Displaying publications 1 - 20 of 92 in total

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  1. Fulltext Fibrillary deposits: amyloids and tactoids
    Looi LM
    Malays J Pathol, 1995 Jun;17(1):1-10.
    PMID: 8906998
    Two forms of abnormal fibrillary protein deposition are considered: amyloidosis and fibrillary (immunotactoid) glomerulonephritis. Amyloid is characterised by an antiparallel, beta-pleated configuration which imparts to it a unique apple-green birefringence after Congo red staining. Inspite of its fairly constant physical properties, the chemical composition of amyloid fibrils is amazingly diverse, encomposing AA protein, light chain fragments, transthyretin, procalcitonin, islet amyloid polypeptide, atrial natriuretic peptides, beta-amyloid protein, beta-2-microglobulin, cystatin C, gelsolin, apolipoprotein A1, lyzozyme and their mutant variants. Amyloid P component and heparan sulphate proteoglycan are ubiquitous non-fibrillary amyloid components which have significant roles in the amyloidogenetic process, as do also precursor fibril proteins. Different amyloid fibril proteins relate to different amyloidosis syndromes and different histological patterns, and provide the basis for new diagnostic approaches to this disorder. Glomerular deposits in fibrillary glomerulonephritis (FGN), although often mistaken for amyloid, differ from it in its negative Congophilia, wider fibril width and highly organised, microtubular-tactoidal appearance ultrastructurally. FGN is essentially a primary glomerulopathy resulting in progressive renal failure. Despite certain differences, intriguing similarities between both entities of fibrillary deposition pose a challenge to researchers as to the mechanisms of abnormal protein crystallization and fibril formation in tissues.
    Matched MeSH terms: Amyloid beta-Peptides/chemistry
  2. Effects of macrophage colony-stimulating factor on microglial responses to lipopolysaccharide and beta amyloid
    Vidyadaran S, Ooi YY, Subramaiam H, Badiei A, Abdullah M, Ramasamy R, et al.
    Cell Immunol, 2009;259(1):105-10.
    PMID: 19577228 DOI: 10.1016/j.cellimm.2009.06.005
    A challenge for studies involving microglia cultures is obtaining sufficient cells for downstream experiments. Macrophage colony-stimulating factor (M-CSF) has been used to improve yield of microglia in culture. However, the effects of M-CSF on activation profiles of microglia cultures are still unclear. Microglia activation is characterised by upregulation of co-stimulatory molecules and an inflammatory phenotype. The aim of this study is to demonstrate whether M-CSF supplementation alters microglial responses in resting and activated conditions. Microglia derived from mixed glia cultures and the BV-2 microglia cell line were cultivated with/without M-CSF and activated with lipopolysaccharide (LPS) and beta amyloid (Abeta). We show M-CSF expands primary microglia without affecting microglial responses to LPS and Abeta, as shown by the comparable expression of MHC class II and CD40 to microglia grown without this growth factor. M-CSF supplementation in BV-2 cells had no effect on nitric oxide (NO) production. Therefore, M-CSF can be considered for improving microglia yield in culture without introducing activation artefacts.
    Matched MeSH terms: Amyloid beta-Peptides/pharmacology*
  3. Drug trapping and delivery for Alzheimer's diagnosis
    Jalil MA, Kamoldilok S, Saktioto T, Ong CT, Yupapin PP
    Artif Cells Blood Substit Immobil Biotechnol, 2012 Oct;40(5):303-8.
    PMID: 22384850 DOI: 10.3109/10731199.2012.657203
    In this investigation, a new design based on a PANDA ring resonator as an optical trapping tool for tangle protein, molecular motor storage, and delivery is proposed. The optical vortices are generated and the trapping mechanism is controlled in the same way as the conventional optical tweezers. The trapping force is produced by a combination of the gradient field and scattering photons. The required molecular volume is trapped and moved dynamically within the molecular network. The tangle protein and molecular motor can be transported and delivered to the required destinations for Alzheimer's diagnosis by molecular buffer and bus network.
    Matched MeSH terms: Amyloid beta-Peptides/metabolism*; Amyloid beta-Peptides/chemistry
  4. Neurorestorative effect of FTY720 in a rat model of Alzheimer's disease: comparison with memantine
    Hemmati F, Dargahi L, Nasoohi S, Omidbakhsh R, Mohamed Z, Chik Z, et al.
    Behav Brain Res, 2013 Sep 1;252:415-21.
    PMID: 23777795 DOI: 10.1016/j.bbr.2013.06.016
    Alzheimer's disease (AD) as a neurodegenerative brain disorder is the most common cause of dementia. To date, there is no causative treatment for AD and there are few preventive treatments either. The sphingosine-1-phosphate receptor modulator FTY720 (fingolimod) prevents lymphocytes from contributing to an autoimmune reaction and has been approved for multiple sclerosis treatment. In concert with other studies showing the anti-inflammatory and protective effect of FTY720 in some neurodegenerative disorders like ischemia, we have recently shown that FTY720 chronic administration prevents from impairment of spatial learning and memory in AD rats. Here FTY720 was examined on AD rats in comparison to the only clinically approved NMDA receptor antagonist, Memantine. Passive avoidance task showed significant memory restoration in AD animals received FTY720 comparable to Memantine. Upon gene profiling by QuantiGene Plex, this behavioral outcomes was concurrent with considerable alterations in some genes transcripts like that of mitogen activated protein kinases (MAPKs) and some inflammatory markers that may particularly account for the detected decline in hippocampal neural damage or memory impairment associated with AD. From a therapeutic standpoint, our findings conclude that FTY720 may suggest new opportunities for AD management probably based on several modulatory effects on genes involved in cell death or survival.
    Matched MeSH terms: Amyloid beta-Peptides/toxicity
  5. Thymoquinone prevents β-amyloid neurotoxicity in primary cultured cerebellar granule neurons
    Ismail N, Ismail M, Mazlan M, Latiff LA, Imam MU, Iqbal S, et al.
    Cell Mol Neurobiol, 2013 Nov;33(8):1159-69.
    PMID: 24101432 DOI: 10.1007/s10571-013-9982-z
    Thymoquinone (TQ), a bioactive constituent of Nigella sativa Linn (N. sativa) has demonstrated several neuropharmacological attributes. In the present study, the neuroprotective properties of TQ were investigated by studying its anti-apoptotic potential to diminish β-amyloid peptide 1-40 sequence (Aβ1-40)-induced neuronal cell death in primary cultured cerebellar granule neurons (CGNs). The effects of TQ against Aβ1-40-induced neurotoxicity, morphological damages, DNA condensation, the generation of reactive oxygen species, and caspase-3, -8, and -9 activation were investigated. Pretreatment of CGNs with TQ (0.1 and 1 μM) and subsequent exposure to 10 μM Aβ1-40 protected the CGNs against the neurotoxic effects of the latter. In addition, the CGNs were better preserved with intact cell bodies, extensive neurite networks, a loss of condensed chromatin and less free radical generation than those exposed to Aβ1-40 alone. TQ pretreatment inhibited Aβ1-40-induced apoptosis of CGNs via both extrinsic and intrinsic caspase pathways. Thus, the findings of this study suggest that TQ may prevent neurotoxicity and Aβ1-40-induced apoptosis. TQ is, therefore, worth studying further for its potential to reduce the risks of developing Alzheimer's disease.
    Matched MeSH terms: Amyloid beta-Peptides/toxicity*
  6. Activation of sphingosine 1-phosphate receptor-1 by SEW2871 improves cognitive function in Alzheimer's disease model rats
    Asle-Rousta M, Oryan S, Ahmadiani A, Rahnema M
    EXCLI J, 2013;12:449-61.
    PMID: 26417237
    Sphingosine-1 phosphate (S1P) is involved in a variety of cellular processes via activation of S1P receptors (S1PRs; S1PR1 to S1PR5) that are highly expressed in the brain. It has been shown that the level of S1P is reduced in the brain of Alzheimer's disease (AD) patients. However, there is no study designed to evaluate the expression of S1PRs in AD brains. The objectives of the present work are (1) to examine the expression of S1PR1-3 in the hippocampus of beta amyloid (Aβ) 1-42 injected rats and (2) to clarify the effects of chronic S1PR1 activation on S1PR1-3 levels, spatial memory deficit and hippocampal damage in AD rats. SEW2871, the S1PR1 selective agonist, repeatedly was injected intraperitoneally during a period of two weeks. Upon Western Blot data bilateral intrahippocampal injection of Aβ1-42 decreased the expression of S1PR1 while increased S1PR2 level and did not affect that of S1PR3. We found that chronic administration of SEW2871 inhibited the reduction of S1PR1 expression and ameliorated spatial memory impairment in the Morris water maze task in rats. In addition, SEW2871 attenuated the Aβ1-42-induced hippocampal neuronal loss according to Nissl staining findings. Data in the current study highlights the importance of S1PR1 signaling pathway deregulation in AD development and suggests that activation of S1PR1 may represent a potential approach for developing new therapeutics to manage memory deficit and apoptosis associated with neurodegenerative disorders such as AD.
    Matched MeSH terms: Amyloid beta-Peptides
  7. Absence of beta-amyloid deposition in the central nervous system of a transgenic mouse model of distal myopathy with rimmed vacuoles
    Anada RP, Wong KT, Malicdan MC, Goh KJ, Hayashi Y, Nishino I, et al.
    Amyloid, 2014 Jun;21(2):138-9.
    PMID: 24601867 DOI: 10.3109/13506129.2014.889675
    Matched MeSH terms: Amyloid beta-Peptides/metabolism*
  8. Synthesis of α, β-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: characterization, molecular modeling, QSAR studies and effect against amyloid β-induced cytotoxicity
    Bukhari SN, Jantan I, Masand VH, Mahajan DT, Sher M, Naeem-ul-Hassan M, et al.
    Eur J Med Chem, 2014 Aug 18;83:355-65.
    PMID: 24980117 DOI: 10.1016/j.ejmech.2014.06.034
    A series of novel carbonyl compounds was synthesized by a simple, eco-friendly and efficient method. These compounds were screened for anti-oxidant activity, in vitro cytotoxicity and for inhibitory activity for acetylcholinesterase and butyrylcholinesterase. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. Among them, compound 14 exhibited strong free radical scavenging activity (18.39 μM) while six compounds (1, 3, 4, 13, 14, and 19) were found to be the most protective against Aβ-induced neuronal cell death in PC12 cells. Compounds 4 and 14, containing N-methyl-4-piperidone linker, showed high acetylcholinesterase inhibitory activity as compared to reference drug donepezil. Molecular docking and QSAR (Quantitative Structure-Activity Relationship) studies were also carried out to determine the structural features that are responsible for the acetylcholinesterase and butyrylcholinesterase inhibitory activity.
    Matched MeSH terms: Amyloid beta-Peptides/toxicity*
  9. 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: Amyloid beta-Peptides/drug effects*; Amyloid beta-Peptides/metabolism
  10. Neuroprotective effect from stem bark extracts of Knema laurina against H₂O₂- and Aβ(1-42)-induced cell death in human SH-SY5Y cells
    Ismail N, Akhtar MN, Ismail M, Zareen S, Shah SA, Lajis NH, et al.
    Nat Prod Res, 2015;29(16):1571-4.
    PMID: 25471591 DOI: 10.1080/14786419.2014.985676
    The stem bark extracts of Knema laurina inhibited the hydrogen peroxide (H2O2)- and aggregated amyloid β-peptide 1-42 length (Aβ(1-42))-induced cell death in differentiated SH-SY5Y cells. Exposure of 250 μM H2O2 or 20 μM Aβ(1-42) to the cells for 24 h reduced 50% of cell viability. Pretreatment of cells with ethyl acetate extract (EAE) or n-butanol extract (BE) at 300 μg/mL and then exposure to H2O2 protected the cells against the neurotoxic effects of H2O2. Besides, methanolic extract (ME) at 1 and 10 μg/mL exerted neuroprotective effect on Aβ(1-42)-induced toxicity to the cells. These results showed that EAE, BE and ME exhibited neuroprotective activities against H2O2- and Aβ(1-42)-induced cell death. Flavonoids (3-6) and β-sitosterol glucoside (8) were isolated from the EAE. Compound 1 was isolated from hexane extract, and compounds 2 and 7 were isolated from dichloromethane extract. All these observations provide the possible evidence for contribution in the neuroprotective effects.
    Matched MeSH terms: Amyloid beta-Peptides/adverse effects
  11. 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: Amyloid beta-Peptides/metabolism*; Amyloid beta-Peptides/ultrastructure
  12. Fulltext Germinated Brown Rice Alters Aβ(1-42) Aggregation and Modulates Alzheimer's Disease-Related Genes in Differentiated Human SH-SY5Y Cells
    Azmi NH, Ismail M, Ismail N, Imam MU, Alitheen NB, Abdullah MA
    Evid Based Complement Alternat Med, 2015;2015:153684.
    PMID: 26858770 DOI: 10.1155/2015/153684
    The pathogenesis of Alzheimer's disease involves complex etiological factors, of which the deposition of beta-amyloid (Aβ) protein and oxidative stress have been strongly implicated. We explored the effects of H2O2, which is a precursor for highly reactive hydroxyl radicals, on neurotoxicity and genes related to AD on neuronal cells. Candidate bioactive compounds responsible for the effects were quantified using HPLC-DAD. Additionally, the effects of germinated brown rice (GBR) on the morphology of Aβ(1-42) were assessed by Transmission Electron Microscopy and its regulatory effects on gene expressions were explored. The results showed that GBR extract had several phenolic compounds and γ-oryzanol and altered the structure of Aβ(1-42) suggesting an antiamyloidogenic effect. GBR was also able to attenuate the oxidative effects of H2O2 as implied by reduced LDH release and intracellular ROS generation. Furthermore, gene expression analyses showed that the neuroprotective effects of GBR were partly mediated through transcriptional regulation of multiple genes including Presenilins, APP, BACE1, BACE2, ADAM10, Neprilysin, and LRP1. Our findings showed that GBR exhibited neuroprotective properties via transcriptional regulation of APP metabolism with potential impact on Aβ aggregation. These findings can have important implications for the management of neurodegenerative diseases like AD and are worth exploring further.
    Matched MeSH terms: Amyloid beta-Peptides
  13. Fulltext Positron Emission Tomographic Imaging in Stroke: Cross-Sectional and Follow-Up Assessment of Amyloid in Ischemic Stroke
    Sahathevan R, Linden T, Villemagne VL, Churilov L, Ly JV, Rowe C, et al.
    Stroke, 2016 Jan;47(1):113-9.
    PMID: 26578658 DOI: 10.1161/STROKEAHA.115.010528
    Cardiovascular risk factors significantly increase the risk of developing Alzheimer disease. A possible mechanism may be via ischemic infarction-driving amyloid deposition. We conducted a study to determine the presence of β-amyloid in infarct, peri-infarct, and hemispheric areas after stroke. We hypothesized that an infarct would trigger β-amyloid deposition, with deposition over time.
    Matched MeSH terms: Amyloid beta-Peptides/metabolism*
  14. Fulltext Neuroprotective Effects of Biochanin A against β-Amyloid-Induced Neurotoxicity in PC12 Cells via a Mitochondrial-Dependent Apoptosis Pathway
    Tan JW, Kim MK
    Molecules, 2016 Apr 25;21(5).
    PMID: 27120593 DOI: 10.3390/molecules21050548
    Alzheimer's disease is considered one of the major neurodegenerative diseases and is characterized by the production of β-amyloid (Aβ) proteins and progressive loss of neurons. Biochanin A, a phytoestrogen compound found mainly in Trifolium pratense, was used in the present study as a potential alternative to estrogen replacement therapy via the investigation of its neuroprotective effects against Aβ25-35-induced toxicity, as well as of its potential mechanisms of action in PC12 cells. Exposure of these cells to the Aβ25-35 protein significantly increased cell viability loss and apoptosis. However, the effects induced by Aβ25-35 were markedly reversed in the present of biochanin A. Pretreatment with biochanin A attenuated the cytotoxic effect of the Aβ25-35 protein by decreasing viability loss, LDH release, and caspase activity in cells. Moreover, we found that expression of cytochrome c and Puma were reduced, alongside with the restoration of Bcl-2/Bax and Bcl-xL/Bax ratio in the presence of biochanin A, which led to a decrease in the apoptotic rate. These data demonstrate that mitochondria are involved in the protective effect of biochanin A against Aβ25-35 and that this drug attenuated Aβ25-35-induced PC12 cell injury and apoptosis by preventing mitochondrial dysfunction. Thus, biochanin A might raise a possibility as a potential therapeutic agent for Alzheimer's disease and other related neurodegenerative diseases.
    Matched MeSH terms: Amyloid beta-Peptides/toxicity*
  15. Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation
    Zha GF, Zhang CP, Qin HL, Jantan I, Sher M, Amjad MW, et al.
    Bioorg Med Chem, 2016 05 15;24(10):2352-9.
    PMID: 27083471 DOI: 10.1016/j.bmc.2016.04.015
    A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1-42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.
    Matched MeSH terms: Amyloid beta-Peptides/antagonists & inhibitors; Amyloid beta-Peptides/metabolism*
  16. Possible role of metal ionophore against zinc induced cognitive dysfunction in D-galactose senescent mice
    Bharti K, Majeed AB, Prakash A
    Biometals, 2016 Jun;29(3):399-409.
    PMID: 26923568 DOI: 10.1007/s10534-016-9922-8
    Metal ionophores are considered as potential anti-dementia agents, and some are currently undergoing clinical trials. Many metals are known to accumulate and distribute abnormally in the aging brain. Alterations in zinc metal homeostasis in the glutaminergic synapse could contribute to ageing and the pathophysiology of Alzheimer's disease (AD). The present study was designed to investigate the effect of metal ionophores on long term administration of zinc in D-galactose induced senescent mice. The ageing model was established by combined administration of zinc and D-galactose to mice for 6 weeks. A novel metal ionophore, PBT-2 was given daily to zinc-induced d-galactose senescent mice. The cognitive behaviour of mice was monitored using the Morris Water Maze. The anti-oxidant status and amyloidogenic activity in the ageing mouse was measured by determining mito-oxidative parameters and deposition of amyloid β (Aβ) in the brain. Systemic administration of both zinc and D-galactose significantly produced memory deficits, mito-oxidative damage, heightened acetylcholinesterase enzymatic activity and deposition of amyloid-β. Treatment with PBT-2 significantly improved behavioural deficits, biochemical profiles, cellular damage, and curbed the deposition of APP in zinc-induced senescent mice. These findings suggest that PBT-2, acting as a metal protein attenuating compound, may be helpful in the prevention of AD or alleviation of ageing.
    Matched MeSH terms: Amyloid beta-Peptides/antagonists & inhibitors; Amyloid beta-Peptides/chemistry
  17. Enzyme-Mimic Peptide Assembly To Achieve Amidolytic Activity
    Wong YM, Masunaga H, Chuah JA, Sudesh K, Numata K
    Biomacromolecules, 2016 Oct 10;17(10):3375-3385.
    PMID: 27642764
    Amyloid fibers are classified as a new generation of tunable bionanomaterials that exhibit new functions related to their distinctive characteristics, such as their universality, tunability, and stiffness. Here, we introduce the catalytic residues of serine protease into a peptide catalyst (PC) via an enzyme-mimic approach. The rational design of a repeating pattern of polar and nonpolar amino acids favors the conversion of the peptides into amyloid-like fibrils via self-assembly. Distinct fibrous morphologies have been observed at different pH values and temperatures, which indicates that different fibril packing schemes can be designed; hence, fibrillar peptides can be used to generate efficient artificial catalysts for amidolytic activities at mild pH values. The results of atomic force microscopy, Raman spectroscopy, and wide-angle X-ray scattering analyses are used to discuss and compare the fibril structure of a fibrillar PC with its amidolytic activity. The pH of the fibrillation reaction crucially affects the pKa of the side chains of the catalytic triads and is important for stable fibril formation. Temperature is another important parameter that controls the self-assembly of peptides into highly stacked and laminated morphologies. The morphology and stability of fibrils are crucial and represent important factors for demonstrating the capability of the peptides to exert amidolytic activity. The observed amidolytic activity of PC4, one of the PCs, was validated using an inhibition assay, which revealed that PC4 can perform enzyme-like amidolytic catalysis. These results provide insights into the potential use of designed peptides in the generation of efficient artificial enzymes.
    Matched MeSH terms: Amyloid beta-Peptides/ultrastructure; Amyloid beta-Peptides/chemistry*
  18. Modulation of LOX and COX pathways via inhibition of amyloidogenesis contributes to mitoprotection against β-amyloid oligomer-induced toxicity in an animal model of Alzheimer's disease in rats
    Kalra J, Kumar P, Majeed AB, Prakash A
    Pharmacol. Biochem. Behav., 2016 Jul-Aug;146-147:1-12.
    PMID: 27106205 DOI: 10.1016/j.pbb.2016.04.002
    Several lines of evidence indicate that beta amyloid (β-A) production, neurofibrillary tangles and neuroinflammation are interrelated in the pathogenesis of Alzheimer's disease (AD). AD is associated with enhanced β-A production and accumulation resulting in neuroinflammation probably via activation of lipoxygenase (LOX) and cyclooxygenase (COX) pathways. Therefore, the present study was designed to investigate the role of LOX and COX inhibitors (zafirlukast and valdecoxib) in amyloidogenesis in β-A1-42 oligomer induced experimental AD in rats. The behavioral activities were assessed using actophotometer, novel object recognition test (ORT), Morris water maze (MWM) followed by biochemical assessments, determination of proinflammatory cytokines and mediators (TNF-α, IL-1β and PGE2), β-A1-42 levels and histopathological analysis. ICV administration of β-A1-42 oligomer produced significant impairment in memory consolidation. In addition to this significant increase in mito-oxidative stress, neuroinflammatory markers, acetylcholinesterase (AChE) toxicity, β-A1-42 level, neuronal cell death and neuroinflammation are more profound in β-A1-42 oligomer treated AD rats. Administration of zafirlukast (15 and 30mg/kg), and valdecoxib (5 and 10mg/kg) significantly improved the behavioral performances and showed significant reversal of mito-oxidative damage declining the neuroinflammation in β-A1-42 oligomer treated rats. Furthermore, more profound effects were observed at the sub-therapeutic dose combination of zafirlukast (15mg/kg) and valdecoxib (5mg/kg). The results of the present study indicate that protective effects of zafirlukast and valdecoxib are achieved through the blockade of release of LOX and COX metabolites therefore, representing a new therapeutic target for treating AD and other neurodegenerative disorders.
    Matched MeSH terms: Amyloid beta-Peptides/administration & dosage; Amyloid beta-Peptides/metabolism; Amyloid beta-Peptides/toxicity*
  19. Fulltext Drosophila melanogaster: Deciphering Alzheimer's Disease
    Tan FHP, Azzam G
    Malays J Med Sci, 2017 Mar;24(2):6-20.
    PMID: 28894399 MyJurnal DOI: 10.21315/mjms2017.24.2.2
    Alzheimer's disease (AD) is the most widespread neurodegenerative disorder worldwide. Its pathogenesis involves two hallmarks: aggregation of amyloid beta (Aβ) and occurrence of neurofibrillary tangles (NFTs). The mechanism behind the disease is still unknown. This has prompted the use of animal models to mirror the disease. The fruit fly, Drosophila melanogaster has garnered considerable attention as an organism to recapitulate human disorders. With the ability to monopolise a multitude of traditional and novel genetic tools, Drosophila is ideal for studying not only cellular aspects but also physiological and behavioural traits of human neurodegenerative diseases. Here, we discuss the use of the Drosophila model in understanding AD pathology and the insights gained in discovering drug therapies for AD.
    Matched MeSH terms: Amyloid beta-Peptides
  20. Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-β aggregation
    Simoni E, Bartolini M, Abu IF, Blockley A, Gotti C, Bottegoni G, et al.
    Future Med Chem, 2017 06;9(10):953-963.
    PMID: 28632446 DOI: 10.4155/fmc-2017-0039
    AIM: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network.

    METHODS: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways.

    RESULTS: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation.

    CONCLUSION: The compounds emerged as a suitable starting point for a further optimization process.

    Matched MeSH terms: Amyloid beta-Peptides/antagonists & inhibitors*; Amyloid beta-Peptides/metabolism
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