Displaying publications 21 - 40 of 62 in total

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  1. A molecular approach in drug development for Alzheimer's disease
    Agatonovic-Kustrin S, Kettle C, Morton DW
    Biomed Pharmacother, 2018 Oct;106:553-565.
    PMID: 29990843 DOI: 10.1016/j.biopha.2018.06.147
    An increase in dementia numbers and global trends in population aging across the world prompts the need for new medications to treat the complex biological dysfunctions, such as neurodegeneration associated with dementia. Alzheimer's disease (AD) is the most common form of dementia. Cholinergic signaling, which is important in cognition, is slowly lost in AD, so the first line therapy is to treat symptoms with acetylcholinesterase inhibitors to increase levels of acetylcholine. Out of five available FDA-approved AD medications, donepezil, galantamine and rivastigmine are cholinesterase inhibitors while memantine, a N-methyl d-aspartate (NMDA) receptor antagonist, blocks the effects of high glutamate levels. The fifth medication consists of a combination of donepezil and memantine. Although these medications can reduce and temporarily slow down the symptoms of AD, they cannot stop the damage to the brain from progressing. For a superior therapeutic effect, multi-target drugs are required. Thus, a Multi-Target-Directed Ligand (MTDL) strategy has received more attention by scientists who are attempting to develop hybrid molecules that simultaneously modulate multiple biological targets. This review highlights recent examples of the MTDL approach and fragment based strategy in the rational design of new potential AD medications.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  2. Synthesis of furocoumarin-stilbene hybrids as potential multifunctional drugs against multiple biochemical targets associated with Alzheimer's disease
    Agbo EN, Gildenhuys S, Choong YS, Mphahlele MJ, More GK
    Bioorg Chem, 2020 08;101:103997.
    PMID: 32554280 DOI: 10.1016/j.bioorg.2020.103997
    A series of furocoumarin-stilbene hybrids has been synthesized and evaluated in vitro for inhibitory effect against acetylcholinesterase (AChE), butyrylcholinestarase (BChE), β-secretase, cyclooxygenase-2 (COX-2), and lipoxygenase-5 (LOX-5) activities including free radical-scavenging properties. Among these hybrids, 8-(3,5-dimethoxyphenyl)-4-(3,5-dimethoxystyryl)furochromen-2-one 4h exhibited significant anticholinesterase activity and inhibitory effect against β-secretase, COX-2 and LOX-5 activities. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and an in vitro cell-based antioxidant activity assay involving lipopolysaccharide induced reactive oxygen species production revealed that 4h has capability of scavenging free radicals. Molecular docking into AChE, BChE, β-secretase, COX-2 and LOX-5 active sites has also been performed.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  3. Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-β peptide in Alzheimer's disease
    Rosini M, Simoni E, Caporaso R, Basagni F, Catanzaro M, Abu IF, et al.
    Eur J Med Chem, 2019 Oct 15;180:111-120.
    PMID: 31301562 DOI: 10.1016/j.ejmech.2019.07.011
    N-methyl-d-aspartate receptors (NMDAR) are critically involved in the pathogenesis of Alzheimer's disease (AD). Acting as an open-channel blocker, the anti-AD drug memantine preferentially targets NMDAR overactivation, which has been proposed to trigger neurotoxic events mediated by amyloid β peptide (Aβ) and oxidative stress. In this study, we applied a multifunctional approach by conjugating memantine to ferulic acid, which is known to protect the brain from Aβ neurotoxicity and neuronal death caused by ROS. The most interesting compound (7) behaved, like memantine, as a voltage-dependent antagonist of NMDAR (IC50 = 6.9 μM). In addition, at 10 μM concentration, 7 exerted antioxidant properties both directly and indirectly through the activation of the Nrf-2 pathway in SH-SY5Y cells. At the same concentration, differently from the parent compounds memantine and ferulic acid alone, it was able to modulate Aβ production, as revealed by the observed increase of the non-amyloidogenic sAPPα in H4-SW cells. These findings suggest that compound 7 may represent a promising tool for investigating NMDAR-mediated neurotoxic events involving Aβ burden and oxidative damage.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  4. Substituted spiro [2.3'] oxindolespiro [3.2″]-5,6-dimethoxy-indane-1″-one-pyrrolidine analogue as inhibitors of acetylcholinesterase
    Ali MA, Ismail R, Choon TS, Yoon YK, Wei AC, Pandian S, et al.
    Bioorg Med Chem Lett, 2010 Dec 1;20(23):7064-6.
    PMID: 20951037 DOI: 10.1016/j.bmcl.2010.09.108
    Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors. Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. Compound 4k, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.10 μmol/L. Pyrolidine analogues might be potential acetyl cholinesterase agents for AD.
    Matched MeSH terms: Alzheimer Disease/drug therapy
  5. Designing of promising medicinal scaffolds for Alzheimer's disease through enzyme inhibition, lead optimization, molecular docking and dynamic simulation approaches
    Hassan M, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Shahzadi S, Raza H, et al.
    Bioorg Chem, 2019 10;91:103138.
    PMID: 31446329 DOI: 10.1016/j.bioorg.2019.103138
    In the designed research work, a series of 2-furoyl piperazine based sulfonamide derivatives were synthesized as therapeutic agents to target the Alzheimer's disease. The structures of the newly synthesized compounds were characterized through spectral analysis and their inhibitory potential was evaluated against butyrylcholinesterase (BChE). The cytotoxicity of these sulfonamides was also ascertained through hemolysis of bovine red blood cells. Furthermore, compounds were inspected by Lipinki Rule and their binding profiles against BChE were discerned by molecular docking. The protein fluctuations in docking complexes were recognized by dynamic simulation. From our in vitro and in silico results 5c, 5j and 5k were identified as promising lead compounds for the treatment of targeted disease.
    Matched MeSH terms: Alzheimer Disease/drug therapy
  6. Fulltext Comparative Effects of Alpha- and Gamma-Tocopherol on Mitochondrial Functions in Alzheimer's Disease In Vitro Model
    Pahrudin Arrozi A, Shukri SNS, Wan Ngah WZ, Mohd Yusof YA, Ahmad Damanhuri MH, Jaafar F, et al.
    Sci Rep, 2020 06 02;10(1):8962.
    PMID: 32488024 DOI: 10.1038/s41598-020-65570-4
    Vitamin E acts as an antioxidant and reduces the level of reactive oxygen species (ROS) in Alzheimer's disease (AD). Alpha-tocopherol (ATF) is the most widely studied form of vitamin E besides gamma-tocopherol (GTF) which also shows beneficial effects in AD. The levels of amyloid-beta (Aβ) and amyloid precursor protein (APP) increased in the brains of AD patients, and mutations in the APP gene are known to enhance the production of Aβ. Mitochondrial function was shown to be affected by the increased level of Aβ and may induce cell death. Here, we aimed to compare the effects of ATF and GTF on their ability to reduce Aβ level, modulate mitochondrial function and reduce the apoptosis marker in SH-SY5Y cells stably transfected with the wild-type or mutant form of the APP gene. The Aβ level was measured by ELISA, the mitochondrial ROS and ATP level were quantified by fluorescence and luciferase assay respectively whereas the complex V enzyme activity was measured by spectrophotometry. The expressions of genes involved in the regulation of mitochondrial membrane permeability such as voltage dependent anion channel (VDAC1), adenine nucleotide translocase (ANT), and cyclophilin D (CYPD) were determined by quantitative real-time polymerase chain reaction (qRT-PCR), while the expressions of cyclophilin D (CypD), cytochrome c, Bcl2 associated X (BAX), B cell lymphoma-2 (Bcl-2), and pro-caspase-3 were determined by western blot. Our results showed that mitochondrial ROS level was elevated accompanied by decreased ATP level and complex V enzyme activity in SH-SY5Y cells expressing the mutant APP gene (p 
    Matched MeSH terms: Alzheimer Disease/drug therapy
  7. Pharmacological approaches for Alzheimer's disease: neurotransmitter as drug targets
    Prakash A, Kalra J, Mani V, Ramasamy K, Majeed AB
    Expert Rev Neurother, 2015 Jan;15(1):53-71.
    PMID: 25495260 DOI: 10.1586/14737175.2015.988709
    Alzheimer's disease (AD) is the most common CNS disorder occurring worldwide. There is neither proven effective prevention for AD nor a cure for patients with this disorder. Hence, there is an urgent need to develop safer and more efficacious drugs to help combat the tremendous increase in disease progression. The present review is an attempt at discussing the treatment strategies and drugs under clinical trials governing the modulation of neurotransmitter. Therefore, looking at neurotransmitter abnormalities, there is an urge for developing the pharmacological approaches aimed at correcting those abnormalities and dysfunctioning. In addition, this review also discusses the drugs that are in Phase III trials for the treatment of AD. Despite advances in treatment strategies aimed at correcting neurotransmitter abnormalities, there exists a need for the development of drug therapies focusing on the attempts to remove the pathogenomic protein deposits, thus combating the disease progression.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  8. Xanthone: Potential Acetylcholinesterase Inhibitor for Alzheimer's Disease Treatment
    Vanessa VV, Mah SH
    Mini Rev Med Chem, 2021;21(17):2507-2529.
    PMID: 33583373 DOI: 10.2174/1389557521666210212152514
    Alzheimer's disease is a neurodegenerative disorder that results in progressive and irreversible central nervous system impairment, which has become one of the severe issues recently. The most successful approach of Alzheimer's treatment is the administration of cholinesterase inhibitors to prevent the hydrolysis of acetylcholine and subsequently improve cholinergic postsynaptic transmission. This review highlights a class of heterocycles, namely xanthone, and its remarkable acetylcholinesterase inhibitory activities. Naturally occurring xanthones, including oxygenated, prenylated, pyrano, and glycosylated xanthones, exhibited promising inhibition effects towards acetylcholinesterase. Interestingly, synthetic xanthone derivatives with complex substituents such as alkyl, pyrrolidine, piperidine, and morpholine have shown greater acetylcholinesterase inhibition activities. The structure-activity relationship of xanthones revealed that the type and position of the substituent(s) attached to the xanthone moiety influenced acetylcholinesterase inhibition activities where hydrophobic moiety will lead to an improved activity by contributing to the π-π interactions, as well as the hydroxy substituent(s) by forming hydrogen-bond interactions. Thus, further studies, including quantitative structure-activity relationship, in vivo and clinical validation studies are crucial for the development of xanthones into novel anti-Alzheimer's disease drugs.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  9. Fulltext γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase
    Gertsik N, Chau DM, Li YM
    ACS Chem. Biol., 2015 Aug 21;10(8):1925-31.
    PMID: 26030233 DOI: 10.1021/acschembio.5b00321
    γ-Secretase inhibitors (GSIs) and modulators (GSMs) are at the frontline of cancer and Alzheimer's disease research, respectively. While both are therapeutically promising, not much is known about their interactions with proteins other than γ-secretase. Signal peptide peptidase (SPP), like γ-secretase, is a multispan transmembrane aspartyl protease that catalyzes regulated intramembrane proteolysis. We used active site-directed photophore walking probes to study the effects of different GSIs and GSMs on the active sites of γ-secretase and SPP and found that nontransition state GSIs inhibit labeling of γ-secretase by activity-based probes but enhance labeling of SPP. The opposite is true of GSMs, which have little effect on the labeling of γ-secretase but diminish labeling of SPP. These results demonstrate that GSIs and GSMs are altering the structure of not only γ-secretase but also SPP, leading to potential changes in enzyme activity and specificity that may impact the clinical outcomes of these molecules.
    Matched MeSH terms: Alzheimer Disease/drug therapy
  10. Receptor-Interacting Protein Kinase 1 (RIPK1) as a Potential Therapeutic Target: An Overview of Its Possible Role in the Pathogenesis of Alzheimer's Disease
    Chan HH, Koh RY, Lim CL, Leong CO
    Curr Alzheimer Res, 2019;16(10):907-918.
    PMID: 31642777 DOI: 10.2174/1567205016666191023102422
    Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder, the most common type of dementia that is clinically characterized by the presence of beta-amyloid (Aβ) extracellularly and intraneuronal tau protein tangles that eventually leads to the onset of memory and cognition impairment, development of psychiatric symptoms and behavioral disorders that affect basic daily activities. Current treatment approved by the U.S Food and Drug Administration (FDA) for AD is mainly focused on the symptoms but not on the pathogenesis of the disease. Recently, receptor-interacting protein kinase 1 (RIPK1) has been identified as a key component in the pathogenesis of AD through necroptosis. Furthermore, genetic and pharmacological suppression of RIPK1 has been shown to revert the phenotype of AD and its mediating pathway is yet to be deciphered. This review is aimed to provide an overview of the pathogenesis and current treatment of AD with the involvement of autophagy as well as providing a novel insight into RIPK1 in reverting the progression of AD, probably through an autophagy machinery.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  11. Fulltext Mechanistic role of boswellic acids in Alzheimer's disease: Emphasis on anti-inflammatory properties
    Siddiqui A, Shah Z, Jahan RN, Othman I, Kumari Y
    Biomed Pharmacother, 2021 Dec;144:112250.
    PMID: 34607104 DOI: 10.1016/j.biopha.2021.112250
    The resin/gum of Boswellia species belonging to the family of Burseraceae is a naturally occurring mixture of bioactive compounds, which was traditionally used as a folk medicine to treat conditions like chronic inflammation. Several research studies have also explored its' therapeutic potential against multiple neurodegenerative diseases such as Alzheimer's disease (AD). The main chemical constituents of this gum include boswellic acids (BAs) like 3-O-acetyl-11-keto-β boswellic acid (AKBA) that possess potent anti-inflammatory and neuroprotective properties in AD. It is also involved in inhibiting the acetylcholinesterase (AChE) activity in the cholinergic pathway and improve choline levels as well as its binding with nicotinic receptors to produce anti-inflammatory effects. Multiple shreds of evidence have demonstrated that BAs modulate key molecular targets and signalling pathways like 5-lipoxygenase/cyclooxygenase, Nrf2, NF-kB, cholinergic, amyloid-beta (Aβ), and neurofibrillary tangles formation (NFTs) that are involved in AD progression. The present review focuses on the possible mechanistic therapeutic role of BAs in modulating the 5-LOX/COX pathway in arachidonic acid metabolism, activating Nrf2 through binding of ARE, inhibiting NF-kB and AChE activity. In addition, an inhibition of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) induced neurotoxicity and neuroinflammation in AD by BAs is also discussed in this review. We have also highlighted that BAs possess beneficial effects in AD by targeting multiple molecular pathways and makes it an emerging drug candidate for treating neurodegenerative diseases.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  12. Fulltext Potential of Naturally Derived Alkaloids as Multi-Targeted Therapeutic Agents for Neurodegenerative Diseases
    Kong YR, Tay KC, Su YX, Wong CK, Tan WN, Khaw KY
    Molecules, 2021 Jan 30;26(3).
    PMID: 33573300 DOI: 10.3390/molecules26030728
    Alkaloids are a class of secondary metabolites that can be derived from plants, fungi and marine sponges. They are widely known as a continuous source of medicine for the management of chronic disease including cancer, diabetes and neurodegenerative diseases. For example, galanthamine and huperzine A are alkaloid derivatives currently being used for the symptomatic management of neurodegenerative disease. The etiology of neurodegenerative diseases is polygenic and multifactorial including but not limited to inflammation, oxidative stress and protein aggregation. Therefore, natural-product-based alkaloids with polypharmacology modulation properties are potentially useful for further drug development or, to a lesser extent, as nutraceuticals to manage neurodegeneration. This review aims to discuss and summarise recent developments in relation to naturally derived alkaloids for neurodegenerative diseases.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  13. Probing the anti-Aβ42 aggregation and protective effects of prenylated xanthone against Aβ42-induced toxicity in transgenic Caenorhabditis elegans model
    Thew HY, Boon Keat K, Tan YC, Ong YS, Parat MO, Murugaiyah V, et al.
    Chem Biol Interact, 2024 May 01;394:110978.
    PMID: 38552766 DOI: 10.1016/j.cbi.2024.110978
    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) protein aggregates, leading to synaptic dysfunction and neuronal cell death. In this study, we used a comprehensive approach encompassing in vitro assays, computational analyses, and an in vivo Caenorhabditis elegans model to evaluate the inhibitory effects of various xanthones, focusing on Garcinone D (GD), on Aβ42 oligomer formation. Dot blot analysis revealed concentration-dependent responses among xanthones, with GD consistently inhibiting Aβ42 oligomer formation at low concentrations (0.1 and 0.5 μM, inhibitions of 84.66 ± 2.25% and 85.06 ± 6.57%, respectively). Molecular docking and dynamics simulations provided insights into the molecular interactions between xanthones and Aβ42, highlighting the disruption of key residues involved in Aβ42 aggregation. The neuroprotective potential of GD was established using transgenic C. elegans GMC101, with substantial delays in paralysis reported at higher concentrations. Our findings show that GD is a potent suppressor of Aβ42 oligomer formation, suggesting its potential as a therapeutic candidate for AD. The concentration-dependent effects observed in both in vitro and in vivo models underscore the need for nuanced dose-response assessments. These findings contribute novel insights into the therapeutic landscape of xanthones against AD, emphasizing the multifaceted potential of GD for further translational endeavors in neurodegenerative disorder research.
    Matched MeSH terms: Alzheimer Disease/drug therapy
  14. Deoxyelephantopin ameliorates lipopolysaccharides (LPS)-induced memory impairments in rats: Evidence for its anti-neuroinflammatory properties
    Andy SN, Pandy V, Alias Z, Kadir HA
    Life Sci, 2018 Aug 01;206:45-60.
    PMID: 29792878 DOI: 10.1016/j.lfs.2018.05.035
    AIM: Neuroinflammation is a critical pathogenic mechanism of most neurodegenerative disorders especially, Alzheimer's disease (AD). Lipopolysaccharides (LPS) are known to induce neuroinflammation which is evident from significant upsurge of pro-inflammatory mediators in in vitro BV-2 microglial cells and in vivo animal models. In present study, we investigated anti-neuroinflammatory properties of deoxyelephantopin (DET) isolated from Elephantopus scaber in LPS-induced neuroinflammatory rat model.

    MATERIALS AND METHODS: In this study, DET (0.625. 1.25 and 2.5 mg/kg, i.p.) was administered in rats for 21 days and those animals were challenged with single injection of LPS (250 μg/kg, i.p.) for 7 days. Cognitive and behavioral assessment was carried out for 7 days followed by molecular assessment on brain hippocampus. Statistical significance was analyzed with one-way analysis of variance followed by Dunnett's test to compare the treatment groups with the control group.

    KEY FINDINGS: DET ameliorated LPS-induced neuroinflammation by suppressing major pro-inflammatory mediators such as iNOS and COX-2. Furthermore, DET enhanced the anti-inflammatory cytokines and concomitantly suppressed the pro-inflammatory cytokines and chemokine production. DET treatment also reversed LPS-induced behavioral and memory deficits and attenuated LPS-induced elevation of the expression of AD markers. DET improved synaptic-functionality via enhancing the activity of pre- and post-synaptic markers, like PSD-95 and SYP. DET also prevented LPS-induced apoptotic neurodegeneration via inhibition of PARP-1, caspase-3 and cleaved caspase-3.

    SIGNIFICANCE: Overall, our studies suggest DET can prevent neuroinflammation-associated memory impairment and neurodegeneration and it could be developed as a therapeutic agent for the treatment of neuroinflammation-mediated and neurodegenerative disorders, such as AD.

    Matched MeSH terms: Alzheimer Disease/drug therapy
  15. Synthetic Curcumin Analogs as Inhibitors of β -Amyloid Peptide Aggregation: Potential Therapeutic and Diagnostic Agents for Alzheimer's Disease
    Bukhari SN, Jantan I
    Mini Rev Med Chem, 2015;15(13):1110-21.
    PMID: 26420724
    There is a crucial need to develop new effective drugs for Alzheimer's disease (AD) as the currently available AD treatments provide only momentary and incomplete symptomatic relief. Amongst natural products, curcumin, a major constituent of turmeric, has been intensively investigated for its neuroprotective effect against β-amyloid (Aβ)-induced toxicity in cultured neuronal cells. The ability of curcumin to attach to Aβ peptide and prevent its accumulation is attributed to its three structural characteristics such as the presence of two aromatic end groups and their co-planarity, the length and rigidity of the linker region and the substitution conformation of these aromatics. However, curcumin failed to reach adequate brain levels after oral absorption in AD clinical trials due to its low water solubility and poor oral bioavailability. A number of new curcumin analogs that mimic the active site of the compound along with analogs that mimic the curcumin anti-amyloid effect combined with anticholinesterase effect have been developed to enhance the bioavailability, pharmacokinetics, water solubility, stability at physiological conditions and delivery of curcumin. In this article, we have summarized all reported synthetic analogs of curcumin showing effects on β-amyloid and discussed their potential as therapeutic and diagnostic agents for AD.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  16. Treatment of dementia with herbs: a short review
    Tang CT, Belani LK, Das S, Jaafar MZ
    Clin Ter, 2013;164(1):43-6.
    PMID: 23455743 DOI: 10.7417/T.2013.1511
    Dementia is a common symptom observed in many psychiatric and neurodegenerative diseases. Alzheimer's disease is the most common form of senile dementia seen in the general population. Multiple factors like oxidative stress, apoptosis, mitochondrial dysfunction and inflammation may be related to the neurodegenerative states. Many drugs like cholinesterase have been used for treatment but the progression of the disease still poses a challenge to the clinician. During recent times, herbs have gained much popularity as supplements because of the cost effectiveness, easy availability and fewer side effects. Early diagnosis and proper treatment may help in the prevention of mortality and morbidity concerned with any neurodegenerative disease. Understanding the cellular and molecular biology of the mode of the action of herbal products may be beneficial for researchers and clinicians. The present review article attempts to look into the potential herbal extracts which may act as an antioxidant in combating dementia.
    Matched MeSH terms: Alzheimer Disease/drug therapy
  17. Fulltext Formulation and evaluation of galantamine gel as drug reservoir in transdermal patch delivery system
    Fong Yen W, Basri M, Ahmad M, Ismail M
    ScientificWorldJournal, 2015;2015:495271.
    PMID: 25853145 DOI: 10.1155/2015/495271
    Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer's disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  18. Melatonin and Sleep Disturbances in Alzheimer's Disease
    Prodhan AHMSU, Cavestro C, Kamal MA, Islam MA
    CNS Neurol Disord Drug Targets, 2021;20(8):736-754.
    PMID: 34348635 DOI: 10.2174/1871527320666210804155617
    Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by sleep, behavioral, memory, and cognitive deteriorations. Sleep disturbance (SD) is a major disease burden in AD, which has a reciprocal relationship with AD pathophysiology. It aggravates memory, behavioral, and cognitive complications in AD. Different studies have found that melatonin hormone levels reduce even in the pre-clinical stages of AD. Melatonin is the primary sleep-regulating hormone and a potent antioxidant with neuroprotective roles. The decrease in melatonin levels can thus promote SD and AD neuropathology. Exogenous melatonin has the potential to alleviate neuropathology and SD in AD by different mechanisms. Various studies have been conducted to assess the efficacy of exogenous melatonin to treat SD in AD. Though most of the studies suggest that melatonin is useful to ameliorate SD in AD, the remaining studies show opposite results. The timing, dosage, and duration of melatonin administration along with disease condition, genetic, environmental, and some other factors can be responsible for the discrepancies between the studies. More extensive trials with longer durations and higher dosage forms and studies including bright light therapy and melatonin agonists (ramelteon, agomelatine, and tasimelteon) should be performed to determine the efficacy of melatonin to treat SD in AD.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  19. Activation of Nrf2 signaling by sitagliptin and quercetin combination against β-amyloid induced Alzheimer's disease in rats
    Li Y, Tian Q, Li Z, Dang M, Lin Y, Hou X
    Drug Dev Res, 2019 09;80(6):837-845.
    PMID: 31301179 DOI: 10.1002/ddr.21567
    The objective of this study was to evaluate the neuroprotective effect of sitagliptin (Sita), quercetin (QCR) and its combination in β-amyloid (Aβ) induced Alzheimer's disease (AD). Male Sprague-Dawley rats, weighing between 220 and 280 g were used for experiment. Rats were divided into 5 groups (n = 10) and the groups were as follows: (a) Sham control; (b) Aβ injected; (c) Aβ injected + Sita 100; (d) Aβ injected + QCR 100; and (e) Aβ injected + Sita 100 + QCR 100. Cognitive performance was observed by the Morris water maze (MWM), biochemical markers, for example, MDA, SOD, CAT, GSH, Aβ1-42 level, Nrf2/HO-1 expression and histopathological study of rat brain were estimated. Pretreatment with Sita, QCR and their combination showed a significant increase in escape latency in particular MWM cognitive model. Further co-administration of sita and QCR significantly reduced Aβ1-42 level when compared with individual treatment. Biochemical markers, for example, increased SOD, CAT and GSH, decreased MDA were seen, and histopathological studies revealed the reversal of neuronal damage in the treatment group. Additionally, Nrf2/HO-1 pathway in rat's brain was significantly increased by Sita, QCR and their combination. Pretreatment with QCR potentiates the action of Sita in Aβ induced AD in rats. The improved cognitive memory could be because of the synergistic effect of the drugs by decreasing Aβ1-42 level, antioxidant activity and increased expression of Nrf2/HO-1 in rat brain.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
  20. Fulltext Embelin Improves the Spatial Memory and Hippocampal Long-Term Potentiation in a Rat Model of Chronic Cerebral Hypoperfusion
    Bhuvanendran S, Bakar SNS, Kumari Y, Othman I, Shaikh MF, Hassan Z
    Sci Rep, 2019 10 10;9(1):14507.
    PMID: 31601902 DOI: 10.1038/s41598-019-50954-y
    Alzheimer's disease (AD) is the second most occurring neurological disorder after stroke and is associated with cerebral hypoperfusion, possibly contributing to cognitive impairment. In the present study, neuroprotective and anti-AD effects of embelin were evaluated in chronic cerebral hypoperfusion (CCH) rat model using permanent bilateral common carotid artery occlusion (BCCAO) method. Rats were administered with embelin at doses of 0.3, 0.6 or 1.2 mg/kg (i.p) on day 14 post-surgery and tested in Morris water maze (MWM) followed by electrophysiological recordings to access cognitive abilities and synaptic plasticity. The hippocampal brain regions were extracted for gene expression and neurotransmitters analysis. Treatment with embelin at the doses of 0.3 and 0.6 mg/kg significantly reversed the spatial memory impairment induced by CCH in rats. Embelin treatment has significantly protected synaptic plasticity impairment as assessed by hippocampal long-term potentiation (LTP) test. The mechanism of this study demonstrated that embelin treatment alleviated the decreased expression of BDNF, CREB1, APP, Mapt, SOD1 and NFκB mRNA levels caused by CCH rats. Furthermore, treatment with embelin demonstrated neuromodulatory activity by its ability to restore hippocampal neurotransmitters. Overall these data suggest that embelin improve memory and synaptic plasticity impairment in CCH rats and can be a potential drug candidate for neurodegenerative disease-related cognitive disorders.
    Matched MeSH terms: Alzheimer Disease/drug therapy*
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