patients using regional homogeneity in the inferior orbitofrontal cortex.

BACKGROUND: Although donepezil is a commonly used drug for treating Alzheimer's disease (AD), the mechanisms by which it affects patients' functional brain activity, and thus modulates clinical symptoms, remain unclear. METHODS: In the present study, we used resting-state functional magnetic resonance imaging (MRI) and regional homogeneity (ReHo) to investigate the effects of donepezil on local brain activity in AD patients. Resting-state functional MRI data were collected from 32 subjects: 16 healthy controls and 16 AD patients. All 16 AD patients underwent 6 months of donepezil treatment and received two MRI scans (pre- and post-intervention). Analysis of covariance and post hoc analyses were used to compare ReHo differences among the healthy controls, pre-intervention AD patients, and post-intervention AD patients. Pearson correlation analysis was used to examine relationships between ReHo values in differential brain regions and clinical symptoms. RESULTS: Compared with healthy controls, post-intervention AD patients had reduced ReHo in the orbital part of the inferior frontal gyrus, and pre-intervention AD patients had reduced ReHo in the orbital part of the right inferior frontal gyrus. Pattern recognition models revealed that pre-intervention ReHo values in abnormal brain regions of AD patients were 76% accurate for predicting the efficacy of donepezil on cognitive function and 65% accurate for predicting its efficacy on depressive symptoms. CONCLUSIONS: These findings deepen our understanding of the brain mechanisms underlying the clinical efficacy of donepezil in AD patients, and provide a novel way to predict its clinical efficacy in such patients.

Novel multifunctional tacrine-donepezil hybrids against Alzheimer's disease: Design synthesis and bioactivity studies.

A series of tacrine-donepezil hybrids were synthesized as potential multifunctional anti-Alzheimer's disease (AD) compounds. For this purpose, tacrine and the benzylpiperidine moiety of donepezil were fused with a hydrazone group to achieve a small library of tacrine-donepezil hybrids. In agreement with the design, all compounds showed inhibitory activity toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values in the low micromolar range. Kinetic studies on the most potent cholinesterase (ChE) inhibitors within the series showed a mixed-type inhibition mechanism on both enzymes. Also, the docking studies indicated that the compounds inhibit ChEs by dual binding site (DBS) interactions. Notably, tacrine-donepezil hybrids also exhibited significant neuroprotection against H2O2-induced cell death in a differentiated human neuroblastoma (SH-SY5Y) cell line at concentrations close to their IC50 values on ChEs and showed high to medium blood-brain barrier (BBB) permeability on human cerebral microvascular endothelial cells (HBEC-5i). Besides, the compounds do not cause remarkable toxicity in a human hepatocellular carcinoma cell line (HepG2) and SH-SY5Y cells. Additionally, the compounds were predicted to also have good bioavailability. Among the tested compounds, H4, H16, H17, and H24 stand out with their biological profile. Taken together, the proposed novel tacrine-donepezil scaffold represents a promising starting point for the development of novel anti-ChE multifunctional agents against AD.

Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography.

Fourteen donepezil-like acetylcholinesterase (AChE) inhibitors from our library were analyzed using reversed-phase thin-layer chromatography to assess their lipophilicity and blood-brain barrier permeability. Compounds possessed N-benzylpiperidine and N,N-diarylpiperazine moieties connected via a short carboxamide or amine linker. Retention parameters RM 0, b, and C0 were considered as the measures of lipophilicity. Besides, logD of the investigated compounds was determined chromatographically using standard compounds with known logPow and logD values at pH 11. Experimentally obtained lipophilicity parameters correlated well with in silico generated results, and the effect of the nature of the linker between two pharmacophores and substituents on the arylpiperazine part of the molecule was observed. As a result of drug-likeness analysis, both Lipinski's rule of five and Veber's rule parameters were determined, suggesting that examined compounds could be potential candidates for further drug development. Principal component analysis was performed to obtain an insight into a grouping of compounds based on calculated structural descriptors, experimentally obtained values of lipophilicity, and AChE inhibitory activity.

The Effect of Donepezil Hydrochloride in the Twitcher Mouse Model of Krabbe Disease.

Krabbe disease (KD) is a rare demyelinating disorder characterized by demyelination caused by mutations in the GALC gene, resulting in toxic accumulation of psychosine. Psychosine has been identified as detrimental to oligodendrocytes, leading to demyelination through diverse hypothesized pathways. Reducing demyelination is essential to maintain neurological function in KD; however, therapeutic interventions are currently limited. Acetylcholinesterase inhibitors (AChEi) are commonly used for symptomatic management of Alzheimer's Disease and are suggested to have potential disease-modifying effects, including regulating myelin state. In particular, donepezil, an AChEi, has demonstrated promising effects in cellular and animal models, including promotion of the expression of myelin-related genes and reduction of glial cell reactivity. This drug also acts as an agonist for sigma-1 receptors (Sig-1R), which are implicated in demyelination diseases. In the context of drug repurposing, here, we demonstrate that administration of donepezil has protective effects in the twitcher mouse model of KD. We provide data showing that donepezil preserves myelin and reduces glial cell reactivity in the brains of twitcher mice. Moreover, donepezil also improves behavioral phenotypes and increases lifespan in twitcher animals. These findings suggest that donepezil, with its dual activity as an AChE inhibitor and Sig-1R agonist, may hold promise as a therapeutic candidate for demyelinating diseases, including KD.