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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 -
Journal of Controlled Release :... Jan 2024The complex etiologies and mechanisms of Alzheimer's disease (AD) underscore the importance for devising multitarget drugs to achieve effective therapy. MicroRNAs...
The complex etiologies and mechanisms of Alzheimer's disease (AD) underscore the importance for devising multitarget drugs to achieve effective therapy. MicroRNAs (miRNAs) are capable of concurrently regulating the expression of multiple proteins by selectively targeting disease- associated genes in a sequence-specific fashion. Nonetheless, as RNA-based drugs, their stability in the circulation and capacity of traversing the blood-brain barrier (BBB) is largely compromised, thereby limiting their potential clinical applications. In this study, we formulated the nanoliposomes encapsulating polyethyleneimine (PEI)/miR-195 complex (DPMT@PEI/miR-195) that was engineered through dual modifications to contain P-aminophenyl-alpha-d-mannopyranoside (MAN) and cationic cell-penetrating peptide (TAT). DPMT@PEI/miR-195 exhibited the enhanced BBB- and cell membrane penetrating capability. As expected, we observed that DPMT@PEI/miR-195 administered through intravenous tail injection of produced greater effectiveness than donepezil and the same range of effect as aducanumab in alleviating the cognitive decline in 7-month-old APP/PS1 mice. Moreover, the combination treatment with DPMT@PEI/miR-195 and donepezil effectively ameliorated the deterioration of cognition in 16-month-old APP/PS1 mice, with enhanced effects than either DPMT@PEI/miR-195 or donepezil alone. Furthermore, DPMT@PEI/miR-195 effectively attenuated the positive signals of Aβ, AT8, and CD68 in APP/PS1 mice without notable side effects. Our findings indicate DPMT@PEI/miR-195 as a promising potentially new agent or approach for the prophylaxis and treatment of early and advanced stages of Alzheimer's disease.
Topics: Humans; Mice; Animals; Infant; Alzheimer Disease; Liposomes; Amyloid beta-Protein Precursor; Donepezil; Mice, Transgenic; MicroRNAs; Disease Models, Animal; Amyloid beta-Peptides
PubMed: 38048963
DOI: 10.1016/j.jconrel.2023.12.003 -
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 -
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 -
CNS & Neurological Disorders Drug... Nov 2023Two classes of medications are used to treat Alzheimer's disease (AD); donepezil, galantamine, and rivastigmine are acetylcholinesterase inhibitors, and memantine is a...
BACKGROUND
Two classes of medications are used to treat Alzheimer's disease (AD); donepezil, galantamine, and rivastigmine are acetylcholinesterase inhibitors, and memantine is a non-competitive antagonist of the N-methyl-D-aspartate receptor. Although these are typically taken orally, there are transdermal therapeutic systems (TTSs) commercially available for rivastigmine and donepezil. The transdermal route has been preferable for guardians/caregivers due to ease of use, reduced side effects, and improved adherence to therapy.
OBJECTIVE
The study aimed to obtain knowledge of the properties of these drugs and to search for patents relating to the TTS for AD using the Espacenet platform.
METHODS
The search terms were "rivastigmine AND transdermal AND skin delivery AND Alzheimer's", changing the drugs "memantine", "donepezil", and "galantamine", between January 2015 and January 2022. Title and abstract were used to choose patents.
RESULTS
TTSs present some limit factors in terms of absorption due to skin physiology and the size of the molecules with established limits of percutaneous penetration (molecular mass of 500 g/mol and log P of 5). We found 1, 4, 4, and 2 patents for galantamine, rivastigmine, donepezil, and memantine, respectively. Galantamine TTS seems to be more challenging due to the molecular mass of 287.35 g/mol and logP of 1.8. The permeator of absorption is necessary. Memantine, rivastigmine, and donepezil present logP of 3.28, 2.3, and 4.27 and molecular weights of 179.30, 250.34, and 415.96 g/mol, respectively.
CONCLUSION
TTSs are primarily effective for delivering small molecules. The use of absorption enhancers and irritation mitigators can be necessary to enhance the performance. The development of these technologies is essential for the convenience of patients and caregivers.
PubMed: 37990896
DOI: 10.2174/0118715273275957231102044934 -
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 -
Reviews in the Neurosciences Aug 2023Alzheimer's disease (AD) is the most common type of dementia in the elderly and causes neurodegeneration, leading to memory loss, behavioral disorder, and psychiatric... (Review)
Review
Alzheimer's disease (AD) is the most common type of dementia in the elderly and causes neurodegeneration, leading to memory loss, behavioral disorder, and psychiatric impairment. One potential mechanism contributing to the pathogenesis of AD may be the imbalance in gut microbiota, local and systemic inflammation, and dysregulation of the microbiota-gut-brain axis (MGBA). Most of the AD drugs approved for clinical use today are symptomatic treatments that do not improve AD pathologic changes. As a result, researchers are exploring novel therapeutic modalities. Treatments involving the MGBA include antibiotics, probiotics, transplantation of fecal microbiota, botanical products, and others. However, single-treatment modalities are not as effective as expected, and a combination therapy is gaining momentum. The purpose of this review is to summarize recent advances in MGBA-related pathological mechanisms and treatment modalities in AD and to propose a new concept of combination therapy. "MGBA-based multitherapy" is an emerging view of treatment in which classic symptomatic treatments and MGBA-based therapeutic modalities are used in combination. Donepezil and memantine are two commonly used drugs in AD treatment. On the basis of the single/combined use of these two drugs, two/more additional drugs and treatment modalities that target the MGBA are chosen based on the characteristics of the patient's condition as an adjuvant treatment, as well as the maintenance of good lifestyle habits. "MGBA-based multitherapy" offers new insights for the treatment of cognitive impairment in AD patients and is expected to show good therapeutic results.
Topics: Humans; Aged; Alzheimer Disease; Brain-Gut Axis; Brain; Inflammation
PubMed: 37076953
DOI: 10.1515/revneuro-2023-0006