Mechanisms of hypochlorous acid mediated neuronal cell death

MECHANISMS OF HYPOCHLOROUS ACID-MEDIATED NEURONAL CELL DEATH YAP YANN WAN (B SC (HONS.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF BIOCHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2006 Acknowledgements First and foremost, to my supervisor, Dr Steve Cheung, for guiding so hard on this project and for truly understanding when the experiments not working so well And to Prof Tan Chee Hong and Prof Matthew Whiteman, for their valuable suggestion and help My sincere appreciation to the entire lab, with special thanks to Meng Shyan, Vivien and Sze Jee My thanks as well to Dr Peng Zhao Feng For their generous assistance in the experiments and data analyses, I would like to acknowledge Prof Bay Boon Huat, Prof Sheu Fwu Shan and his student Ms Li Yuhong, as well as Prof Alirio J Melendez i Table of Contents Contents Page Acknowledgements i Table of Contents ii viii Summary Publications x List of Tables xi List of Figures xii List of Abbreviations Used in Text xiii Chapter 1.1 INTRODUCTION Neurons die by apoptosis in neurodegenerative disorders 1.1.1 Types of cell death: apoptosis and necrosis 1.1.2 Apoptosis – a feature of neurologic diseases 1.1.3 Executioners of apoptotic cell death 1.2 1.1.3.1 Caspases 1.1.3.2 Calpains 1.1.3.3 Lysosome and cathepsin proteases Oxidative stress and neurodegenerative diseases 1.2.1 Evidences of oxidative stress in neurodegenerative diseases 10 11 1.2.1.1 Elevation of oxidized biomolecules 11 1.2.1.2 Changes of endogenous defense mechanisms 12 1.2.2 Phagocytes are mediators of oxidative stress 13 1.2.3 Oxidants generated by activated phagocytes 14 ii Contents Page 1.3 19 HOCl: an under appreciated mediator of neurodegeneration 1.3.1 Evidences for HOCl as a mediator of neurodegeneration 1.3.1.1 Parkinson’s disease 19 1.3.1.2 Alzheimer’s disease 20 1.3.1.3 Cerebral ischemia 21 1.3.1.4 Multiple sclerosis 21 1.3.2 Possible routes of HOCl generation in diseased brain 1.3.2.1 1.3.3 Sources of H2O2 22 22 1.3.2.1.1 NADPH oxidase 22 1.3.2.1.2 Other H2O2-generating enzymes 24 1.3.2.2 1.4 19 Sources of MPO Destructive effects of HOCl generation 25 26 1.3.3.1 Direct damage of biomolecules 26 1.3.3.2 Destruction of extracellular matrix 28 1.3.3.3 Cell death 29 Rationale and objective of the study 30 1.4.1 Rationale 30 1.4.2 Objective 30 Chapter 2.1 MATERIALS AND METHODS Primary culture of mouse cortical neurons 2.1.1 Plate coating 32 33 33 iii Contents 2.1.2 Page Cell culture 33 2.2 Measurement of HOCl 34 2.3 Induction of apoptosis 34 2.4 Assessment of cellular viability 35 2.5 Morphological assessment of cell death 36 2.6 Transmission electron microscopy 36 2.7 Western blotting 37 2.7.1 Protein extraction 37 2.7.2 Protein determination 37 2.7.3 Sample preparation for protein electrophoresis 38 2.7.4 SDS-polyacrylamide gel preparation 38 2.7.4.1 Pouring resolving gel 38 2.7.4.2 Pouring stacking gel 39 2.7.5 Protein electrophoresis 39 2.7.6 Blotting Transfer proteins from gel to PVDF 39 2.7.7 Blocking 40 2.7.8 Probing the blot 40 2.7.9 Detection 41 2.7.10 Stripping and reprobing blot 41 2.8 Caspase activity measurement 41 2.9 Fluorochrome-labeled inhibitors of caspases (FLICA) staining 42 2.10 Intracellular Ca2+ measurement 42 iv Contents Page 2.11 Assessment of lysosomal membrane integrity 44 2.12 Microarray analyses 45 2.12.1 Target preparation 2.12.1.1 Total RNA extraction 45 45 2.12.1.2 Quantity, purity and integrity determination of extracted total RNA 46 2.12.1.3 One-cycle cDNA synthesis and its clean-up 46 2.12.1.4 Synthesis and clean-up of biotin-labeled cRNA 49 2.12.1.5 Quantification of cRNA 50 2.12.1.6 50 Fragmenting the cRNA 2.12.2 Target hybridization 50 2.12.2.1 Reagent preparation for target hybridization 51 2.12.2.2 Hybridization 51 2.12.3 Washing and staining of hybridized arrays 52 2.12.4 Probe array scan and data analyses 53 2.13 ATP and GSH measurement 54 2.14 Statistical analyses 55 Chapter HOCL-MEDIATED NEURONAL APOPTOSIS 56 3.1 Introduction 57 3.2 Treatment of HOCl causes concentration-dependent cell injury 57 3.3 HOCl mediates apoptosis-necrotic continuum neuronal cell death 59 v Contents Chapter Page THE UNDERLYING MECHANISMS OF HOCl-INDUCED APOPTOSIS 62 4.1 Introduction 63 4.2 Caspase involvement in HOCl-induced apoptosis 63 4.3 HOCl stimulates calpain activation and calpain inhibitors provide protection against HOCl-induced cell death 67 4.4 Intracellular Ca2+ levels are increased in HOCl-treated cortical neurons 69 4.5 Extracellular and intracellular pools are sources for elevated Ca2+ 70 4.6 Rupture of lysosomes followed calpain activation 72 4.7 HOCl-induced apoptosis is rescued by inhibitors of cathepsins D and L 74 Chapter APOPTOTIC AND SURVIVAL MECHANISMS INDUCED BY HOCl: A MICROARRAY STUDY 75 5.1 Introduction 76 5.2 Differentially expressed genes upon HOCl treatment 76 5.3 Validation of microarray analysis 86 5.4 HOCl induces changes on apoptosis-related genes expression 87 5.5 HOCl stimulates stress response: maintenance of cellular redox state 87 5.6 HOCl causes the salvage of energy: maintenance of cellular ATP level 88 Chapter DISCUSSION AND CONCLUSION 90 6.1 Introduction 91 6.2 HOCl mediates concentration-dependent apoptosis-necrotic continuum neuronal cell death Underlying mechanisms of neuronal apoptosis caused by HOCl 91 6.3 93 vi Contents Page 6.4 101 HOCl-induced cellular adaptation at gene expression level 6.4.1 Suppression of cell cycle genes 101 6.4.2 Induction of Nrf2-ARE pathway (namely programmed cell life pathway) 101 6.4.3 103 Energy salvage 6.5 Drawbacks of current study 105 6.6 Concluding remarks and future directions 106 References 108 vii Summary Oxidative stress has been implicated as playing a role in neurodegenerative disorders, such as ischemic stroke, Alzheimer’s, Huntington’s, and Parkinson’s disease Persuasive evidences have shown that microglial-mediated oxidative stress contributes significantly to cell loss and accompanying cognitive decline characteristic of the diseases Based on the facts that (i) levels of catalytically active myeloperoxidase are elevated in diseased brains and (ii) myeloperoxidase polymorphism is associated with the risk of developing neurodegenerative disorders, HOCl as a major oxidant produced by activated phagocytes in the presence of myeloperoxidase is therefore suggested to be involved in neurodegeneration Its association with neurodegeneration is further showed by elevated level of 3-chlorotyrosine (bio-marker of HOCl in vivo) in affected brain regions as well as HOCl scavenging ability of neuroprotectants, desferrioxamine and uric acid Therefore, primary mouse cortical neurons treated with HOCl were employed to investigate the mechanistic insight of HOCl on neuronal cell death The current study reports for the first time that HOCl mediates concentration-dependent apoptosis-necrotic continuum neuronal cell death Neurotoxicity caused by intermediate concentration of HOCl (250 μM) exhibited ATP depletion and several biochemical markers of apoptosis in the absence of caspase activation Yet, the involvement of calpains was demonstrated by data showing that calpain inhibitors protect cortical neurons from apoptosis and the formation of 145/150 kDa α-fodrin fragments Further, elevation of cytosolic calcium concentration was observed and calcium channel antagonists and EGTA prevented cleavage of α-fodrin and the induction of apoptosis Finally, calpain activation causes the onset of lysosomal pathway With the aid of DNA microarray, orphan nuclear receptor viii Nr4a1 that engaged in caspase-independent cell death was up-regulated nearly 10 folds after h of treatment In addition, three survival mechanisms such as suppression of cell cycle genes, induction of NF-E2-related factor-2-antioxidant response element (Nrf2ARE) pathway and down-regulation of genes involved in energy-dependent processes were identified at gene expression level In conclusion, the present study proposes that HOCl triggers caspase-independent apoptosis by activating redox sensitive calcium channels e.g L-type channel, ryanodine receptor and IP3 receptor leading to increase of intracellular calcium concentration and subsequent activation of calpain and release of cathepsins from destabilized lysosomes Elevated calcium level also induces the expression of Nr4a1 which transmits apoptotic signalling from nucleus to mitochondria and causes concomitant release of mitochondrial cell death mediators The participation of calpain, cathepsins, Nr4a1 and defense mechanisms in the neurotoxicity of HOCl enables them to be targeted for multiple disorders which HOCl is found associated As a result, this study might offer a novel potential therapeutic area for multiple sclerosis, Parkinson’s and Alzheimer’s diseases and probably allow clinical research to mature from ‘‘promise’’ to ‘‘practice’’ ix Mu, X and Chang, C (2003) TR3 orphan nuclear receptor mediates apoptosis through up-regulating E2F1 in human prostate cancer LNCaP cells J Biol Chem 278, 4284042845 Munger, J.S., Haass, C., Lemere, C.A., Shi, G.P., Wong, W.S., Teplow, D.B., Selkoe, D.J and Chapman, H.A (1995) Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S Biochem J 311, 299-305 Nagra, R.M., Becher, B., Tourtellotte, W.W., Antel, J.P., Gold, D., Paladino, T., Smith, R.A., Nelson, J.R and Reynolds, W.F (1997) Immunohistochemical and genetic evidence of myeloperoxidase involvement in multiple sclerosis J Neuroimmunol 78, 97-107 Nagy, Z.S and Esiri, M.M (1997) Apoptosis-related protein expression in the hippocampus in Alzheimer's disease Neurobiol Aging 18, 565-571 Nakagawa, T and Yuan, J (2000) Cross-talk between two cysteine protease families Activation of caspase-12 by calpain in apoptosis J Cell Biol 150, 887-894 Nakamura, S., Kawamata, T., Akiguchi, I., Kameyama, M., Nakamura, N and Kimura, H (1990) Expression of monoamine oxidase B activity in astrocytes of senile plaques Acta Neuropathol (Berl) 80, 419-425 Nakanishi, M (2003) New strategy in gene transfection by cationic transfection lipids with a cationic cholesterol Curr Med Chem 10, 1289-1296 Nelissen, I., Fiten, P., Vandenbroeck, K., Hillert, J., Olsson, T., Marrosu, M.G and Opdenakker, G (2000) PECAM1, MPO and PRKAR1A at chromosome 17q21-q24 and susceptibility for multiple sclerosis in Sweden and Sardinia J Neuroimmunol 108, 153159 Nelson, K.K and Melendez, J.A (2004) Mitochondrial redox control of matrix metalloproteinases Free Radic Biol Med 37, 768-784 Neumar, R.W., Xu, Y.A., Gada, H., Guttmann, R.P and Siman, R (2003) Cross-talk between calpain and caspase proteolytic systems during neuronal apoptosis J Biol Chem 278, 14162-14167 Nguyen, T., Huang, H.C and Pickett, C.B (2000) Transcriptional regulation of the antioxidant response element Activation by Nrf2 and repression by MafK J Biol Chem 275, 15466-15473 Nilsson, E., Ghassemifar, R and Brunk, U.T (1997) Lysosomal heterogeneity between and within cells with respect to resistance against oxidative stress Histochem J 29, 857865 129 Nishimura, T., Akiyama, H., Yonehara, S., Kondo, H., Ikeda, K., Kato, M., Iseki, E and Kosaka, K (1995) Fas antigen expression in brains of patients with Alzheimer-type dementia Brain Res 695, 137-145 Nixon, R.A., Cataldo, A.M and Mathews, P.M (2000) The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review Neurochem Res 25, 11611172 Nobel, C.S., Burgess, D.H., Zhivotovsky, B., Burkitt, M.J., Orrenius, S and Slater, A.F (1997) Mechanism of dithiocarbamate inhibition of apoptosis: thiol oxidation by dithiocarbamate disulfides directly inhibits processing of the caspase-3 proenzyme Chem Res Toxicol 10, 636-643 Noh, K.M and Koh, J.Y (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes J Neurosci 20, RC111 Olson, E.E and McKeon, R.J (2004) Characterization of cellular and neurological damage following unilateral hypoxia/ischemia J Neurol Sci 227, 7-19 Onizuka, K., Kunimatsu, M., Ozaki, Y., Muramatsu, K., Sasaki, M and Nishino, H (1995) Distribution of mu-calpain proenzyme in the brain and other neural tissues in the rat Brain Res 697, 179-186 Pamplona, R., Dalfo, E., Ayala, V., Bellmunt, M.J., Prat, J., Ferrer, I and Portero-Otin, M (2005) Proteins in human brain cortex are modified by oxidation, glycoxidation, and lipoxidation Effects of Alzheimer disease and identification of lipoxidation targets J Biol Chem 280, 21522-21530 Pappolla, M.A., Omar, R.A., Kim, K.S and Robakis, N.K (1992) Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer's disease Am J Pathol 140, 621628 Paravicini, T.M and Sobey, C.G (2003) Cerebral vascular effects of reactive oxygen species: recent evidence for a role of NADPH-oxidase Clin Exp Pharmacol Physiol 30, 855-859 Park, D.S., Farinelli, S.E and Greene, L.A (1996) Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons J Biol Chem 271, 8161-8169 Park, D.S., Levine, B., Ferrari, G and Greene, L.A (1997) Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase and promote survival of NGF-deprived sympathetic neurons J Neurosci 17, 8975-8983 Park, H.S., Lee, J.S., Huh, S.H., Seo, J.S and Choi, E.J (2001) Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase EMBO J 20, 446-456 130 Park, L., Anrather, J., Zhou, P., Frys, K., Pitstick, R., Younkin, S., Carlson, G.A and Iadecola, C (2005) NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide J Neurosci 25, 17691777 Park, Y.M., Han, M.Y., Blackburn, R.V and Lee, Y.J (1998) Overexpression of HSP25 reduces the level of TNF alpha-induced oxidative DNA damage biomarker, 8-hydroxy-2'deoxyguanosine, in L929 cells J Cell Physiol 174, 27-34 Pasinetti, G.M and Aisen, P.S (1998) Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain Neuroscience 87, 319-324 Pattison, D.I and Davies, M.J (2001) Absolute rate constants for the reaction of hypochlorous acid with protein side chains and peptide bonds Chem Res Toxicol 14, 1453-1464 Pattison, D.I., Hawkins, C.L and Davies, M.J (2003) Hypochlorous acid-mediated oxidation of lipid components and antioxidants present in low-density lipoproteins: absolute rate constants, product analysis, and computational modeling Chem Res Toxicol 16, 439-449 Pedersen, W.A., Fu, W., Keller, J.N., Markesbery, W.R., Appel, S., Smith, R.G., Kasarskis, E and Mattson, M.P (1998) Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients Ann Neurol 44, 819-824 Perry, V.H and Gordon, S (1991) Macrophages and the nervous system Int Rev Cytol 125, 203-244 Persidsky, Y., Zheng, J., Miller, D and Gendelman, H.E (2000) Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia J Leukoc Biol 68, 413-422 Persson, H.L., Yu, Z., Tirosh, O., Eaton, J.W and Brunk, U.T (2003) Prevention of oxidant-induced cell death by lysosomotropic iron chelators Free Radic Biol Med 34, 1295-1305 Pettigrew, A.R and Fell, G.S (1972) Simplified colorimetric determination of thiocyanate in biological fluids, and its application to investigation of the toxic amblyopias Clin Chem 18, 996-1000 Pike, B.R., Zhao, X., Newcomb, J.K., Posmantur, R.M., Wang, K.K and Hayes, R.L (1998) Regional calpain and caspase-3 proteolysis of alpha-spectrin after traumatic brain injury Neuroreport 9, 2437-2442 131 Pompl, P.N., Yemul, S., Xiang, Z., Ho, L., Haroutunian, V., Purohit, D., Mohs, R and Pasinetti, G.M (2003) Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease Arch Neurol 60, 369-376 Prutz, W.A (1996) Hypochlorous acid interactions with thiols, nucleotides, DNA, and other biological substrates Arch Biochem Biophys 332, 110-120 Prutz, W.A (1998) Interactions of hypochlorous acid with pyrimidine nucleotides, and secondary reactions of chlorinated pyrimidines with GSH, NADH, and other substrates Arch Biochem Biophys 349, 183-191 Prutz, W.A (1999) Consecutive halogen transfer between various functional groups induced by reaction of hypohalous acids: NADH oxidation by halogenated amide groups Arch Biochem Biophys 371, 107-114 Pullar, J.M., Vissers, M.C and Winterbourn, C.C (2000) Living with a killer: the effects of hypochlorous acid on mammalian cells IUBMB Life 50, 259-266 Pullar, J.M., Winterbourn, C.C and Vissers, M.C (1999) Loss of GSH and thiol enzymes in endothelial cells exposed to sublethal concentrations of hypochlorous acid Am J Physiol 277, H1505-H1512 Rabuffetti, M., Sciorati, C., Tarozzo, G., Clementi, E., Manfredi, A.A and Beltramo, M (2000) Inhibition of caspase-1-like activity by Ac-Tyr-Val-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines J Neurosci 20, 4398-4404 Rajpal, A., Cho, Y.A., Yelent, B., Koza-Taylor, P.H., Li, D., Chen, E., Whang, M., Kang, C., Turi, T.G and Winoto, A (2003) Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor EMBO J 22, 6526-6536 Rami, A., Agarwal, R., Botez, G and Winckler, J (2000) mu-Calpain activation, DNA fragmentation, and synergistic effects of caspase and calpain inhibitors in protecting hippocampal neurons from ischemic damage Brain Res 866, 299-312 Rami, A., Volkmann, T., Agarwal, R., Schoninger, S., Nurnberger, F., Saido, T.C and Winckler, J (2003) beta2-Adrenergic receptor responsiveness of the calpain-calpastatin system and attenuation of neuronal death in rat hippocampus after transient global ischemia Neurosci Res 47, 373-382 Ramos, C.L., Pou, S., Britigan, B.E., Cohen, M.S and Rosen, G.M (1992) Spin trapping evidence for myeloperoxidase-dependent hydroxyl radical formation by human neutrophils and monocytes J Biol Chem 267, 8307-8312 Ranganathan, S and Bowser, R (2003) Alterations in G(1) to S phase cell-cycle regulators during amyotrophic lateral sclerosis Am J Pathol 162, 823-835 132 Reimertz, C., Kogel, D., Lankiewicz, S., Poppe, M and Prehn, J.H (2001) Ca(2+)induced inhibition of apoptosis in human SH-SY5Y neuroblastoma cells: degradation of apoptotic protease activating factor-1 (APAF-1) J Neurochem 78, 1256-1266 Reinikainen, K.J., Paljarvi, L., Halonen, T., Malminen, O., Kosma, V.M., Laakso, M and Riekkinen, P.J (1988) Dopaminergic system and monoamine oxidase-B activity in Alzheimer's disease Neurobiol Aging 9, 245-252 Reynolds, W.F., Rhees, J., Maciejewski, D., Paladino, T., Sieburg, H., Maki, R.A and Masliah, E (1999) Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease Exp Neurol 155, 31-41 Ribeiro, A., Bronk, S.F., Roberts, P.J., Urrutia, R and Gores, G.J (1999) The transforming growth factor β1-inducible trancription factor, TIEG1, mediates apoptosis through oxidative stress Hepatology 30,1490-1497 Roberg, K., Johansson, U and Ollinger, K (1999a) Lysosomal release of cathepsin D precedes relocation of cytochrome c and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress Free Radic Biol Med 27, 1228-1237 Roberg, K and Ollinger, K (1998) Oxidative stress causes relocation of the lysosomal enzyme cathepsin D with ensuing apoptosis in neonatal rat cardiomyocytes Am J Pathol 152, 1151-1156 Roberts, L.R., Adjei, P.N and Gores, G.J (1999b) Cathepsins as effector proteases in hepatocyte apoptosis Cell Biochem Biophys 30, 71-88 Robinson, D.S., Davis, J.M., Nies, A., Ravaris, C.L and Sylwester, D (1971) Relation of sex and aging to monoamine oxidase activity of human brain, plasma, and platelets Arch Gen Psychiatry 24, 536-539 Rohn, T.T., Head, E., Nesse, W.H., Cotman, C.W and Cribbs, D.H (2001) Activation of caspase-8 in the Alzheimer's disease brain Neurobiol Dis 8, 1006-1016 Rojo, A.I., Salinas, M., Martin, D., Perona, R and Cuadrado, A (2004) Regulation of Cu/Zn-superoxide dismutase expression via the phosphatidylinositol kinase/Akt pathway and nuclear factor-kappaB J Neurosci 24, 7324-7334 Ronquist, G and Waldenstrom, A (2003) Imbalance of plasma membrane ion leak and pump relationship as a new aetiological basis of certain disease states J Intern Med 254, 517-526 Rossi, F and Zatti, M (1964) Biochemical aspects of phagocytosis in polymorphonuclear leucocytes NADH and NADPH oxidation by the granules of resting and phagocytizing cells Experientia 20, 21-23 133 Ruiz-Vela, A., Gonzalez de Buitrago, G and Martinez-A, C (1999) Implication of calpain in caspase activation during B cell clonal deletion EMBO J 18, 4988-4998 Saito, K., Elce, J.S., Hamos, J.E and Nixon, R.A (1993) Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration Proc Natl Acad Sci USA 90, 26282632 Sakahira, H., Enari, M and Nagata, S (1998) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis Nature 391, 96-99 Salvemini, F., Franze, A., Iervolino, A., Filosa, S., Salzano, S and Ursini, M.V (1999) Enhanced glutathione levels and oxidoresistance mediated by increased glucose-6phosphate dehydrogenase expression J Biol Chem 274, 2750-2757 Sambrook, J., Fritsch, E.F and Maniatis, T (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press., New York Sanchez, I., Xu, C.J., Juo, P., Kakizaka, A., Blenis, J and Yuan, J (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats Neuron 22, 623-633 Saran, M., Michel, C and Bors, W (1990) Reaction of NO with O2- implications for the action of endothelium-derived relaxing factor (EDRF) Free Radic Res Commun 10, 221-226 Sasaki, N., Fukatsu, R., Tsuzuki, K., Hayashi, Y., Yoshida, T., Fujii, N., Koike, T., Wakayama, I., Yanagihara, R., Garruto, R., Amano, N and Makita, Z (1998) Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases Am J Pathol 153, 1149-1155 Sastre, M and Garcia-Sevilla, J.A (1993) Opposite age-dependent changes of alpha 2Aadrenoceptors and nonadrenoceptor [3H]idazoxan binding sites (I2-imidazoline sites) in the human brain: strong correlation of I2 with monoamine oxidase-B sites J Neurochem 61, 881-889 Sastry, P.S and Rao, K.S (2000) Apoptosis and the nervous system J Neurochem 74,120 Saura, J., Bleuel, Z., Ulrich, J., Mendelowitsch, A., Chen, K., Shih, J.C., Malherbe, P., Da Prada, M and Richards, J.G (1996) Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistry Neuroscience 70, 755-774 Saura, J., Luque, J.M., Cesura, A.M., Da Prada, M., Chan-Palay, V., Huber, G., Loffler, J and Richards, J.G (1994) Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography Neuroscience 62, 15-30 134 Sayre, L.M., Smith, M.A and Perry, G (2001) Chemistry and biochemistry of oxidative stress in neurodegenerative disease Curr Med Chem 8, 721-738 Schraufstatter, I.U., Browne, K., Harris, A., Hyslop, P.A., Jackson, J.H., Quehenberger, O and Cochrane, C.G (1990) Mechanisms of hypochlorite injury of target cells J Clin Invest 85, 554-562 Selkoe, D.J (1991) The molecular pathology of Alzheimer's disease Neuron 6, 487-498 Selley, M.L., Close, D.R and Stern, S.E (2002) The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease Neurobiol Aging 23, 383-388 Shaw, P.J., Ince, P.G., Falkous, G and Mantle, D (1995) Oxidative damage to protein in sporadic motor neuron disease spinal cord Ann Neurol 38, 691-695 Shi, Y (2002) Mechanisms of caspase activation and inhibition during apoptosis Mol Cell 9, 459-470 Shibata, N., Nagai, R., Uchida, K., Horiuchi, S., Yamada, S., Hirano, A., Kawaguchi, M., Yamamoto, T., Sasaki, S and Kobayashi, M (2001) Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients Brain Res 917, 97-104 Shie, J-.L Chen, Z.Y., Fu, M., Pestell, R.G and Tseng, C-.C (2000) Gut-enriched kruppel-like factor represses cyclin D1 promoter activity through Sp1 motif Nuclei Acids Res 28, 2969-2976 Shimohama, S., Tanino, H., Kawakami, N., Okamura, N., Kodama, H., Yamaguchi, T., Hayakawa, T., Nunomura, A., Chiba, S., Perry, G., Smith, M.A and Fujimoto, S (2000) Activation of NADPH oxidase in Alzheimer's disease brains Biochem Biophys Res Commun 273, 5-9 Siesjo, B.K., Bengtsson, F., Grampp, W and Theander, S (1989) Calcium, excitotoxins, and neuronal death in the brain Ann N Y Acad Sci 568, 234-251 Slungaard, A and Mahoney, J.R Jr (1991) Thiocyanate is the major substrate for eosinophil peroxidase in physiologic fluids Implications for cytotoxicity J Biol Chem 266, 4903-4910 Solaroglu, I., Okutan, O., Kaptanoglu, E., Beskonakli, E and Kilinc, K (2005) Increased xanthine oxidase activity after traumatic brain injury in rats J Clin Neurosci 12, 273275 Stadelmann, C., Deckwerth, T.L., Srinivasan, A., Bancher, C., Bruck, W., Jellinger, K and Lassmann, H (1999) Activation of caspase-3 in single neurons and autophagic 135 granules of granulovacuolar degeneration in Alzheimer's disease Evidence for apoptotic cell death Am J Pathol 155, 1459-1466 Stamler, J.S (1996) Alzheimer's disease A radical vascular connection Nature 380, 108111 Stoll, G and Jander, S (1999) The role of microglia and macrophages in the pathophysiology of the CNS Prog Neurobiol 58, 233-247 Strolin Benedetti, M and Dostert, P (1989) Monoamine oxidase, brain ageing and degenerative diseases Biochem Pharmacol 38, 555-561 Su, C.Y., Chong, K.Y., Edelstein, K., Lille, S., Khardori, R and Lai, C.C (1999) Constitutive hsp70 attenuates hydrogen peroxide-induced membrane lipid peroxidation Biochem Biophys Res Commun 265, 279-284 Su, J.H., Anderson, A.J., Cummings, B.J and Cotman, C.W (1994) Immunohistochemical evidence for apoptosis in Alzheimer's disease Neuroreport 5, 2529-2533 Su, J.H., Deng, G and Cotman, C.W (1997) Bax protein expression is increased in Alzheimer's brain: correlations with DNA damage, Bcl-2 expression, and brain pathology J Neuropathol Exp Neurol 56, 86-93 Sugaya, K., Reeves, M and McKinney, M (1997) Topographic associations between DNA fragmentation and Alzheimer's disease neuropathology in the hippocampus Neurochem Int 31, 275-281 Sugiyama, S., Kugiyama, K., Aikawa, M., Nakamura, S., Ogawa, H and Libby, P (2004) Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis Arterioscler Thromb Vasc Biol 24, 1309-1314 Tammariello, S.P., Quinn, M.T and Estus, S (2000) NADPH oxidase contributes directly to oxidative stress and apoptosis in nerve growth factor-deprived sympathetic neurons J Neurosci 20, RC53 Tarkowski, E., Wallin, A., Regland, B., Blennow, K and Tarkowski, A (2001) Local and systemic GM-CSF increase in Alzheimer's disease and vascular dementia Acta Neurol Scand 103, 166-174 Taskiran, D., Sagduyu, A., Yuceyar, N., Kutay, F.Z and Pogun, S (2000) Increased cerebrospinal fluid and serum nitrite and nitrate levels in amyotrophic lateral sclerosis Int J Neurosci 101, 65-72 Thomas, E.L., Grisham, M.B and Jefferson, M.M (1986) Preparation and characterization of chloramines Methods Enzymol 132, 569-585 136 Thomas, T., Thomas, G., McLendon, C., Sutton, T and Mullan, M (1996) beta-Amyloidmediated vasoactivity and vascular endothelial damage Nature 380, 168-171 Tsan, M.F and Denison, R.C (1981) Oxidation of amino acids by human neutrophils Inflammation 5, 379-386 Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., Koizumi, S and Inoue, K (2004) Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury Glia 45, 89-95 Tsuji, T., Shimohama, S., Kimura, J and Shimizu, K (1998) m-Calpain (calciumactivated neutral proteinase) in Alzheimer's disease brains Neurosci Lett 248, 109-112 Turk, B., Bieth, J.G., Bjork, I., Dolenc, I., Turk, D., Cimerman, N., Kos, J., Colic, A., Stoka, V and Turk, V (1995) Regulation of the activity of lysosomal cysteine proteinases by pH-induced inactivation and/or endogenous protein inhibitors, cystatins Biol Chem Hoppe Seyler 376, 225-230 Turk, B., Turk, D and Turk, V (2000) Lysosomal cysteine proteases: more than scavengers Biochim Biophys Acta 1477, 98-111 Turk, V., Turk, B and Turk, D (2001) Lysosomal cysteine proteases: facts and opportunities EMBO J 20, 4629-4633 Uetsuki, T., Takemoto, K., Nishimura, I., Okamoto, M., Niinobe, M., Momoi, T., Miura, M and Yoshikawa, K (1999) Activation of neuronal caspase-3 by intracellular accumulation of wild-type Alzheimer amyloid precursor protein J Neurosci 19, 69556964 Vallet, P., Charnay, Y., Steger, K., Ogier-Denis, E., Kovari, E., Herrmann, F., Michel, J.P and Szanto, I (2005) Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia Neuroscience 132, 233-238 Van Muiswinkel, F.L., Raupp, S.F., de Vos, N.M., Smits, H.A., Verhoef, J., Eikelenboom, P and Nottet, H.S (1999) The amino-terminus of the amyloid-beta protein is critical for the cellular binding and consequent activation of the respiratory burst of human macrophages J Neuroimmunol 96, 121-130 Van Muiswinkel, F.L., Veerhuis, R and Eikelenboom, P (1996) Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetateinduced respiratory burst activity J Neurochem 66, 2468-2476 Vignais, P.V (2002) The superoxide-generating NADPH oxidase: structural aspects and activation mechanism Cell Mol Life Sci 59,1428-1459 137 Vila, M and Przedborski, S (2004) Genetic clues to the pathogenesis of Parkinson's disease Nat Med 10, S58-62 Vissers, M.C., Carr, A.C and Winterbour, C.C (2001) Fatty acid chlorohydrins and bromohydrins are cytotoxic to human endothelial cells Redox Rep 6, 49-55 Vissers, M.C., Lee, W.G and Hampton, M.B (2001) Regulation of apoptosis by vitamin C Specific protection of the apoptotic machinery against exposure to chlorinated oxidants J Biol Chem 276, 46835-46840 Vissers, M.C., Pullar, J.M and Hampton, M.B (1999) Hypochlorous acid causes caspase activation and apoptosis or growth arrest in human endothelial cells Biochem J 344, 443-449 Vissers, M.C., Stern, A., Kuypers, F., van den Berg, J and Winterbourn, C.C (1994) Membrane changes associated with lysis of red blood cells by hypochlorous acid Free Radic Biol Med 16, 703-712 Vissers, M.C and Winterbourn, C.C (1995) Oxidation of intracellular glutathione after exposure of human red blood cells to hypochlorous acid Biochem J 307, 57-62 Wagner, B.A., Britigan, B.E., Reszka, K.J., McCormick, M.L and Burns, C.P (2002) Hydrogen peroxide-induced apoptosis of HL-60 human leukemia cells is mediated by the oxidants hypochlorous acid and chloramines Arch Biochem Biophys 401, 223-234 Wang, E (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved Cancer Res 55, 2284-2292 Wang, J., Xiong, S., Xie, C., Markesbery, W.R and Lovell, M.A (2005) Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease J Neurochem 93, 953-962 Wang, K.K., Posmantur, R., Nath, R., McGinnis, K., Whitton, M., Talanian, R.V., Glantz, S.B and Morrow, J.S (1998) Simultaneous degradation of alphaII- and betaII-spectrin by caspase (CPP32) in apoptotic cells J Biol Chem 273, 22490-22497 Waring, P (2005) Redox active calcium ion channels and cell death Arch Biochem Biophys 434, 33-42 Wasil, M., Halliwell, B., Hutchison, D.C and Baum, H (1987) The antioxidant action of human extracellular fluids Effect of human serum and its protein components on the inactivation of alpha 1-antiproteinase by hypochlorous acid and by hydrogen peroxide Biochem J 243, 219-223 Wasserman, W.W and Fahl, W.E (1997) Functional antioxidant responsive elements Proc Natl Acad Sci U S A 94, 5361-5366 138 Weinberg, J.B., Misukonis, M.A., Shami, P.J., Mason, S.N., Sauls, D.L., Dittman, W.A., Wood, E.R., Smith, G.K., McDonald, B., Bachus, K.E., et al (1995) Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages Blood 86, 1184-1195 Weiss, S.J (1989) Tissue destruction by neutrophils N Engl J Med 320, 365-376 Weiss, S.J., Klein, P., Slivka, A and Wei, M (1982) Chlorination of taurine by human neutrophils Evidence for hypochlorous acid generation J Clin Invest 70, 598-607 Weiss, S.J., Lampert, M.B and Test, S.T (1983) Long-lived oxidants generated by human neutrophils: characterization and bioactivity Science 222, 625-628 Weldon, D.T., Rogers, S.D., Ghilardi, J.R., Finke, M.P., Cleary, J.P., O'Hare, E., Esler, W.P., Maggio, J.E and Mantyh, P.W (1998) Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo J Neurosci 18, 2161-2173 Werneburg, N.W., Guicciardi, M.E., Bronk, S.F and Gores, G.J (2002) Tumor necrosis factor-alpha-associated lysosomal permeabilization is cathepsin B dependent Am J Physiol Gastrointest Liver Physiol 283, G947-956 Westlund, K.N., Denney, R.M., Rose, R.M and Abell, C.W (1988) Localization of distinct monoamine oxidase A and monoamine oxidase B cell populations in human brainstem Neuroscience 25, 439-456 Whiteman, M., Hooper, D.C., Scott, G.S., Koprowski, H and Halliwell, B (2002) Inhibition of hypochlorous acid-induced cellular toxicity by nitrite Proc Natl Acad Sci U S A 99, 12061-12066 Whiteman, M., Rose, P., Siau, J.L., Cheung, N.S., Tan, G.S., Halliwell, B and Armstrong, J.S (2005) Hypochlorous acid-mediated mitochondrial dysfunction and apoptosis in human hepatoma HepG2 and human fetal liver cells: role of mitochondrial permeability transition Free Radic Biol Med 38, 1571-1584 Whiteman, M., Rose, P., Siau, J.L and Halliwell, B (2003) Nitrite-mediated protection against hypochlorous acid-induced chondrocyte toxicity: a novel cytoprotective role of nitric oxide in the inflamed joint? Arthrit Rheum 48, 3140-3150 Wild, A.C., Moinova, H.R and Mulcahy, R.T (1999) Regulation of gammaglutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2 J Biol Chem 274, 33627-33636 Winterbourn, C.C (1985) Comparative reactivities of various biological compounds with myeloperoxidase-hydrogen peroxide-chloride, and similarity of the oxidant to hypochlorite Biochim Biophys Acta 840, 204-210 139 Winterbourn, C.C (2002) Biological reactivity and biomarkers of the neutrophil oxidant, hypochlorous acid Toxicology 181-182, 223-227 Winterbourn, C.C., van den Berg, J.J., Roitman, E and Kuypers, F.A (1992) Chlorohydrin formation from unsaturated fatty acids reacted with hypochlorous acid Arch Biochem Biophys 296, 547-555 Woessner, J.F and Nagase, H (2000) Matrix Metalloproteinases and TIMPs Oxford University Press, Oxford Wolf, B.B., Goldstein, J.C., Stennicke, H.R., Beere, H., Amarante-Mendes, G.P., Salvesen, G.S and Green, D.R (1999) Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activation Blood 94, 1683-1692 Woo, M., Hakem, R., Soengas, M.S., Duncan, G.S., Shahinian, A., Kagi, D., Hakem, A., McCurrach, M., Khoo, W., Kaufman, S.A., Senaldi, G., Howard, T., Lowe, S.W and Mak, T.W (1998) Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes Genes Dev 12, 806-819 Wood, D.E and Newcomb, E.W (2000) Cleavage of Bax enhances its cell death function Exp Cell Res 256, 375-382 Wood, D.E., Thomas, A., Devi, L.A., Berman, Y., Beavis, R.C., Reed, J.C and Newcomb, E.W (1998) Bax cleavage is mediated by calpain during drug-induced apoptosis Oncogene 17, 1069-1078 Wood, J.L (1975) in Chemistry and Biochemistry of Thiocyanic Acid and Its Deriuatiues (Newman, A A., ed) pp 156-221, Academic Press, Orlando, FL Wu, D.C., Jackson-Lewis, V., Vila, M., Tieu, K., Teismann, P., Vadseth, C., Choi, D.K., Ischiropoulos, H and Przedborski, S (2002a) Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease J Neurosci 22, 1763-1771 Wu, D.C., Teismann, P., Tieu, K., Vila, M., Jackson-Lewis, V., Ischiropoulos, H and Przedborski, S (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease Proc Natl Acad Sci U S A 100, 6145-6150 Yamamoto, H., Yamamoto, Y., Yamagami, K., Kume, M., Kimoto, S., Toyokuni, S., Uchida, K., Fukumoto, M., and Yamaoka, Y (2000) Heat-shock preconditioning reduces oxidative protein denaturation and ameliorates liver injury by carbon tetrachloride in rats Res Exp Med (Berl) 199, 309-318 Yamashima, T., Tonchev, A.B., Tsukada, T., Saido, T.C., Imajoh-Ohmi, S., Momoi, T and Kominami, E (2003) Sustained calpain activation associated with lysosomal rupture 140 executes necrosis of the postischemic CA1 neurons in primates Hippocampus 13, 791800 Yamashita, T., Ando, Y., Obayashi, K., Uchino, M and Ando, M (1997) Changes in nitrite and nitrate (NO2-/NO3-) levels in cerebrospinal fluid of patients with multiple sclerosis J Neurol Sci 153, 32-34 Yang, F., Sun, X., Beech, W., Teter, B., Wu, S., Sigel, J., Vinters, H.V., Frautschy, S.A and Cole, G.M (1998) Antibody to caspase-cleaved actin detects apoptosis in differentiated neuroblastoma and plaque-associated neurons and microglia in Alzheimer's disease Am J Pathol 152, 379-389 Yang, H.M., Lee, P.H., Lim, T.M and Sheu, F.S (2004) Neurogranin expression in stably transfected N2A cell line affects cytosolic calcium level by nitric oxide stimulation Brain Res Mol Brain Res 129, 171-178 Yoon, H.S and Yang, V.W (2004) Requirement of kruppel-like factor in preventing entry into mitosis following DNA damage J Biol Chem 279, 5035-5041 Youn, H.D., Grozinger, C.M and Liu, J,O (2000) Calcium regulates transcriptional repression of myocyte enhancer factor by histone deacetylase J Biol Chem 275, 22563-22567 Youn, H.D and Liu, J.O (2000) Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2 Immunity 13, 85-94 Yuan, J and Yankner, B.A (2000) Apoptosis in the nervous system Nature 407, 802809 Yuceyar, N., Taskiran, D and Sagduyu, A (2001) Serum and cerebrospinal fluid nitrite and nitrate levels in relapsing-remitting and secondary progressive multiple sclerosis patients Clin Neurol Neurosurg 103, 206-211 Zakrzewska-Pniewska, B., Styczynska, M., Podlecka, A., Samocka, R., Peplonska, B., Barcikowska, M and Kwiecinski H (2004) Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis Mult Scler 10, 266-271 Zavodnik, L.B., Zavodnik, I.B., Lapshina, E.A., Shkodich, A.P., Bryszewska, M and Buko, V.U (2000) Hypochlorous acid-induced lysis of human erythrocytes Inhibition of cellular damage by the isoflavonoid genistein-8-C-glucoside Biochemistry (Mosc) 65, 946-951 Zdolsek, J.M., Olsson, G.M and Brunk, U.T (1990) Photooxidative damage to lysosomes of cultured macrophages by acridine orange Photochem Photobiol 51, 67-76 141 Zdolsek, J., Zhang, H., Roberg, K and Brunk, U (1993) H2O2-mediated damage to lysosomal membranes of J-774 cells Free Radic Res Commun 18, 71-85 Zemlan, F.P., Thienhaus, O.J and Bosmann, H.B (1989) Superoxide dismutase activity in Alzheimer's disease: possible mechanism for paired helical filament formation Brain Res 476, 160-162 Zeuner, A., Eramo, A., Peschle, C and De Maria, R (1999) Caspase activation without death Cell Death Differ 6, 1075-1080 Zlokovic, B.V., Deane, R., Sallstrom, J., Chow, N and Miano, J.M (2005) Neurovascular pathways and Alzheimer amyloid beta-peptide Brain Pathol 15, 78-83 142 143 ... to the death of neurons (Ekshyyan and Aw, 2004) 1.1.1 Types of cell death: apoptosis and necrosis Mammalian cells can die by one of several different defined pathways, the most common of which... of all animal cell types Originally, they are thought as involved only in the digestion of cell nutrients, cell protein turnover, tissue remodeling, lysis of invaders, and autolysis of dead cells... the inhibitor of MMPs or by direct degradation of the protein core (hyaluronic acid) and the sulphated glycosaminoglycans of PGs (Hawkins and Davies, 1998) 1.3.3.3 Cell death Cell death induced