Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application

Pharmacology & Therapeutics, Journal Year: 2006, Volume and Issue: 110(2), P. 135 - 370

Published: May 1, 2006

Language: Английский

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Signalling to translation: how signal transduction pathways control the protein synthetic machinery

Biochemical Journal, Journal Year: 2007, Volume and Issue: 403(2), P. 217 - 234

Published: March 26, 2007

Recent advances in our understanding of both the regulation components translational machinery and upstream signalling pathways that modulate them have provided important new insights into mechanisms by which hormones, growth factors, nutrients cellular energy status control protein synthesis mammalian cells. The importance proper mRNA translation is strikingly illustrated fact defects this process or its are implicated a number disease states, such as cancer, tissue hypertrophy neurodegeneration. Signalling those involving mTOR (mammalian target rapamycin) mitogen-activated kinases phosphorylation activities act upon association RNA-binding proteins with specific mRNAs. These effects contribute to overall (which linked cell growth) modulation stability However, questions remain about contributions individual regulatory events general mRNAs controlled.

Language: Английский

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Curcumin-Loaded Nanoparticles Potently Induce Adult Neurogenesis and Reverse Cognitive Deficits in Alzheimer’s Disease Model via Canonical Wnt/β-Catenin Pathway

ACS Nano, Journal Year: 2013, Volume and Issue: 8(1), P. 76 - 103

Published: Dec. 4, 2013

Neurogenesis, a process of generation new neurons, is reported to be reduced in several neurodegenerative disorders including Alzheimer's disease (AD). Induction neurogenesis by targeting endogenous neural stem cells (NSC) could promising therapeutic approach such diseases influencing the brain self-regenerative capacity. Curcumin, neuroprotective agent, has poor bioavailability. Herein, we report that curcumin-encapsulated PLGA nanoparticles (Cur-PLGA-NPs) potently induce NSC proliferation and neuronal differentiation vitro hippocampus subventricular zone adult rats, as compared uncoated bulk curcumin. Cur-PLGA-NPs internalization into hippocampal NSC. significantly increase expression genes involved cell (reelin, nestin, Pax6) (neurogenin, neuroD1, neuregulin, neuroligin, Stat3). Curcumin activating Wnt/β-catenin pathway, regulation neurogenesis. These caused enhanced nuclear translocation β-catenin, decreased GSK-3β levels, increased promoter activity TCF/LEF cyclin-D1. Pharmacological siRNA-mediated genetic inhibition Wnt pathway blocked neurogenesis-stimulating effects reverse learning memory impairments an amyloid beta induced rat model AD-like phenotypes, inducing In silico molecular docking studies suggest curcumin interacts with Wif-1, Dkk, GSK-3β. results through activation canonical may offer treating AD, enhancing self-repair mechanism.

Language: Английский

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Polycomb Limits the Neurogenic Competence of Neural Precursor Cells to Promote Astrogenic Fate Transition

Neuron, Journal Year: 2009, Volume and Issue: 63(5), P. 600 - 613

Published: Sept. 1, 2009

Language: Английский

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Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases

Nature Reviews Drug Discovery, Journal Year: 2007, Volume and Issue: 6(6), P. 464 - 479

Published: June 1, 2007

Aggregation of hyperphosphorylated tau is involved in neurodegeneration Alzheimer's disease and other disorders. The authors discuss the progress design selective kinase inhibitors that suppress hyperphosphorylation as a therapeutic strategy for neurodegenerative tauopathies. one characteristic neuropathological lesions Pharmacological modulation might represent valid feasible such Here, we consider recent evidence supporting validity three most relevant kinases affecting — GSK3β, CDK5 ERK2 drug targets describe these kinases.

Language: Английский

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IFN-γ Suppresses IL-10 Production and Synergizes with TLR2 by Regulating GSK3 and CREB/AP-1 Proteins

Immunity, Journal Year: 2006, Volume and Issue: 24(5), P. 563 - 574

Published: May 1, 2006

Language: Английский

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Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs

Neuropsychopharmacology, Journal Year: 2005, Volume and Issue: 30(7), P. 1223 - 1237

Published: April 13, 2005

Language: Английский

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Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

Journal of Clinical Investigation, Journal Year: 2012, Volume and Issue: 123(1), P. 224 - 235

Published: Dec. 3, 2012

Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is pathological hallmark Alzheimer’s disease (AD). Aβ generated from sequential cleavages β-amyloid precursor (APP) by β- and γ-secretases, β-site APP-cleaving enzyme 1 (BACE1) β-secretase essential for generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role APP processing modulating γ-secretase activity, thereby facilitating production. There are two highly conserved isoforms GSK3: GSK3α GSK3β. We now report specific inhibition GSK3β, but not GSK3α, reduced BACE1-mediated cleavage production decreasing BACE1 gene transcription expression. The regulation expression GSK3β was dependent on NF-κB signaling. Inhibition GSK3 signaling markedly deposition plaque formation, rescued memory deficits double transgenic AD model mice. These data provide evidence pathogenesis can reduce neuropathology alleviate Our study suggests interventions specifically target β-isoform be safe effective approach treating AD.

Language: Английский

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Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi

BMC Genomics, Journal Year: 2005, Volume and Issue: 6(1)

Published: Sept. 15, 2005

Abstract Background The trypanosomatids Leishmania major , Trypanosoma brucei and cruzi cause some of the most debilitating diseases humankind: cutaneous leishmaniasis, African sleeping sickness, Chagas disease. These protozoa possess complex life cycles that involve development in mammalian insect hosts, a tightly coordinated cell cycle ensures propagation highly polarized cells. However, ways which parasites respond to their environment coordinate intracellular processes are poorly understood. As part an effort understand parasite signaling functions, we report results genome-wide analysis protein kinases (PKs) these three trypanosomatids. Results Bioinformatic searches trypanosomatid genomes for eukaryotic PKs (ePKs) atypical (aPKs) revealed total 176 T. 190 199 L. orthologous across species. This is approximately 30% number human host double malaria parasite, Plasmodium falciparum . representation various groups ePKs differs significantly as compared humans: lack receptor-linked tyrosine kinase-like kinases, although they do dual-specificity kinases. A relative expansion CMGC, STE NEK has occurred. large unique show no strong affinity any known group. few with predicted transmembrane domains, suggesting receptor rare. Accessory Pfam frequently present ePKs, uncommon ePKs. Conclusion Trypanosomatids set PKs, comprising 2% each genome, key role phosphorylation biology. Whilst it was possible place into seven established using bioinformatic analyses, not been ascribe function based solely on sequence similarity. Hence connection stimuli networks remains enigmatic. presence numerous significant similarity drug targets, well unusual might represent novel strongly argue functional molecules.

Language: Английский

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The Roles of Cyclin-dependent Kinase 5 and Glycogen Synthase Kinase 3 in Tau Hyperphosphorylation

Journal of Biological Chemistry, Journal Year: 2006, Volume and Issue: 281(35), P. 25457 - 25465

Published: June 28, 2006

Hyperphosphorylation of the microtubule-associated protein tau is a characteristic feature neurodegenerative tauopathies including Alzheimer disease. Over-activation proline-directed kinases, such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase 3 (GSK3), has been implicated in aberrant phosphorylation at sites. In this study we tested roles Cdk5 GSK3 hyperphosphorylation vivo using transgenic mice with p25-induced over-activation. We found that over-activation young animals does not induce sites recognized by antibodies AT8, AT100, PHF-1, TG3. fact, observed leads to inhibition GSK3. However, old lost results increased activity, which coincides AT8 PHF-1 Pharmacological chronic treatment lithium reduction age-dependent increase hyperphosphorylation. Furthermore, Cdk5, GSK3, PP2A co-immunoprecipitate, suggesting functional association these molecules. Together, reveal role key mediator hyperphosphorylation, whereas acts modulator via inhibitory regulation findings suggest disruption activity underlies tauopathies. Hence, may be prime target for therapeutic intervention Neurodegenerative tauopathies, disease (AD), 3The abbreviations used are: AD, disease; APP, amyloid precursor protein; 5; ERK, extracellular signal-regulated kinase; GSK-3, 3; IP, immunoprecipitation; JNK, c-Jun N-terminal MAPK, mitogen-activated MEK, MAPK/ERK PP1, phosphatase 1; PP2A, 2A; TBS, Tris-buffered saline; TG, transgenic; WT, wild-type; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid. are characterized abnormal serine/threonine (1Lee V.M.Y. Goedert M. Trojanowski J.Q. Annu. Rev. Neurosci. 2001; 24: 1121-1159Crossref PubMed Scopus (2162) Google Scholar). Amongst main aberrantly hyperphosphorylated on pathological phosphosites Ser-202/Thr-205 (AT8 site), Ser-214 and/or Ser-212 (AT100 Thr-231 Ser-235 (TG3 Ser-396/Ser-404 (PHF-1 site) Scholar, 2Drechsel D.N. Hyman A.A. Cobb M.H. Kirschner M.W. Mol. Biol. Cell. 1992; 3: 1141-1154Crossref (774) 3Buee L. Bussiere T. Buee-Scherrer V. Delacourte A. Hof P.R. Brain. Res. 2000; 33: 95-130Crossref (1574) A well function assembly stabilization microtubules Tau binds directly promotes microtubule polymerization (2Drechsel Increasing its dissociation from turn destabilization (4Bramblett G.T. Jakes R. Merrick S.E. Lee Neuron. 1993; 10: 1089-1099Abstract Full Text PDF (765) 5Biernat J. Guske N. Drewes G. Mandelkow E.M. E. 11: 153-163Abstract (651) The interaction also plays an important microtubule-dependent axonal transport (6Stamer K. Vogel Thies Cell 2002; 156: 1051-1063Crossref (752) 7Mandelkow Trinczek B. Biernat 2004; 167: 99-110Crossref (221) recent proposed deficient early stages pathogenesis AD (8Stokin G.B. Lillo C. Falzone T.L. Brusch R.G. Rockenstein Mount S.L. Raman Davies P. Masliah Williams D.S. Goldstein L.S.B. Science. 2005; 307: 1282-1288Crossref (981) Precise probably normal cellular functions; believed disrupt processes transport. it still established what physiological importance individual is. state balanced antagonistic activity. Thus, numerous kinases phosphatases have (for review, see Ref. identified candidates mediating disease-associated (9Hanger D.P. Hughes Woodgett J.R. Brion J.P. Anderton B.H. Lett. 147: 58-62Crossref (657) 10Ishiguro Takamatsu Tomizawa Omori Takahashi Arioka Uchida Imahori Chem. 267: 10897-10901Abstract 11Mandelkow Gustke Van Lint Vandenheede FEBS 314: 315-321Crossref (483) 12Paudel H.K. Lew Ali Z. Wang J.H. 268: 23512-23518Abstract co-localizes filamentous deposits several (Refs. 13Liu F. Su Y. Li Zhou Ryder Gonzalez-DeWhitt May P.C. Ni 2003; 547: 193-196Crossref (92) 14Nakamura S. Kawamoto Nakano Ikemoto Akiguchi I. Kimura Neurology. 1997; 48: 267-270Crossref (48) 15Patrick G.N. Zukerberg Nikolic de la Monte Dikkes Tsai L.H. Nature. 1999; 402: 615-622Crossref (1323) Scholar; 16Shelton S.B. Johnson G.V.W. Neurochem. 88: 1313-1326Crossref (131) generates phospho-epitopes (17Nishimura Yang Lu 116: 671-682Abstract (278) Scholar) aggregates (18Ishizawa Sahara Ishiguro Kersh McGowan Lewis Hutton Dickson D.W. Yen S.H. Am. Pathol. 163: 1057-1067Abstract (89) Based this, much research effort focused development specific inhibitors potential treatments Refs. 19Lau L.F. Seymour P.A. Sanner M.A. Schachter J.B. 19: 267-273Crossref (53) Scholar 20Cohen Nat. Drug Discov. 479-487Crossref (677) fully established, remains determine critical factors leading present (TG) mouse line expressing low levels activator p25 (21Angelo Plattner Irvine E.E. Giese K.P. Eur. 18: 423-431Crossref (80) analyze impact assessed characteristically TG3, Surprisingly, find activation affect TG mice. This cross-talk correlated finding associated complex. lost, significantly increased. observe sites, accords enhanced Consistently, pharmacological Our shows first time can indirectly establishes inappropriate Animals—Heterozygous wild-type (WT) control littermates C57BL/6 genetic background were bred genotyped PCR analysis reported housed groups 2-5 treated according Animals (Scientific Procedures) Act or 1986, UK. Antibodies Reagents—Primary immunoblotting listed Table 1. Horseradish peroxidase-conjugated secondary Perbio, protease inhibitor Complete tablets EDTA-free Roche. All chemicals Sigma unless stated otherwise.TABLE 1Antibodies immunoblottingAntibodyEpitopeIsotypeBufferDilutionSourceCdk5 (C-8)Cdk5 C terminusRabbit IgGMilk1:200Santa Cruzp35 (C-19)p35 Cruz4G-1ETotal GSK3α/βMouse IgGMilk1:1000Upstate9332Total GSK3βRabbit IgGMilk1:1000Cell Signaling Technology9331Phospho-GSK3α/β (Ser-21/9)Rabbit Technology5G-2FPhospho-GSK3α/β (Tyr-279/216)Mouse IgGMilk1:1000UpstateAT-8Tau phospho-Ser-202/205Mouse IgGMilk1:1000PierceAT-100Tau phospho-Thr-212/S214Mouse IgGBSA1:2000InnogeneticsPHF1Tau phospho-Ser-396/404Mouse IgGMilk1:100P. DaviesTG3Tau phospho-Thr-231/S235, conformation-dependentMouse IgMBSA1:100P. DaviesBR134Pan-tauRabbit IgGMilk1:750M. GoedertTAU-5Pan-tau (residues 220–240)Mouse IgGMilk1:1000ChemiconSMI31Phospho-neurofilament antibody cross-reacting site tauMouse IgGMilk1:1000Sternberger Monoclonals, Inc.9562β-CateninRabbit IgGBSA1:3000Cell Technology06-182Total ERK1/2Mouse IgGMilk1:1000Upstate4377Phospho-ERK1/2 (Thr-202/Tyr-204)Monoclonal rabbit IgGBSA1:1000Cell Technology9121Phospho-MEK1/2 (Ser-217/221)Rabbit Technology9251Phospho-SAPK/JNK (Thr-183/Tyr-185)aSAPK, stress-activated kinaseRabbig TechnologyPP2AcCatalytic subunit PP2AMouse IgGMilk1:1000S. DilworthPR65/AScaffolding/regulatory Dilworthsc-7482Catalytic PP1 (total protein)Mouse IgGMilk1:2000Santa Cruz2581Phospho-PP1 (Thr-320)Rabbit IgGBSA1:500Cell Technology2452APP (around unphosphorylated Thr-668)Rabbit Technology2451Phospho-APP (Thr-668)Rabbit TechnologyA5441β-ActinMouse IgGMilk1:50000SigmaS2177SynaptotagminRabbit IgGMilk1:40000Sigmaa SAPK, Open table new tab Lysate Preparation—Mice euthanized CO2, brain was quickly removed, hippocampus dissected 4 °C lysate buffer. hippocampi Dounce-homogenized buffer stored -80 °C. (10 mm Tris, pH 7.4, 320 sucrose, 1% Triton X-100, CHAPS 0.025% NaN3) contained (1 EDTA, 1 EGTA, 50 sodium fluoride, 2 orthovanadate, 0.1 ammonium molybdate, 0.2 phenylarsine oxide, tablets). Protein concentrations determined BCA assay (Perbio). Immunoblot Analysis—Equal amounts separated 4-16% polyacrylamide gels (Bio-Rad), transferred onto polyvinylidene difluoride membranes incubated blocking consisting TBS 7.6, 150 NaCl) either 3% milk bovine serum albumin. Blots overnight primary (Table 1) After washing volumes 0.05% Tween 20 (TBST), blots horseradish washed again TBST, signals visualized chemiluminescent system Band intensities x-ray film (Amersham Biosciences) quantified Densitometer Quantity One (Bio-Rad) linear range. stripped stripping (Perbio) reprobed anti-β-actin anti-synaptotagmin normalize amount loaded protein. Immunoprecipitation (IP)—Hippocampal content mg diluted ml ice-cold IP (150 NaCl, 10 Tris-HCl, inhibitors. mix precleared, μg GSK3β added. h rotator hundred microliters IgG bead slurry added rotated beads times containing sample denatured μl SDS loading 90 15 min, (Bio-Rad). True Blot (eBioscience) detecting only native, un-denatured IgG. Activity Assay—Lysate 200 350 centrifuged, supernatant tube. microgram anti-Cdk5 per tube, 1.5 under constant shaking. Thirty settling beads, discarded, 400 Forty reaction (20 25 MgCl2, 0.5 β-glycerol phosphate, orthovanadate) substrate histone (Upstate) mixture μm peptide, cyclic AMP-dependent Compound R24571 beads. initiated addition 100 ATP solution μCi radioactive-labeled [γ-32P]ATP (GE Healthcare). samples 30-60 min 30 stopped spotting p81 nitrocellulose paper (Upstate). 0.75% phosphoric acid once acetone. radioactivity measured Cherenkov counting polyethylene scintillation vials filled 12 H2O. calculated difference between without presence roscovitine, inhibitor. Assay—The performed similarly following changes; immunoprecipitated anti-GSK3β antibody. phospho-glycogen peptide-2 (Upstate), okadaic (a 2A (PP1; PP2A) inhibitor), roscovitine inhibitor). LiCl, Chronic Lithium Administration—22-24-month-old (n = 4) 18-19-month-old WT 3) chronically month. For injection, m LiCl prepared filter-sterilized. days injected intraperitoneally meq/kg (corresponding 10.4 mg/kg). From 3-7 dose administered. Control aged saline. Thereafter, fed powdered chow 1.7 g LiCl/kg weeks. given LiCl. To prevent hyponatremia, water NaCl available ad libitum Data Analysis—Statistical one-way variance. expressed mean ± Age-dependent Increase Mice Constant Over-activation—In analyzed investigate line, transgene driven α-Ca2+/calmodulin-dependent II promoter, displayed level postnatal expression restricted forebrain, highest 22Ris Angelo Capron Errington M.L. Bliss T.V. Godaux 21: 3023-3033Crossref (39) biochemical changes hippocampus, area affected many 23Braak H. Braak Acta Neuropathol. (Berl.). 1991; 82: 239-259Crossref (11766) examined abnormally both (3 months) (18 disease-related tau, phospho-specific commonly employed neuropathological studies recognize epitopes (Ser-202/Thr-205), AT100 (Thr-214 Ser-212), TG3 (Thr-231/Ser-235), (Ser-396/Ser-404). AT-8 (Fig. 1, B). no B; supplemental Fig. even though constantly ∼2-fold demonstrated 2D). contrast, elevated ∼90% confirmed phosphorylation-dependent neurofilament antibody, SMI31, known cross-react (24Lichtenberg-Kraag Steiner Schroter Meyer H.E. Proc. Natl. Acad. Sci. U. 89: 5384-5388Crossref (179) SMI31 showed but revealed did detect significant age 1A 1).FIGURE 2Constant induced A, genotypes found. Immunoblots hippocampal lysates 3- 18-month-old probed C-19 (antibody proteins, p35) Cdk5-specific antibodies. B, (mean S.E.) compared (3-month, n 4, F1,6 29.0, **, p < 0.01; 18-month, 33.2, 0.01). C, APP (pAPP) Thr-668 (as APP695 isoform) detected No differences total against epitope around APP. D, quantification phospho-APP (Thr-668) signal ∼60% months 6, F1,10 11.1, 0.01) 18 175, ***, 0.001).View Large Image Figure ViewerDownload Hi-res image Download (PPT) whether related p25, p35, parameters 33% endogenous p35 21Angelo 2A). Consistent results, controls 2B). alteration cannot account (APP) (annotated isoform). specifically phosphorylated and, hence, displays p25-expressing (25Iijima Ando Takeda Satoh Seki Itohara Greengard Kirino Nairn A.C. Suzuki 75: 1085-1091Crossref (208) 26Cruz J.C. Tseng H.C. Goldman J.A. Shih 40: 471-483Abstract (505) 2, D). 2C). elevation accordance assay. confirm Nevertheless, tau. Inhibitory Regulation Mice—Because there age-related mice, studied involvement other linked First, activating regulatory 1/2 (ERK1/2), (JNK), (MEK1/2). JNK MEK1/2 3A 2). ERK reduced 3, consistent observation regulates MEK1 (27Sharma Veeranna Sharma Amin N.D. Sihag R.K. Grant Ahn Kulkarni A.B. Pant 277: 528-534Abstract (135) Assessment change controls. one major candidate mediators shown phosphorylate (Ref. particular requires priming some (28Sengupta Wu Q. Grundke-Iqbal Iqbal Singh T.J. Biochem. 99-105Crossref (154) 29Dajani Fraser Roe S.M. Young Good Dale T.C. Pear 105: 721-732Abstract (588) It modified, able sequentially adjacent (30Cho G.V. 278: 187-193Abstract (212) regulated serine tyrosine phosphorylation. Phosphorylation Ser-9 β-isoform Ser-21 α-isoform inhibits (31Stambolic 1994; 303: 701-704Crossref (512) Scholar), Tyr-216 Tyr-279 essential (32Hughes Nikolakaki Plyte Totty N.F. EMBO 12: 803-808Crossref (525) differentially ∼85%

Language: Английский

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