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Zhongguo Zhong Yao Za Zhi = Zhongguo... Apr 2024The Chinese medical mechanism of Huanglian Jieduo Decoction on treating Alzheimer's disease(AD) characterized by "toxin damaging brain collateral" is still...
The Chinese medical mechanism of Huanglian Jieduo Decoction on treating Alzheimer's disease(AD) characterized by "toxin damaging brain collateral" is still unclear. This study aims to explore the mechanism of Huanglian Jieduo Decoction on regulating triggering receptor expressed on myeloid cells 2(TREM2)/protein kinase B(Akt)/glycogen synthase kinase 3β(GSK3β) pathway to improve the cognitive deficit in APP/PS1 transgenic mice. APP/PS1 mice of approximately nine months old were randomly divided into the model group, the low, medium, and high(2.5, 5, and 10 g·kg~(-1)) groups of Huanglian Jiedu Decoction, and 0.75 mg·kg~(-1) donepezil hydrochloride group, and the C57BL/6J mice with the same age were taken as the normal group. After one month of continuous oral administration, a Morris water maze was performed to detect the learning and memory ability of mice. Hematoxylin-eosin(HE) staining was applied to observe the morphology of neuronal cells in the cortical area of mice. Immunofluorescence was used to detect the protein expressions of β-amyloid(Aβ_(1-42)), CD86, and arginase 1(Arg1). The mRNA levels of interleukin(IL)-1β, IL-6, and IL-10 in the cortex of mice were detected by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR). The protein expressions of TREM2, phosphoinositide-3 kinase(PI3K), Akt, GSK3β, and beta-catenin(β-catenin) in mouse cortex were determined by Western blot. The results indicated that the escape latency of the model group was significantly prolonged, and the residence time in the target quadrant and the number of crossing the platform were significantly reduced compared with the normal group. Mice in the model group had a significantly lower number of neurons in the cortex and showed nuclear pyknosis and a significant increase in the expressions of Aβ_(1-42) and CD86. The mRNA levels of IL-1β and IL-6 in tissue were significantly increased, IL-10 were increased, while Arg1 were significantly decreased. The expression of TREM2, p-PI3K(Y607), p-Akt(T308), p-GSK3β(Ser9), and β-catenin in the cortex were significantly down-regulated. Compared with the model group, the escape latency of the mice in the administration group was significantly shortened, and the number of crossing the platform and the residence time in the target quadrant were significantly increased. Furthermore, the number of neurons in the cortex of mice was increased, and nuclear pyknosis was improved. Aβ_(1-42) deposition was decreased significantly. The mRNA levels of IL-1β, IL-6 and CD86 were significantly decreased, while IL-10 and Arg1 levels were significantly increased. The expression of TREM2, p-PI3K(Y607), p-Akt(T308), p-GSK3β(Ser9), and β-catenin protein in the cortex of each administration group was significantly up-regulated compared with the model group. In conclusion, Huanglian Jiedu Decoction reduced the expression of Aβ_(1-42) and neuroinflammation to a neuro-protective effect, thereby improving the learning and memory ability in APP/PS1 mice, which may be related to the TREM2/Akt/GSK3β signaling pathway.
Topics: Animals; Glycogen Synthase Kinase 3 beta; Drugs, Chinese Herbal; Mice; Mice, Transgenic; Cerebral Cortex; Proto-Oncogene Proteins c-akt; Alzheimer Disease; Receptors, Immunologic; Mice, Inbred C57BL; Membrane Glycoproteins; Male; Signal Transduction; Humans
PubMed: 38812205
DOI: 10.19540/j.cnki.cjcmm.20240115.702 -
Medicinal Chemistry (Shariqah (United... May 2024Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.
INTRODUCTION
Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.
METHOD
This study utilized computational methods to explore 14 anti-acetylcholinesterase (AChE) derivatives (1 ̶ 14) as potential treatments. By scrutinizing their interactions with 11 essential target proteins (AChE, Aβ, BChE, GSK-3β, MAO B, PDE-9, Prion, PSEN-1, sEH, Tau, and TDP-43) and comparing them with established drugs such as donepezil, galantamine, memantine, and rivastigmine, ligand 14 emerged as notable. During molecular dynamics simulations, the protein boasting the strongest bond with the critical 1QTI protein and exceeding drug-likeness criteria also exhibited remarkable stability within the enzyme's pocket across diverse temperatures (300 ̶ 320 K). In addition, we utilized density functional theory (DFT) to compute dipole moments and molecular orbital properties, including assessing the thermodynamic stability of AChE derivatives.
RESULT
This finding suggests a welldefined, potentially therapeutic interaction further supported by theoretical and future in vitro and in vivo investigations.
CONCLUSION
Ligand 14 thus emerges as a promising candidate in the fight against Alzheimer's disease.
PubMed: 38803179
DOI: 10.2174/0115734064304100240511112619 -
Communicative & Integrative Biology 2024Alzheimer's disease (AD) is a common brain disease associated with cognitive impairment and dementia. donepezil, an acetylcholinesterase (AChE) inhibitor drug as a...
Alzheimer's disease (AD) is a common brain disease associated with cognitive impairment and dementia. donepezil, an acetylcholinesterase (AChE) inhibitor drug as a commercial AD drug represents a non-cost-effective treatment with the toxic effects reported. As the prevalence of AD increases, the development of effective therapeutic treatments is urgently required. Laminaria digitata is a brown seaweed claimed to be able to prevent and treat neurodegenerative diseases. Therefore, this study measured and compared the binding affinity and toxicity of seven common phytoconstituents in against acetylcholinesterase (AChE) with those of donepezil using a molecular docking approach. The binding free energy values of donepezil, dieckol, eckol, fucodiphlorethol G, 7-Phloroecol, laminaran, alginic acid, and fucoidan with acetylcholinesterase (AChE) were -12.3, -13.5, -10.5, -8,7, -9.7, -8.0, -10.3, and -7.4 kcal/mol. All ligands constantly interacted with the AChE amino acid residues, namely Tyr124. Dieckol, with the strongest and most stable interaction, is classified as class IV toxicity, with an LD50 value of 866 mg/kg. It has aryl hydrocarbon receptor (AhR) and mitochondrial membrane potential (MMP) toxicity at certain doses. Theoretically, based on Lipinski's rule, dieckol is likely to have poor absorption and permeation properties; therefore, several considerations during the drug discovery process are needed.
PubMed: 38798825
DOI: 10.1080/19420889.2024.2357346 -
Molecules (Basel, Switzerland) May 2024A previous study reported that the ethanolic extract of the edible fern, (Retz.) Sw. (DE), obtained from a non-optimized extraction condition exhibited anti-Alzheimer's...
A previous study reported that the ethanolic extract of the edible fern, (Retz.) Sw. (DE), obtained from a non-optimized extraction condition exhibited anti-Alzheimer's disease (AD) properties through the inhibition of a rate-limiting enzyme in amyloid peptide formation, β-secretase-1 (BACE-1). Nevertheless, a non-optimized or suboptimal extraction may lead to several issues, such as a reduction in extraction efficiency and increased time and plant materials. In this study, extraction of the DE was optimized to obtain appropriate BACE-1 inhibition using a Box-Behnken design (BBD) and response surface methodology (RSM). Data revealed that the optimal extraction condition was 70% (/) aqueous ethanol, 50 min extraction time, 30 °C extraction temperature, and 1:30 g/mL solid/liquid ratio, giving BACE-1 inhibition at 56.33%. In addition, the extract also exhibited significant antioxidant activities compared to the non-optimized extraction. Metabolomic phytochemical profiles and targeted phytochemical analyses showed that kaempferol, quercetin, and their derivatives as well as rosmarinic acid were abundant in the extract. The optimized DE extract also acted synergistically with donepezil, an AD drug suppressing BACE-1 activities. Data received from -expressing human amyloid precursor proteins (APPs) and BACE-1, representing the amyloid hypothesis, showed that the optimized DE extract penetrated the fly brains, suppressed BACE-1 activities, and improved locomotor functions. The extract quenched the expression of glutathione S transferase D1 (GSTD1), inositol-requiring enzyme (IRE-1), and molecular chaperone-binding immunoglobulin (Bip), while donepezil suppressed these genes and other genes involved in antioxidant and endoplasmic reticulum (ER) stress response, including superoxide dismutase type 1 (SOD1), activating transcription factor 6 (ATF-6), and protein kinase R-like endoplasmic reticulum kinase (PERK). To sum up, the optimized extraction condition reduced extraction time while resulting in higher phytochemicals, antioxidants, and BACE-1 inhibitors.
Topics: Antioxidants; Alzheimer Disease; Plant Extracts; Phytochemicals; Amyloid Precursor Protein Secretases; Animals; Ferns; Humans; Aspartic Acid Endopeptidases
PubMed: 38792065
DOI: 10.3390/molecules29102204 -
Biomedicines May 2024Human dihydrofolate reductase (DHFR) is an essential cellular enzyme, and inhibiting its activity is a promising strategy for cancer therapy. We have chosen the...
Human dihydrofolate reductase (DHFR) is an essential cellular enzyme, and inhibiting its activity is a promising strategy for cancer therapy. We have chosen the trimethoprim molecule () as a model compound in our search for a new class of DHFR inhibitors. We incorporated an amide bond, a structural element typical of netropsin, a ligand that binds selectively in the minor groove of DNA, into the molecules of analogs. In this work, we present previously obtained and evaluated eleven benzamides (-; , , ). Recently, these compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). was most active against AChE, with an inhibitory concentration of AChE IC = 0.056 µM, while the IC for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC value was 9.01 µM compared to that for quercetin, with IC = 4.89 µM. All the benzamides were active against DHFR, with IC values ranging from 4.72 to 20.17 µM, and showed activity greater than (55.26 µM). Quantitative results identified the derivatives and as the most promising. A molecular modeling study demonstrates that interacts strongly with the key residue Gly-117, while interacts strongly with Asn-64 and Arg-70. Furthermore, and demonstrate the ability to stabilize the DHFR enzyme, despite forming fewer hydrogen bonds with the protein compared to reference ligands. It can be concluded that this class of compounds certainly holds great promise for good active leads in medicinal chemistry.
PubMed: 38791041
DOI: 10.3390/biomedicines12051079 -
Expert Review of Neurotherapeutics Jun 2024Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically... (Review)
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.
Topics: Humans; Donepezil; Alzheimer Disease; Cholinesterase Inhibitors; Administration, Cutaneous; Transdermal Patch; Rivastigmine; Severity of Illness Index
PubMed: 38785454
DOI: 10.1080/14737175.2024.2355981 -
Age and Ageing May 2024An updated time-trend analysis of anti-dementia drugs (ADDs) is lacking. The aim of this study is to assess the incident rate (IR) of ADD in individuals with dementia...
BACKGROUND
An updated time-trend analysis of anti-dementia drugs (ADDs) is lacking. The aim of this study is to assess the incident rate (IR) of ADD in individuals with dementia using real-world data.
SETTING
Primary care data (country/database) from the UK/CPRD-GOLD (2007-20), Spain/SIDIAP (2010-20) and the Netherlands/IPCI (2008-20), standardised to a common data model.
METHODS
Cohort study. Participants: dementia patients ≥40 years old with ≥1 year of previous data. Follow-up: until the end of the study period, transfer out of the catchment area, death or incident prescription of rivastigmine, galantamine, donepezil or memantine. Other variables: age/sex, type of dementia, comorbidities. Statistics: overall and yearly age/sex IR, with 95% confidence interval, per 100,000 person-years (IR per 105 PY (95%CI)).
RESULTS
We identified a total of (incident anti-dementia users/dementia patients) 41,024/110,642 in UK/CPRD-GOLD, 51,667/134,927 in Spain/SIDIAP and 2,088/17,559 in the Netherlands/IPCI.In the UK, IR (per 105 PY (95%CI)) of ADD decreased from 2007 (30,829 (28,891-32,862)) to 2010 (17,793 (17,083-18,524)), then increased up to 2019 (31,601 (30,483 to 32,749)) and decrease in 2020 (24,067 (23,021-25,148)). In Spain, IR (per 105 PY (95%CI)) of ADD decreased by 72% from 2010 (51,003 (49,199-52,855)) to 2020 (14,571 (14,109-15,043)). In the Netherlands, IR (per 105 PY (95%CI)) of ADD decreased by 77% from 2009 (21,151 (14,967-29,031)) to 2020 (4763 (4176-5409)). Subjects aged ≥65-79 years and men (in the UK and the Netherlands) initiated more frequently an ADD.
CONCLUSIONS
Treatment of dementia remains highly heterogeneous. Further consensus in the pharmacological management of patients living with dementia is urgently needed.
Topics: Humans; Male; Female; Dementia; Aged; Aged, 80 and over; Middle Aged; Netherlands; Databases, Factual; Time Factors; Nootropic Agents; Spain; United Kingdom; Practice Patterns, Physicians'; Age Factors; Drug Utilization
PubMed: 38783756
DOI: 10.1093/ageing/afae106 -
Communications Medicine May 2024Alzheimer's disease (AD) is the most common neurodegenerative disease. Studying the effects of drug treatments on multiple health outcomes related to AD could be...
BACKGROUND
Alzheimer's disease (AD) is the most common neurodegenerative disease. Studying the effects of drug treatments on multiple health outcomes related to AD could be beneficial in demonstrating which drugs reduce the disease burden and increase survival.
METHODS
We conducted a comprehensive causal inference study implementing doubly robust estimators and using one of the largest high-quality medical databases, the Oracle Electronic Health Records (EHR) Real-World Data. Our work was focused on the estimation of the effects of the two common Alzheimer's disease drugs, Donepezil and Memantine, and their combined use on the five-year survival since initial diagnosis of AD patients. Also, we formally tested for the presence of interaction between these drugs.
RESULTS
Here, we show that the combined use of Donepezil and Memantine significantly elevates the probability of five-year survival. In particular, their combined use increases the probability of five-year survival by 0.050 (0.021, 0.078) (6.4%), 0.049 (0.012, 0.085), (6.3%), 0.065 (0.035, 0.095) (8.3%) compared to no drug treatment, the Memantine monotherapy, and the Donepezil monotherapy respectively. We also identify a significant beneficial additive drug-drug interaction effect between Donepezil and Memantine of 0.064 (0.030, 0.098).
CONCLUSIONS
Based on our findings, adopting combined treatment of Memantine and Donepezil could extend the lives of approximately 303,000 people with AD living in the USA to be beyond five-years from diagnosis. If these patients instead have no drug treatment, Memantine monotherapy or Donepezil monotherapy they would be expected to die within five years.
PubMed: 38783011
DOI: 10.1038/s43856-024-00527-6 -
Hypertension Research : Official... May 2024
PubMed: 38773336
DOI: 10.1038/s41440-024-01726-3 -
ACS Omega May 2024Crocetin is a promising phyto-based molecule to treat Alzheimer's disease (AD). The chemical structure of crocetin is incongruent with various standard structural...
Crocetin is a promising phyto-based molecule to treat Alzheimer's disease (AD). The chemical structure of crocetin is incongruent with various standard structural features of CNS drugs. As poor pharmacokinetic behavior is the major hurdle for any candidate to become a drug, we elucidated its druggable characteristics by implementing in silico, in vitro, and in vivo approaches, as limited ADME/PK information is available. Results demonstrate several attributes of crocetin based on rules of drug-likeness, lipophilicity, p, P-gp inhibitory activity, plasma stability, RBC partitioning, metabolic stability, CYP inhibitory action, blood-brain barrier (BBB) permeability, oral bioavailability, and pharmacokinetic interaction with marketed anti-Alzheimer's drugs (memantine, donepezil, galantamine, and rivastigmine). However, aqueous solubility, chemical stability, plasma protein binding, and P-gp induction are some concerns associated with this molecule that should be taken into consideration during its further development. Overall results indicate favorable ADME/PK behavior and potential druggable candidature of crocetin.
PubMed: 38764638
DOI: 10.1021/acsomega.4c02116