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Zhen Ci Yan Jiu = Acupuncture Research May 2024To 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... (Randomized Controlled Trial)
Randomized Controlled Trial
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 (0.05) and the ADAS-Cog score was lower (0.05) than those before treatment in both groups. Compared with the control group, the MMSE and ADL scores were increased (0.05) and ADAS-Cog score was decreased (0.05) in the observation group. The total effective rate of the observation group (26/30, 86.67%) was higher (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.
Topics: Humans; Donepezil; Alzheimer Disease; Female; Acupuncture Therapy; Male; Aged; Scalp; Acupuncture Points; Abdomen; Middle Aged; Cognition; Treatment Outcome; Piperidines; Combined Modality Therapy; Aged, 80 and over; Indans
PubMed: 38764122
DOI: 10.13702/j.1000-0607.20230220 -
Apoptosis : An International Journal on... May 2024Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive impairment accompanied by aberrant neuronal apoptosis. Reports...
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive impairment accompanied by aberrant neuronal apoptosis. Reports suggest that the pro-apoptotic mammalian set20-like kinase 1/2 (MST1/2) instigates neuronal apoptosis via activating the Hippo signaling pathway under various stress conditions, including AD. However, whether inhibiting MST1/2 has any therapeutic benefits in AD remains unknown. Thus, we tested the therapeutic effects of intervening MST1/2 activation via the pharmacological inhibitor Xmu-mp-1 in a sporadic AD rat model. Sporadic AD was established in adult rats by intracerebroventricular streptozotocin (ICV-STZ) injection (3 mg/kg body weight). Xmu-mp-1 (0.5 mg/kg/body weight) was administered once every 48 h for two weeks, and Donepezil (5 mg/kg body weight) was used as a reference standard drug. The therapeutic effects of Xmu-mp-1 on ICV-STZ rats were determined through various behavioral, biochemical, histopathological, and molecular tests. At the behavioral level, Xmu-mp-1 improved cognitive deficits in sporadic AD rats. Further, Xmu-mp-1 treatment reduced STZ-associated tau phosphorylation, amyloid-beta deposition, oxidative stress, neurotoxicity, neuroinflammation, synaptic dysfunction, neuronal apoptosis, and neurodegeneration. Mechanistically, Xmu-mp-1 exerted these neuroprotective actions by inactivating the Hippo signaling while potentiating the Wnt/β-Catenin signaling in the AD rats. Together, the results of the present study provide compelling support that Xmu-mp-1 negated the neuronal dysregulation in the rat model of sporadic AD. Therefore, inhibiting MST/Hippo signaling and modulating its crosstalk with the Wnt/β-Catenin pathway can be a promising alternative treatment strategy against AD pathology. This is the first study providing novel mechanistic insights into the therapeutic use of Xmu-mp-1 in sporadic AD.
PubMed: 38760516
DOI: 10.1007/s10495-024-01975-0 -
Food and Chemical Toxicology : An... Jul 2024An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into...
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.
Topics: Animals; Donepezil; Doxorubicin; Male; Rats, Wistar; Gastrointestinal Microbiome; Rats; Fatty Acids, Volatile; Dysbiosis; Methylamines; Endotoxins
PubMed: 38759714
DOI: 10.1016/j.fct.2024.114741 -
Journal of Alzheimer's Disease : JAD 2024Early intervention is essential for meaningful disease modification in Alzheimer's disease (AD). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Early intervention is essential for meaningful disease modification in Alzheimer's disease (AD).
OBJECTIVE
We aimed to determine the efficacy and safety of pharmacologic and nutritional interventions for early AD.
METHODS
PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 1 September 2023. We included randomized controlled trials that evaluated the efficacy of interventions in early AD. Only interventions that demonstrated efficacy compared to placebo were included in the network meta-analysis (NMA). Then we performed frequentist fixed-effects NMA to rank the interventions. GRADE criteria were used to evaluate the level of evidence.
RESULTS
Fifty-eight trials including a total of 33,864 participants and 48 interventions were eligible for inclusion. Among the 48 interventions analyzed, only 6 (12.5%) treatments- ranging from low to high certainty- showed significant improvement in cognitive decline compared to placebo. High certainty evidence indicated that donanemab (standardized mean difference [SMD] -0.239, 95% confidence interval [CI] -0.343 to -0.134) and lecanemab (SMD -0.194, 95% CI -0.279 to -0.108) moderately slowed the clinical progression in patients with amyloid pathology. Additionally, methylphenidate, donepezil, LipiDiDiet, and aducanumab with low certainty showed significant improvement in cognitive decline compared to placebo. However, there was no significant difference in serious adverse events as reported between the six interventions and placebo.
CONCLUSIONS
Only 12.5% of interventions studied demonstrated efficacy in reducing cognitive impairment in early AD. Donanemab and lecanemab have the potential to moderately slow the clinical progression in patients with amyloid pathology. Further evidence is required for early intervention in AD.
Topics: Alzheimer Disease; Humans; Randomized Controlled Trials as Topic; Network Meta-Analysis
PubMed: 38759015
DOI: 10.3233/JAD-240161 -
Central Nervous System Agents in... May 2024Alzheimer's disease is a neurodegenerative disorder that affects learning, memory and behavioral turbulence in elderly patients. Acetylcholinesterase (AChE) inhibitors...
BACKGROUND
Alzheimer's disease is a neurodegenerative disorder that affects learning, memory and behavioral turbulence in elderly patients. Acetylcholinesterase (AChE) inhibitors act as anti-Alzheimer's agents. Phenothiazine derivatives are considered momentous anti-Alzheimer's agents because of their AChE inhibitory activity. The elevated levels and increased expression of this protein have been associated with Alzheimer's disease. Coumarin-fused phenothiazines have emerged as significant anti-Alzheimer's agents due to their notable receptor inhibitory activity.
OBJECTIVE
Some unique phenothiazine analogs were designed, and computational studies were conducted to explore their inhibitory activity against the AChE enzyme (PDB id: 4EY7) by using the Schrodinger suite-2019-4.
METHODS
Docking studies were conducted by using the Glide module; binding free energies were calculated by means of the Prime MM-GBSA module, and Molecular dynamics (MD) simulation was performed by using the Desmond module of the Schrodinger suite. Glide scores were used to find out the binding affinity of the ligands with the target 4EY7.
RESULTS
The compounds exhibited enhanced hydrophobic interactions and formed hydrogen bonds, effectively impeding Acetylcholinesterase. The Glide scores for the compounds ranged from -13.4237 to -8.43439, surpassing the standard (Donepezil) with a score of -16.9898. Interestingly, a positive value was obtained for the MM-GBSA binding of the potent inhibitor. To gain insights into the dynamic behavior of the protein A8, molecular dynamics (MD) simulations were employed.
CONCLUSION
Based on the results, the study concludes that phenothiazine derivatives show promise as acetylcholinesterase inhibitors. Compounds with notable Glide scores are poised to exhibit significant anti-Alzheimer's activity, suggesting their potential therapeutic efficacy. Further in vitro and in vivo investigations are warranted to validate and explore the therapeutic potentials of these compounds.
PubMed: 38757327
DOI: 10.2174/0118715249300784240430110628 -
International Immunopharmacology Jun 2024The 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....
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-1β 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-1β 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.
Topics: Male; Animals; Sirtuin 1; Quercetin; Oxidative Stress; Apoptosis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Testis; Donepezil; Valproic Acid; Rats; NF-kappa B; Signal Transduction; Interleukin-1beta; AMP-Activated Protein Kinases; Antioxidants; p38 Mitogen-Activated Protein Kinases; Inflammation; Anti-Inflammatory Agents
PubMed: 38744177
DOI: 10.1016/j.intimp.2024.112240 -
International Journal of Molecular... May 2024Donepezil (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...
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.
Topics: Donepezil; ATP Binding Cassette Transporter, Subfamily G, Member 2; Blood-Brain Barrier; Animals; Humans; Brain; Cholinesterase Inhibitors; Biological Transport; Choroid Plexus; Alzheimer Disease; Mice; Circadian Rhythm; Neoplasm Proteins
PubMed: 38732233
DOI: 10.3390/ijms25095014 -
Cureus Apr 2024Dementia, particularly Alzheimer's disease, affects millions globally, with its prevalence increasing notably with age. Early-onset Alzheimer's disease, however, affects...
Dementia, particularly Alzheimer's disease, affects millions globally, with its prevalence increasing notably with age. Early-onset Alzheimer's disease, however, affects individuals under 65 years old. Unfortunately, diagnosing dementia in patients under 65 years old is quite challenging and is often delayed, missed, or wrong. Thus, we present the case of a 60-year-old female, with a medical history of hypothyroidism and presumed dementia on donepezil, who presented to the emergency department for agitation, dramatic change in personality and behavior, as well as cognitive decline that started in her late 50s. We discuss the importance of performing a thorough history and physical examination, as well as a comprehensive workup for patients who present with dramatic changes in behavior due to the wide range of potential diagnoses. While certain reversible causes, such as hypothyroidism, nutritional deficiencies, and polypharmacy, can be promptly identified and treated, chronic neurocognitive disorders such as Alzheimer's disease demand a timely evaluation for early multidisciplinary treatment to enhance patient outcomes.
PubMed: 38725758
DOI: 10.7759/cureus.57897 -
Molecular Biology Reports May 2024Alzheimer's disease is a leading neurological disorder that gradually impairs memory and cognitive abilities, ultimately leading to the inability to perform even basic...
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.
Topics: Animals; Mice; Alzheimer Disease; Behavior, Animal; Brain; Chromones; Cognition; Cognitive Dysfunction; Crotonates; Disease Models, Animal; Donepezil; Hydroxybutyrates; Maze Learning; Memory; Morpholines; Nitriles; Oxidative Stress; Phosphatidylinositol 3-Kinases; Scopolamine; Toluidines
PubMed: 38722394
DOI: 10.1007/s11033-024-09502-9 -
Journal of Clinical Oncology : Official... May 2024To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years...
Phase III Randomized, Placebo-Controlled Clinical Trial of Donepezil for Treatment of Cognitive Impairment in Breast Cancer Survivors After Adjuvant Chemotherapy (WF-97116).
PURPOSE
To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy.
PATIENTS AND METHODS
Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time.
RESULTS
Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results.
CONCLUSION
BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.
PubMed: 38709986
DOI: 10.1200/JCO.23.01100