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International Journal of Molecular... Aug 2022Since 1906, when Dr. Alois Alzheimer first described in a patient "a peculiar severe disease process of the cerebral cortex", people suffering from this pathology have... (Review)
Review
Since 1906, when Dr. Alois Alzheimer first described in a patient "a peculiar severe disease process of the cerebral cortex", people suffering from this pathology have been waiting for a breakthrough therapy. Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder and the most common form of dementia in the elderly with a long presymptomatic phase. Worldwide, approximately 50 million people are living with dementia, with AD comprising 60-70% of cases. Pathologically, AD is characterized by the deposition of amyloid β-peptide (Aβ) in the neuropil (neuritic plaques) and blood vessels (amyloid angiopathy), and by the accumulation of hyperphosphorylated tau in neurons (neurofibrillary tangles) in the brain, with associated loss of synapses and neurons, together with glial activation, and neuroinflammation, resulting in cognitive deficits and eventually dementia. The current competitive landscape in AD consists of symptomatic treatments, of which there are currently six approved medications: three AChEIs (donepezil, rivastigmine, and galantamine), one NMDA-R antagonist (memantine), one combination therapy (memantine/donepezil), and GV-971 (sodium oligomannate, a mixture of oligosaccharides derived from algae) only approved in China. Improvements to the approved therapies, such as easier routes of administration and reduced dosing frequencies, along with the developments of new strategies and combined treatments are expected to occur within the next decade and will positively impact the way the disease is managed. Recently, Aducanumab, the first disease-modifying therapy (DMT) has been approved for AD, and several DMTs are in advanced stages of clinical development or regulatory review. Small molecules, mAbs, or multimodal strategies showing promise in animal studies have not confirmed that promise in the clinic (where small to moderate changes in clinical efficacy have been observed), and therefore, there is a significant unmet need for a better understanding of the AD pathogenesis and the exploration of alternative etiologies and therapeutic effective disease-modifying therapies strategies for AD. Therefore, a critical review of the disease-modifying therapy pipeline for Alzheimer's disease is needed.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Donepezil; Humans; Memantine; Patient-Centered Care; Polypharmacology
PubMed: 36012569
DOI: 10.3390/ijms23169305 -
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 -
The Cochrane Database of Systematic... Nov 2022Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of... (Review)
Review
BACKGROUND
Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 12, 2014.
OBJECTIVES
To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adults treated with cranial irradiation.
SEARCH METHODS
For this review update we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and PsycInfo via Ovid to 12 September 2022.
SELECTION CRITERIA
We included randomised controlled (RCTs) trials that evaluated pharmacological or non-pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure.
DATA COLLECTION AND ANALYSIS
Two review authors (MK, JD) independently extracted data from selected studies and carried out a risk of bias assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled.
MAIN RESULTS
Eight studies met the inclusion criteria and were included in this updated review. Six were from the original version of the review, and two more were added when the search was updated. Nineteen further studies were assessed as part of this update but did not fulfil the inclusion criteria. Of the eight included studies, four studies investigated "prevention" of cognitive problems (during radiotherapy and follow-up) and four studies investigated "amelioration" (interventions to treat cognitive impairment as a late complication of radiotherapy). There were five pharmacological studies (two studies on prevention and three in amelioration) and three non-pharmacological studies (two on prevention and one in amelioration). Due to differences between studies in the interventions being evaluated, a meta-analysis was not possible. Studies in early radiotherapy treatment phase (five studies) Pharmacological studies in the "early radiotherapy treatment phase" were designed to prevent or ameliorate cognitive deficits and included drugs used in dementia (memantine) and fatigue (d-threo-methylphenidate hydrochloride). Non-pharmacological studies in the "early radiotherapy treatment phase" included a ketogenic diet and a two-week cognitive rehabilitation and problem-solving programme. In the memantine study, the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The d-threo-methylphenidate hydrochloride study found no statistically significant difference between arms, with few adverse events. The study of a calorie-restricted ketogenic diet found no effect, although a lower than expected calorie intake in the control group complicates interpretation of the results. The study investigating the utility of a rehabilitation program did not carry out a statistical comparison of cognitive performance between groups. Studies in delayed radiation or late effect phase (four studies) The "amelioration" pharmacological studies to treat cognitive complications of radiotherapy included drugs used in dementia (donepezil) or psychostimulants (methylphenidate and modafinil). Non-pharmacological measures included cognitive rehabilitation and problem solving (Goal Management Training). These studies included patients with cognitive problems at entry who had "stable" brain cancer. The donepezil study did not find an improvement in the primary cognitive outcome of overall cognitive performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. A study comparing methylphenidate with modafinil found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. Another study comparing two different doses of modafinil combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The Goal Management Training study suggested a benefit of the intervention, a behavioural intervention that combined mindfulness and strategy training, on executive function and processing speed. There were a number of limitations across studies and few were without high risks of bias.
AUTHORS' CONCLUSIONS
In this update, limited additional evidence was found for the treatment or amelioration of cognitive deficits in adults treated with cranial irradiation. As concluded in the original review, there is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil, methylphenidate and modafinil may have a role in treating cognitive deficits in adults with brain tumours who have been treated with cranial irradiation; patient withdrawal affected the statistical power of these studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher certainty of evidence. There is evidence from only a single small study to support non-pharmacological interventions in the amelioration of cognitive deficits. Further research is required.
Topics: Adult; Humans; Modafinil; Donepezil; Memantine; Quality of Life; Cognitive Dysfunction; Cranial Irradiation; Cognition; Methylphenidate; Brain Neoplasms; Fatigue; Dementia
PubMed: 36427235
DOI: 10.1002/14651858.CD011335.pub3 -
Molecular Brain Jul 2022The cholinesterase inhibitor donepezil is used to improve Aβ pathology and cognitive function in patients with Alzheimer's disease (AD). However, the impact of...
The cholinesterase inhibitor donepezil is used to improve Aβ pathology and cognitive function in patients with Alzheimer's disease (AD). However, the impact of donepezil on tau pathology is unclear. Thus, we examined the effects of donepezil on Aβ and tau pathology in 5xFAD mice (a model of AD) in this study. We found that intraperitoneal injection of donepezil (1 mg/kg, i.p.) exhibited significant reductions in Aβ plaque number in the cortex and hippocampal DG region. In addition, donepezil treatment (1 mg/kg, i.p.) reduced Aβ-mediated microglial and, to a lesser extent, astrocytic activation in 5xFAD mice. However, neither intraperitoneal/oral injection of donepezil nor oral injection of rivastigmine altered tau phosphorylation at Thr212/Ser214 (AT100), Thr396, and Thr231 in 5xFAD mice. Surprisingly, we observed that intraperitoneal/oral injection of donepezil treatment significantly increased tau phosphorylation at Thr212 in 5xFAD mice. Taken together, these data suggest that intraperitoneal injection of donepezil suppresses Aβ pathology but not tau pathology in 5xFAD mice.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Donepezil; Mice; Mice, Transgenic; Plaque, Amyloid
PubMed: 35850693
DOI: 10.1186/s13041-022-00948-1 -
Frontiers in Cardiovascular Medicine 2021The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been...
The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated. The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated. Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation. Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.
PubMed: 33791350
DOI: 10.3389/fcvm.2021.639541 -
Biomedicine & Pharmacotherapy =... Jul 2021Alzheimer's disease (AD), is the most common type of dementia primarily affecting the later years of life. Its prevalence is likely to increase in any aging population... (Review)
Review
Alzheimer's disease (AD), is the most common type of dementia primarily affecting the later years of life. Its prevalence is likely to increase in any aging population and will be a major burden on healthcare system by the mid of the century. Despite scientific and technological breakthroughs in the last 50 years, that have expanded our understanding of the disease on a system, cellular and molecular level, therapies that could stop or slow the progression of the disease are still unavailable. The Food and Drug Administration (FDA), has approved acetylcholinesterase (AChE) inhibitors (donepezil, galantamine, tacrine and rivastigmine) and glutamate receptor antagonist (memantine) for the treatment of AD. In this review we summarize the studies reporting phytocompounds and extracts from medicinal plants that show AChE inhibitory activities and could be of potential benefit in AD. Future research directions are suggested and recommendations made to expand the use of medicinal plants and their formulations to prevent, mitigate and treat AD.
Topics: Alzheimer Disease; Animals; Biological Products; Cholinesterase Inhibitors; Humans; Structure-Activity Relationship
PubMed: 33915501
DOI: 10.1016/j.biopha.2021.111609 -
Drug Design, Development and Therapy 2022Chronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess...
PURPOSE
Chronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess antioxidant and anti-inflammatory properties believed to be contributory factors in reversing cognitive decline. 6-Methoxyflavone (6-MOF), a flavonoid occurring naturally in medicinal plants, has been reported to instigate neuroprotection by reversing cisplatin-induced hyperalgesia and allodynia. Consequently, this study was designed to investigate 6-MOF activity in models of chronic ethanol-induced cognitive impairment along with neurochemical correlates.
METHODS
Mice were given ethanol orally (2.0 g/kg daily) for 24 days plus either saline, 6-MOF (25-75mg/kg) or donepezil (4mg/kg) and then ethanol was withdrawn for the next 6 days. Animals were subsequently assessed for their cognitive performance in several models on days 1, 12, and 24, during abstinence (Day-26) and on the 7th day of the washout period. Following behavioral assessment, post-mortem dopamine, noradrenaline and vitamin C concentrations were quantified in the frontal cortex, hippocampus and striatum, using HPLC with UV detection.
RESULTS
Chronic ethanol treatment suppressed locomotor activity and impaired cognitive tasks, which included novel object recognition, performance in the Morris water maze as well as the Y-maze, socialization and nest-building behavior throughout the protocol and during withdrawal. These behavioral deficits were at least partially restored by the co-administration of 6-MOF or donepezil with ethanol as were ethanol-induced deficits in frontal cortical and hippocampal dopamine plus noradrenaline, together with striatal dopamine. 6-MOF co-administration with ethanol also modestly restored striatal vitamin C levels.
CONCLUSION
It is postulated that, apart from donepezil, 6-MOF may be useful not only in the treatment of ethanol withdrawal severity but also in the management of chronic ethanol withdrawal induced cognitive impairment.
Topics: Animals; Ascorbic Acid; Cognitive Dysfunction; Donepezil; Dopamine; Ethanol; Flavones; Hippocampus; Maze Learning; Mice; Norepinephrine
PubMed: 35665194
DOI: 10.2147/DDDT.S360677 -
Brain Sciences Feb 2021Alzheimer's disease (AD) is a burgeoning social and healthcare problem. Cholinesterase inhibitors (ChEIs) are employed for symptomatic treatment of AD, but often elicit...
Alzheimer's disease (AD) is a burgeoning social and healthcare problem. Cholinesterase inhibitors (ChEIs) are employed for symptomatic treatment of AD, but often elicit adverse drug reactions (ADRs). Herein, the potency of the ChEIs, donepezil, tacrine, berberine, and galantamine to inhibit human or acetylcholinesterase (AChE) proteins were evaluated. The efficacy of dual-drug combinations to inhibit human AChE directly and within differentiated neurons was also quantified. ChEI potency was in the order: donepezil > tacrine > berberine > galantamine for both AChEs. Dual-drug combinations of berberine and tacrine (BerTac), berberine and galantamine (BerGal), and tacrine and donepezil (TacDon) all produced synergistic outcomes for AChE inhibition. Donepezil and berberine (DonBer) and tacrine and galantamine (TacGal) elicited antagonistic responses. Donepezil and galantamine (DonGal) was synergistic for human AChE but antagonistic for AChE. After application of dual-drug combinations to neuronal cells, BerTac, BerGal, DonGal, and DonBer all showed synergistic inhibition of AChE, TacDon additive, and TacGal antagonistic effects. BerGal produced the most potent synergism and reduced total drug dose by 72%. Individual ChEIs or dual-drug combinations were relatively non-toxic to neuronal cells, and only reduced cell viability at concentrations two-three orders of magnitude greater than that required to inhibit AChE. In summary, dual-drug combinations of ChEIs potentially represent a novel means of AD patient treatment, with reduced and more cost-effective drug dosing, and lowered likelihood of ADRs.
PubMed: 33540879
DOI: 10.3390/brainsci11020184 -
Pharmacology Research & Perspectives Dec 2021Cardiovascular complications in Alzheimer's disease (AD) patients can occur years to decades prior to the onset of clinical symptoms of the disease. Donepezil represents...
Cardiovascular complications in Alzheimer's disease (AD) patients can occur years to decades prior to the onset of clinical symptoms of the disease. Donepezil represents the most effective drug in the treatment of AD. However, the potential effect of donepezil on vascular function and structure remains largely unexplored. Here, we assessed the impact of donepezil on the vascular phenotype of an established model of accelerated senescence that develops spontaneously AD, the SAMP8 mouse. Three groups of animals were included: SAMR1 (control strain), SAMP8, and SAMP8 treated with donepezil. Treatment with donepezil was administered from the 4th to the 6th month of life. At 6 months, after cognitive tests by Morris Water Maze, animals were euthanized, and their mesenteric arteries were processed for functional experiments. Untreated SAMP8 developed cognitive impairment compared to SAMR1, while donepezil treatment significantly attenuated cognitive dysfunction. SAMP8 exhibited a higher media-to-lumen ratio than SAMR1 and donepezil-treated animals. Endothelial function was impaired in SAMP8 animals compared to SAMR1. The addition of vitamin C improved the vasodilatory response to acetylcholine in SAMP8. Treatment with donepezil improved endothelial function in SAMP8 animals and reduced the additional vasodilation induced by vitamin C. In conclusion, in the SAMP8 AD model, cognitive impairment is associated with endothelial dysfunction and vascular remodeling which could contribute to cardiovascular events in AD since the prodromal phases of the disease. Treatment with donepezil alleviates vascular dysfunction associated with AD through an increase in NO availability likely by counteracting inflammation and oxidative stress.
Topics: Acetylcholine; Alzheimer Disease; Animals; Cardiovascular Diseases; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Models, Animal; Donepezil; Inflammation; Maze Learning; Mice; Nitric Oxide; Oxidative Stress; Vascular Remodeling; Vasodilation
PubMed: 34713597
DOI: 10.1002/prp2.871 -
Frontiers in Neuroscience 2023This study compared different extraction methods of Yizhiqingxin formula (YQF) and its neuroprotective effects based on pharmacodynamic indices such as learning and...
OBJECTIVES
This study compared different extraction methods of Yizhiqingxin formula (YQF) and its neuroprotective effects based on pharmacodynamic indices such as learning and memory ability, brain tissue histopathology and morphology, and inflammatory factor expression in a mouse model of Alzheimer's disease (AD).
METHODS
The pharmaceutical components of YQF were extracted using three extraction processes, and the components were analyzed by high performance liquid chromatography. Donepezil hydrochloride was used as a positive control drug. Fifty 7-8-month-old 3 × Tg AD mice were randomly divided into three YQF groups (YQF-1, YQF-2, and YQF-3), a donepezil group, and a model group. Ten age-matched C57/BL6 mice were used as normal controls. YQF and Donepezil were administered by gavage at a clinically equivalent dose of 2.6 and 1.3 mg⋅kg⋅d, respectively, with a gavage volume of 0.1 ml/10 g. Control and model groups received equal volumes of distilled water by gavage. After 2 months, the efficacy was evaluated using behavioral experiments, histopathology, immunohistochemistry, and serum assays.
RESULTS
The main components in YQF are ginsenoside Re, ginsenoside Rg1, ginsenoside Rb1, epiberberine, coptisine chloride, palmatine, berberine, and ferulic acid. YQF-3 (alcohol extraction) has the highest content of active compounds, followed by YQF-2 (water extraction and alcohol precipitation method). Compared to the model group, the three YQF groups showed alleviated histopathological changes and improved spatial learning and memory, with the effect in YQF-2 being the most significant. YQF showed protection of hippocampal neurons, most significantly in the YQF-1 group. YQF significantly reduced Aβ pathology and tau hyperphosphorylation, decreased expressions of serum pro-inflammatory factors interleukin-2 and interleukin-6 as well as serum chemokines MCP-1 and MIG.
CONCLUSION
YQF prepared by three different processes showed differences in pharmacodynamics in an AD mouse model. YQF-2 was significantly better than the other extraction processes in improving memory.
PubMed: 36875667
DOI: 10.3389/fnins.2023.1097859