Comparative study of choline alfoscerate as a combination therapy with donepezil: A mixed double-blind randomized controlled and open-label observation trial.

BACKGROUND: Choline alfoscerate (alpha-glycerylphosphorylcholine) is a phospholipid that includes choline, which increases the release of acetylcholine. The ASCOMALVA trial, a combination of donepezil and choline alfoscerate, slowed cognitive decline in Alzheimer disease. This study aims to replicate the effect by combining donepezil with other nootropics currently used in South Korea. METHODS: The 119 patients with cognitive decline who were eligible to use donepezil, with an mini-mental state examination (MMSE) score of 26 or less, were assigned to: donepezil alone (DO); donepezil and choline alfoscerate (DN); donepezil and acetyl-l-carnitine (DA); or donepezil and ginkgo biloba extract (DG). Cognitive evaluations such as MMSE, clinical dementia rating, Alzheimer disease assessment scale-cognitive subscale (ADAS-Cog), and Alzheimer disease assessment scale-noncognitive subscale were performed at the 12th and 24th weeks from the baseline time point. RESULTS: At the 12th week, the MMSE score increased 3.52% in the DN group, whereas it increased by 1.36% in the DO group. In the DA + DG group, it decreased by 2.17%. At the 24th week, the MMSE score showed an increase of 1.07% in the DO group and 1.61% in the DN group, but decreased by 5.71% in the DA + DG group. ADAS-Cog decreased by 0.9% in the DO group, while it improved by 13.9% in the DN group at the 12th week. At the 24th week, ADAS-Cog showed improvement in the DN group by 18.5%, whereas it improved by 9.4% in the DO group. Alzheimer disease assessment scale-noncognitive subscale also revealed better performance in the DN group than in the DO group at the 12th and 24th weeks. CONCLUSION: Choline alfoscerate exhibits additional cognitive improvement in both cognitive and noncognitive domains, supporting the findings of the ASCOMALVA trial.

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.

Zexieyin formula alleviates Alzheimer's disease via post-synaptic CaMKII modulating AMPA receptor: Involved in promoting neurogenesis to strengthen synaptic plasticity in mice hippocampus.

BACKGROUND: Alzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of AD, it's urgent to develop new and effective drug for the treatment of AD. PURPOSE: The study aimed to investigate the potential of Zexieyin formula (ZXYF), a Chinese medicine formula, for the treatment of AD and its potential mechanism of action. METHODS: We used chronic scopolamine (SCOP) induction mice model and APP/PS1 mice to reveal and confirm ZXYF for the treatment of AD with donepezil (DON) as a positive reference. The learning and memory function were detected by morris water maze test (MWM) and y-maze test. Moreover, western blot and immunofluorescence were used to detect the molecular mechanism of ZXYF for the alleviation of AD in hippocampus. Lastly, pharmacological technology was applied to evaluate AMPA receptor involved in the role of ZXYF in the treatment of AD. RESULTS: The results showed that ZXYF could improve memory and learning deficits both in two AD models including scopolamine (SCOP)-induced mice model and APP/PS1mice. Moreover, ZXYF or not DON increased expressions of BrdU/DCX and Ki67 positive cells in dentate gyrus (DG), up-regulated the levels of AMPA subunit type (GluA1) and PKA in hippocampus in SCOP-induced mice model, although ZXYF and DON activated CaMKII, CaMKII-phosphorylation, CREB, CREB-phosphorylation and PSD95 in hippocampus in SCOP-induced mice model. ZXYF also activated CaMKII, CaMKII-phosphorylation and GluA1 in HT22 cells. Furthermore, transient inhibiting AMPA receptor was capable of blocking the effects of ZXYF to treat AD in MWM and suppressing the number of BrdU/DCX positive cells increased by ZXYF in DG in SCOP-induced mice model, but had no effect on the alteration of Ki67 positive cells. CONCLUSION: ZXYF had the therapeutic effects on AD-treatment, which activated CaMKII to promote AMPA receptor (GluA1) and subsequently up-regulated PKA/CREB signaling to facilitate neurogenesis to achieve enhanced postsynaptic protein.

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 of vilazodone-donepezil chimeric derivatives as acetylcholinesterase inhibitors by QSAR, molecular docking and molecular dynamics simulations.

Alzheimer's disease (AD) is a disease that affects the cognitive abilities of older adults, and it is one of the biggest global medical challenges of the 21st century. Acetylcholinesterase (AChE) can increase acetylcholine concentrations and improve cognitive function in patients, and is a potential target to develop small molecule inhibitors for the treatment of Alzheimer's disease (AD). In this study, 29 vilazodone-donepezil chimeric derivatives are systematically studied using 3D-QSAR modeling, and a robust and reliable Topomer CoMFA model was obtained with: q2 = 0.720, r2 = 0.991, F = 287.234, N = 6, and SEE = 0.098. Based on the established model and combined with the ZINC20 database, 33 new compounds with ideal inhibitory activity are successfully designed. Molecular docking and ADMET property prediction also show that these newly designed compounds have a good binding ability to the target protein and can meet the medicinal conditions. Subsequently, four new compounds with good comprehensive ability are selected for molecular dynamics simulation, and the simulation results confirm that the newly designed compounds have a certain degree of reliability and stability. This study provides guidance for vilazodone-donepezil chimeric derivatives as a potential AChE inhibitor and has certain theoretical value.

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer's Disease: An In Vitro and In Vivo Investigation.

A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer's disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic ß-amyloid (Aß42) species in human neuronal cells in response to treatment. Among the most promising compounds were 3a and 3c, which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD50 (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.

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.

Mitigating cognitive deficits with teriflunomide: unraveling PI3K-modulated behavioral outcomes in mice.

BACKGROUND: Alzheimer's disease is a leading neurological disorder that gradually impairs memory and cognitive abilities, ultimately leading to the inability to perform even basic daily tasks. Teriflunomide is known to preserve neuronal activity and protect mitochondria in the brain slices exposed to oxidative stress. The current research was undertaken to investigate the teriflunomide's cognitive rescuing abilities against scopolamine-induced comorbid cognitive impairment and its influence on phosphatidylinositol-3-kinase (PI3K) inhibition-mediated behavior alteration in mice. METHODS: Swiss albino mice were divided into 7 groups; vehicle control, scopolamine, donepezil + scopolamine, teriflunomide (10 mg/kg) + scopolamine; teriflunomide (20 mg/kg) + scopolamine, LY294002 and LY294002 + teriflunomide (20 mg/kg). Mice underwent a nine-day protocol, receiving scopolamine injections (2 mg/kg) for the final three days to induce cognitive impairment. Donepezil, teriflunomide, and LY294002 treatments were given continuously for 9 days. MWM, Y-maze, OFT and rota-rod tests were conducted on days 7 and 9. On the last day, blood samples were collected for serum TNF-α analysis, after which the mice were sacrificed, and brain samples were harvested for oxidative stress analysis. RESULTS: Scopolamine administration for three consecutive days increased the time required to reach the platform in the MWM test, whereas, reduced the percentage of spontaneous alternations in the Y-maze, number of square crossing in OFT and retention time in the rota-rod test. In biochemical analysis, scopolamine downregulated the brain GSH level, whereas it upregulated the brain TBARS and serum TNF-α levels. Teriflunomide treatment effectively mitigated all the behavioral and biochemical alterations induced by scopolamine. Furthermore, LY294002 administration reduced the memory function and GSH level, whereas, uplifted the serum TNF-α levels. Teriflunomide abrogated the memory-impairing, GSH-lowering, and TNF-α-increasing effects of LY294002. CONCLUSION: Our results delineate that the improvement in memory, locomotion, and motor coordination might be attributed to the oxidative and inflammatory stress inhibitory potential of teriflunomide. Moreover, PI3K inhibition-induced memory impairment might be attributed to reduced GSH levels and increased TNF-α levels.

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.

Donepezil and quercetin alleviate valproate-induced testicular oxidative stress, inflammation and apoptosis: Imperative roles of AMPK/SIRT1/ PGC-1α and p38-MAPK/NF-κB/ IL-1ß signaling cascades.

The mounting evidence of valproate-induced testicular damage in clinical settings is alarming, especially for men taking valproate (VPA) for long-term or at high doses. Both donepezil (DON) and quercetin (QUE) have promising antioxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, this study aimed to determine whether DON, QUE, and their combination could mitigate VPA-induced testicular toxicity and unravel the mechanisms underlying their protective effect. In this study, male albino rats were randomly categorized into six equal groups: control, VPA (500 mg/kg, I.P., for 14 days), DON (3 and 5 mg/kg), QUE (50 mg/kg), and DON 3 + QUE combination groups. The DON and QUE treatments were administered orally for 7 consecutive days before VPA administration and then concomitantly with VPA for 14 days. VPA administration disrupted testicular function by altering testicular architecture, ultrastructure, reducing sperm count, viability, and serum testosterone levels. Additionally, VPA triggered oxidative damage, inflammatory, and apoptotic processes and suppressed the AMPK/SIRT1/PGC-1α signaling cascade. Pretreatment with DON, QUE, and their combination significantly alleviated histological and ultrastructure damage caused by VPA and increased the serum testosterone level, sperm count, and viability. They also suppressed the oxidative stress by reducing testicular MDA content and elevating SOD activity. In addition, they reduced the inflammatory response by suppressing IL-1ß level, NF-κB, and the p38-MAPK expression as well as inhibiting apoptosis by diminishing caspase-3 and increasing Bcl-2 expression. These novel protective effects were mediated by upregulating AMPK/SIRT1/PGC-1α signaling cascade. In conclusion, these findings suggest that DON, QUE, and their combination possess potent protective effects against VPA-induced testicular toxicity.

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.

Clinical observation on treatment of Alzheimer's disease with Sun's scalp-abdominal acupuncture combined with donepezil hydrochloride. / å­™æ°å¤´é’ˆè ¹é’ˆè”åˆç›é ¸å¤šå¥ˆå“Œé½æ²»ç–—é˜¿å°”èŒ¨æµ·é»˜ç— çš„ä¸´åºŠè§‚å¯Ÿ.

OBJECTIVES: To observe the effect of scalp-abdominal acupuncture combined with donepezil hydrochloride on cognition and life ability of patients with Alzheimer's disease (AD), so as to evaluate its clinical efficacy. METHODS: Sixty AD patients were collected and randomly divided into control group (30 cases) and observation group (30 cases). Patients in the control group were treated with oral donepezil hydrochloride (5 mg, once daily). Patients in the observation group were treated with scalp-abdominal acupuncture at Baihui (GV20), Yintang (GV24+), Sishencong (EX-HN1), "emotional area", Shenting (GV24), "abdominal area 1""abdominal area 8", and bilateral Fengchi (GB20), Taixi (KI3), Xuanzhong (GB39), Zusanli (ST36) on the basis of control group, and electroacupuncture (10 Hz/50 Hz, 0.5 to 5.0 mA) was applied to EX-HN1, "emotional area""abdominal area 1" and "abdominal area 8", once daily, 30 min each time. Four weeks as a course of treatment, both the two groups were treated for two consecutive courses. Before and after treatment, the mini-mental state examination (MMSE), AD assessmennt scale-cognitive subscale (ADAS-Cog) and activity of daily living scale (ADL) were evaluated. The clinical efficacy index was calculated and safety was evaluated. RESULTS: After treatment, the MMSE and ADL scores were higher (P<0.05) and the ADAS-Cog score was lower (P<0.05) than those before treatment in both groups. Compared with the control group, the MMSE and ADL scores were increased (P<0.05) and ADAS-Cog score was decreased (P<0.05) in the observation group. The total effective rate of the observation group (26/30, 86.67%) was higher (P<0.05) than that of the control group (23/30, 76.67%). No adverse reactions occurred in both groups during the treatment. CONCLUSIONS: Scalp-abdominal acupuncture combined with donepezil hydrochloride can effectively improve the cognitive ability and daily living ability of AD patients, and the efficacy is better than that of oral donepezil hydrochloride alone.

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.

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.

Effect of total flavonoids of Dracocephalum moldavica L. On neuroinflammation in Alzheimer's disease model amyloid-ß (Aß1-42)-peptide-induced astrocyte activation.

One of the main pathological features noted in Alzheimer's disease (AD) is the presence of plagues of aggregated ß-amyloid (Aß1-42)-peptides. Excess deposition of amyloid-ß oligomers (AßO) are known to promote neuroinflammation. Sequentially, following neuroinflammation astrocytes become activated with cellular characteristics to initiate activated astrocytes. The purpose of this study was to determine whether total flavonoids derived from Dracocephalum moldavica L. (TFDM) inhibited Aß1-42-induced damage attributed to activated C8-D1A astrocytes. Western blotting and ELISA were used to determine the expression of glial fibrillary acidic protein (GFAP), and complement C3 to establish the activation status of astrocytes following induction from exposure to Aß1-42. Data demonstrated that stimulation of C8-D1A astrocytes by treatment with 40 µM Aß1-42 for 24 hr produced significant elevation in protein expression and protein levels of acidic protein (GFAP) and complement C3 accompanied by increased expression and levels of inflammatory cytokines. Treatment with TFDM or the clinically employed drug donepezil in AD therapy reduced production of inflammatory cytokines, and toxicity initiated following activation of C8-D1A astrocytes following exposure to Aß1-42. Therefore, TFDM similar to donepezil inhibited inflammatory secretion in reactive astrocytes, suggesting that TFDM may be considered as a potential compound to be utilized in AD therapy.

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.

Evaluating the efficacy and safety of Alzheimer's disease drugs: A meta-analysis and systematic review.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial. OBJECTIVE: The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis. METHODS: We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results. RESULTS: All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs. CONCLUSION: ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.

Oxyresveratrol-ß-cyclodextrin mitigates streptozotocin-induced Alzheimer's model cognitive impairment, histone deacetylase activity in rats: in silico & in vivo studies.

Alzheimer's disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-ß-cyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2). We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC activity were significantly increased in AD disease group comparison to the sham. Interestingly, the ORV reversed the cognitive-behavioural deficit and prominently reduced the MDA and HDAC levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-AD role of ORV via antioxidant effect and inhibition of HDAC in the hippocampal and frontal cortical area of rats for AD.

Effects of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) on cognitive impairment and serum levels of Aß1-42, tau, P-tau in patients with mild to moderate Alzheimer's disease. / åŽ‹ç¸ç™¾ä¼šã€å ³å ƒå¯¹è½»ä¸­åº¦é˜¿å°”èŒ¨æµ·é»˜ç— æ‚£è€ è®¤çŸ¥éšœç¢åŠè¡€æ¸ Aß1-42、tau、P-tau水平的影响.

OBJECTIVES: To compare the effects of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) combined with donepezil hydrochloride tablets and donepezil hydrochloride tablets alone on cognitive impairment in patients with mild to moderate Alzheimer's disease(AD), and to explore the mechanism of pressing moxibustion in the treatment of mild to moderate AD from the serum levels of ß-amyloid 1-42 (Aß1-42), microtubule-associated protein tau and phosphorylated tau (P-tau). METHODS: A total of 76 patients with mild to moderate AD were randomly divided into an observation group (38 cases, 4 cases dropped out) and a control group (38 cases, 2 cases dropped out). Patients in the control group were given oral donepezil hydrochloride tablets (5 mg each time, once a day). On the basis of the control group, patients in the observation group were treated with pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4), 5 cones per acupoint, once every other day, three times a week. Both groups were treated for 8 weeks. The scores of mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) were compared between the two groups before treatment, after treatment and after 4 and 12 weeks of treatment completion. The serum levels of Aß1-42, tau and P-tau were detected before and after treatment in the two groups, and the safety was evaluated. RESULTS: At each time point after treatment, the MMSE and MoCA scores of the two groups were higher than those before treatment (P<0.05), and the scores in the observation group were higher than those in the control group (P<0.05). After treatment, the serum levels of Aß1-42, tau and P-tau in the two groups were lower than those before treatment (P<0.05), and above indexes in the observation group were lower than those in the control group (P<0.05). There was no significant difference in the safety level between the two groups (P>0.05). CONCLUSIONS: The short-term and long-term effect of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) combined with donepezil hydrochloride tablets in improving cognitive impairment in mild to moderate AD is better than that of donepezil hydrochloride tablets alone, and can reduce serum levels of Aß1-42, tau and P-tau, which may be one of the mechanisms of pressing moxibustion to improve cognitive impairment.