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The Journal of Clinical Psychiatry Jul 2023Delusions and hallucinations are common in Alzheimer disease (AD) and Parkinson disease (PD), especially in the later stages of illness. Antipsychotic drugs are... (Meta-Analysis)
Meta-Analysis
Delusions and hallucinations are common in Alzheimer disease (AD) and Parkinson disease (PD), especially in the later stages of illness. Antipsychotic drugs are effective in treating these psychotic symptoms but are associated with an increased risk of serious adverse events, including mortality. There is therefore a need to explore other treatment approaches. In this context, a recent individual patient data meta-analysis of 17 randomized controlled trials (RCTs) conducted in AD (12 RCTs) and PD (5 RCTs) found that the cholinesterase inhibitor (ChEI) drugs donepezil, rivastigmine, and galantamine attenuated the severity of both delusions and hallucinations in both AD and PD. Most of these trials were 24 weeks in duration. The effect sizes, expressed as standardized mean differences (SMDs), were, however, small, lying in the -0.08 to -0.14 range. These values are so small as to be perhaps clinically insignificant. When analyses were restricted to data from patients who actually had delusions and hallucinations at baseline, all effect sizes became larger, lying in the -0.13 to -0.39 range; however, after correcting for multiple hypothesis testing, only the finding for delusions in PD remained statistically significant. The meta-analysis did not provide information on what the best doses were, how long it took for improvement to become evident, and what proportion of patients showed remission from psychotic symptoms. Whereas the signal identified in this meta-analysis merits examination in appropriately designed RCTs, the findings of the meta-analysis may not much change current treatment strategies because patients with dementia would probably anyway receive a ChEI. Therefore, if psychotic symptoms persist for 24 weeks despite optimally dosed ChEI treatment, and if behavioral and psychosocial interventions do not help, clinicians may need to consider the potential benefits vs risks of other drugs, such as atypical antipsychotics and pimavanserin, in a shared decision-making process.
Topics: Humans; Cholinesterase Inhibitors; Alzheimer Disease; Delusions; Parkinson Disease; Antipsychotic Agents; Hallucinations
PubMed: 37530610
DOI: 10.4088/JCP.23f15009 -
International Journal of Nanomedicine 2023Donepezil (DPL), a specific acetylcholinesterase inhibitor, is used as a first-line treatment to improve cognitive deficits in Alzheimer's disease (AD) and it might have...
INTRODUCTION
Donepezil (DPL), a specific acetylcholinesterase inhibitor, is used as a first-line treatment to improve cognitive deficits in Alzheimer's disease (AD) and it might have a disease modifying effect. Astaxanthin (AST) is a natural potent antioxidant with neuroprotective, anti-amyloidogenic, anti-apoptotic, and anti-inflammatory effects. This study aimed to prepare nanostructured lipid carriers (NLCs) co-loaded with donepezil and astaxanthin (DPL/AST-NLCs) and evaluate their in vivo efficacy in an AD-like rat model 30 days after daily intranasal administration.
METHODS
DPL/AST-NLCs were prepared using a hot high-shear homogenization technique, in vitro examined for their physicochemical parameters and in vivo evaluated. AD induction in rats was performed by aluminum chloride. The cortex and hippocampus were isolated from the brain of rats for biochemical testing and histopathological examination.
RESULTS
DPL/AST-NLCs showed z-average diameter 149.9 ± 3.21 nm, polydispersity index 0.224 ± 0.017, zeta potential -33.7 ± 4.71 mV, entrapment efficiency 81.25 ±1.98% (donepezil) and 93.85 ±1.75% (astaxanthin), in vitro sustained release of both donepezil and astaxanthin for 24 h, spherical morphology by transmission electron microscopy, and they were stable at 4-8 ± 2°C for six months. Differential scanning calorimetry revealed that donepezil and astaxanthin were molecularly dispersed in the NLC matrix in an amorphous state. The DPL/AST-NLC-treated rats showed significantly lower levels of nuclear factor-kappa B, malondialdehyde, β-site amyloid precursor protein cleaving enzyme-1, caspase-3, amyloid beta (Aβ), and acetylcholinesterase, and significantly higher levels of glutathione and acetylcholine in the cortex and hippocampus than the AD-like untreated rats and that treated with donepezil-NLCs. DPL/AST-NLCs showed significantly higher anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, anti-inflammatory, and anti-apoptotic effects, resulting in significant improvement in the cortical and hippocampal histopathology.
CONCLUSION
Nose-to-brain delivery of DPL/AST-NLCs is a promising strategy for the management of AD.
Topics: Rats; Animals; Drug Carriers; Donepezil; Alzheimer Disease; Antioxidants; Amyloid beta-Peptides; Brain; Nanostructures; Lipids; Particle Size
PubMed: 37534058
DOI: 10.2147/IJN.S417928 -
CNS Neuroscience & Therapeutics Mar 2024Accumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors of Alzheimer's disease (AD).... (Review)
Review
BACKGROUND
Accumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors of Alzheimer's disease (AD). However, oligodendrocytes (OLs) were also widely investigated in the pathogenesis and treatment for AD.
AIMS
We aimed to update the regulatory targets of the differentiation and maturation of OLs, and emphasized the key role of OLs in the occurrence and treatment of AD.
METHODS
This review first concluded the targets of OL differentiation and maturation with AD pathogenesis, and then advanced the key role of OLs in the pathogenesis of AD based on both clinic and basic experiments. Later, we extensively discussed the possible application of the current progress in the diagnosis and treatment of this complex disease.
RESULTS
Molecules involving in OLs' differentiation or maturation, including various transcriptional factors, cholesterol homeostasis regulators, and microRNAs could also participate in the pathogenesis of AD. Clinical data point towards the impairment of OLs in AD patients. Basic research further supports the central role of OLs in the regulation of AD pathologies. Additionally, classic drugs, including donepezil, edaravone, fluoxetine, and clemastine demonstrate their potential in remedying OL impairment in AD models, and new therapeutics from the perspective of OLs is constantly being developed.
CONCLUSIONS
We believe that OL dysfunction is one important pathogenesis of AD. Factors regulating OLs might be biomarkers for early diagnosis and agents stimulating OLs warrant the development of anti-AD drugs.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Oligodendroglia
PubMed: 38516808
DOI: 10.1111/cns.14688 -
Molecular Medicine (Cambridge, Mass.) Sep 2023Trastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation,...
BACKGROUND
Trastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases. However, it remains unknown whether donepezil exerts anti-cardiotoxic effects in rats with TIC. We hypothesized that donepezil reduces mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death, leading to improved left ventricular (LV) function in rats with TIC.
METHODS
Male Wistar rats were randomly assigned to be Control or Trz groups (Trz 4 mg/kg/day, 7 days, I.P.). Rats in Trz groups were assigned to be co-treated with either drinking water (Trz group) or donepezil 5 mg/kg/day (Trz + DPZ group) via oral gavage for 7 days. Cardiac function, heart rate variability (HRV), and biochemical parameters were evaluated.
RESULTS
Trz-treated rats had impaired LV function, HRV, mitochondrial function, and increased inflammation and oxidative stress, leading to apoptosis, ferroptosis, and pyroptosis. Donepezil co-treatment effectively decreased those adverse effects of TIC, resulting in improved LV function. An in vitro study revealed that the cytoprotective effects of donepezil were abolished by a muscarinic acetylcholine receptor (mAChR) antagonist.
CONCLUSIONS
Donepezil exerted cardioprotection against TIC via attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, leading to improved LV function through mAChR activation. This suggests that donepezil could be a novel intervention strategy in TIC.
Topics: Male; Animals; Rats; Rats, Wistar; Acetylcholinesterase; Cardiotoxicity; Trastuzumab; Donepezil; Apoptosis; Inflammation
PubMed: 37691124
DOI: 10.1186/s10020-023-00686-7 -
Frontiers in Pharmacology 2024Alois 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... (Review)
Review
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-β (Aβ) 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-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aβ will benefit the majority of subjects with AD that the anti-Aβ 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.
PubMed: 38868666
DOI: 10.3389/fphar.2024.1399121 -
Journal of Cellular Physiology Aug 2023This study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate acetylcholine receptors and are used to...
This study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate acetylcholine receptors and are used to treat Alzheimer's disease (AD), is associated with osteoporosis protection and inhibition of osteoclast differentiation and function. Firstly, we examined the effects of AChEIs on RANKL-induced osteoclast differentiation and function with osteoclastogenesis and bone resorption assays. Next, we investigated the impacts of AChEIs on RANKL-induced nuclear factor κB and NFATc1 activation and expression of osteoclast marker proteins CA-2, CTSK and NFATc1, and dissected the MAPK signaling in osteoclasts in vitro by using luciferase assay and Western blot. Finally, we assessed the in vivo efficacy of AChEIs using an ovariectomy-induced osteoporosis mouse model, which was analyzed using microcomputed tomography, in vivo osteoclast and osteoblast parameters were assessed using histomorphometry. We found that Donepezil and Rivastigmine inhibited RANKL-induced osteoclastogenesis and impaired osteoclastic bone resorption. Moreover, AChEIs reduced the RANKL-induced transcription of Nfatc1, and expression of osteoclast marker genes to varying degrees (mainly Donepezil and Rivastigmine but not Galantamine). Furthermore, AChEIs variably inhibited RANKL-induced MAPK signaling accompanied by downregulation of AChE transcription. Finally, AChEIs protected against OVX-induced bone loss mainly by inhibiting osteoclast activity. Taken together, AChEIs (mainly Donepezil and Rivastigmine) exerted a positive effect on bone protection by inhibiting osteoclast function through MAPK and NFATc1 signaling pathways through downregulating AChE. Our findings have important clinical implications that elderly patients with dementia who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEI drugs. Our study may influence drug choice in those patients with both AD and osteoporosis.
Topics: Mice; Animals; Female; Humans; Osteogenesis; Cholinesterase Inhibitors; Acetylcholinesterase; Rivastigmine; Donepezil; X-Ray Microtomography; Bone Resorption; Osteoclasts; Transcription Factors; NF-kappa B; Osteoporosis; RANK Ligand; NFATC Transcription Factors; Cell Differentiation; Ovariectomy
PubMed: 37334837
DOI: 10.1002/jcp.31057 -
Frontiers in Neurology 2023Alzheimer's disease is one of the most common degenerative diseases of the central nervous system, with progressive cognitive and memory impairment and decreased ability... (Review)
Review
Alzheimer's disease is one of the most common degenerative diseases of the central nervous system, with progressive cognitive and memory impairment and decreased ability of daily life as the cardinal symptoms, influencing the life quality of patients severely. There are currently approximately 46 million people living with Alzheimer's disease worldwide, and the number is expected to triple by 2050, which will pose a huge challenge for healthcare. At present, the Food and Drug Administration of the United States has approved five main drugs for the clinical treatment of Alzheimer's disease, which are cholinesterase inhibitors tacrine, galantamine, capalatine and donepezil, and N-methyl-d-aspartate receptor antagonist memantine, although these drugs have shown good efficacy in clinical trials, the actual clinical effect is less effective due to the existence of blood brain barrier. With the continuous development of ultrasound technology in recent years, focused ultrasound, as a non-invasive treatment technique, may target ultrasound energy to the deep brain for treatment without damaging the surrounding tissue. For the past few years, some studies could use focused ultrasound combined with microvesicles to induce blood brain barrier opening and targeted drug delivery to treat Alzheimer's disease, providing new opportunities for the treatment of Alzheimer's disease. This article reviews the application research and progress of focused ultrasound in the treatment of Alzheimer's disease, in order to provide new directions and ideas for the treatment of Alzheimer's disease.
PubMed: 38187144
DOI: 10.3389/fneur.2023.1323386 -
Brazilian Journal of Microbiology :... Sep 2023Neuroprotection is one of the important protection methods against neuronal cells and tissue damage caused by neurodegenerative diseases such as Alzheimer's,... (Review)
Review
Neuroprotection is one of the important protection methods against neuronal cells and tissue damage caused by neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and multiple sclerosis. Various bioactive compounds produced by medicinal plants can potentially treat central nervous system (CNS) disorders. Apart from these resources, endophytes also produce diverse secondary metabolites capable of protecting the CNS. The bioactive compounds produced by endophytes play essential roles in enhancing the growth factors, antioxidant defence functions, diminishing neuroinflammatory, and apoptotic pathways. The efficacy of compounds produced by endophytic fungi was also evaluated by enzymes, cell lines, and in vivo models. Acetylcholine esterase (AChE) inhibition is frequently used to assess in vitro neuroprotective activity along with cytotoxicity-induced neuronal cell lines. Some of drugs, such as tacrine, donepezil, rivastigmine, galantamine, and other compounds, are generally used as reference standards. Furthermore, clinical trials are required to confirm the role of these natural compounds in neuroprotection efficacy and evaluate their safety profile. This review illustrates the production of various bioactive compounds produced by endophytic fungi and their role in preventing neurodegeneration.
Topics: Humans; Plants, Medicinal; Donepezil; Rivastigmine; Endophytes; Fungi; Central Nervous System Diseases
PubMed: 37165297
DOI: 10.1007/s42770-023-00997-1 -
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 -
Journal of Enzyme Inhibition and... Dec 2023Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The...
Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid-donepezil-rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that was a reversible and selective BChE inhibitor (IC = 0.53 μM), and the docking provided the possible mechanism. Compound also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, was a potential multifunctional lead compound against AD.
Topics: Humans; Aged; Donepezil; Rivastigmine; Alzheimer Disease; Cholinesterase Inhibitors; Neuroprotective Agents; Acetylcholinesterase; Structure-Activity Relationship
PubMed: 37414563
DOI: 10.1080/14756366.2023.2231661