Degeneration of neuronal cells due to oxidative stress—microglial contribution

Parkinsonism and Related Disorders 8 (2002) 401–406 www.elsevier.com/locate/parkreldis

Degeneration of neuronal cells due to oxidative stress—microglial contribution E. Koutsilieria,b,*, C. Schellerb, F. Tribla, P. Riederera a

Clinical Neurochemistry and NPF Center of Excellence Research Laboratory, Department of Psychiatry and Psychotherapy, Julius–Maximilians-University, Fuechsleinstr. 15, 97080 Wuerzburg, Germany b Institute of Virology and Immunobiology, University of Wuerzburg, Germany Received 25 March 2002; accepted 25 March 2002

Abstract Various neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis have been causally linked to the generation of free radicals and oxidative stress. In this review, we discuss the implication of oxidative stress in neuronal death and point out the role of intracellular signaling pathways leading to activation of transcription factors associated with cell death and repair. In particular, the impact of microglia as contributors in promoting oxidative stress in neurodegeneration is highlighted. Finally, pivotal molecular targets for drug therapies of brain disorders are reported. q 2002 Elsevier Science Ltd. All rights reserved. Keywords: Oxidative stress; Neurodegeneration; NF-kB; Microglia; Signal transduction

1. Introduction Oxidative stress is implicated in the etiopathogenesis of several pathological entities including inflammation [1], AIDS [2], atherosclerosis, [3] and carcinogenesis [4] but also in physiological ageing [5]. Because the nervous system is particularly vulnerable to reactive oxygen species (ROS) due to its high metabolic rate, its deficient oxidant defense mechanisms and its diminished cellular turn over, oxidative stress is discussed as a contributor to the initiation or progression of neurodegenerative diseases. Various neurodegenerative disorders such as Parkinson’s disease (PD), [6 –10], Alzheimer’s disease (AD) [11 –13], and amyotrophic lateral sclerosis (ALS) [14] have been causally linked to the generation of ROS and oxidative stress. Elucidation of the intracellular pathways associated with free radicals in neuronal cells is essential in order to gain insight into the pathophysiologic basis for neuronal death, but also to devise pharmacologic strategies to ameliorate neuronal degeneration. In this article, we review current knowledge about oxidative stress and recent advances in the * Corresponding author. Address: Clinical Neurochemistry and NPF Center of Excellence Research Laboratory, Department of Psychiatry and Psychotherapy, Julius– Maximilians-University, Fuechsleinstr. 15, 97080 Wuerzburg, Germany. Tel.: þ 49-931-2017730; fax: þ 49-931-2017722. E-mail address: [email protected] (E. Koutsilieri).

intracellular pathways associated with free radical production and defense and their contribution to neuronal damage and repair, respectively. In particular, the role of microglia in promoting oxidative stress is addressed.

2. Oxidative stress Oxidative stress refers to an imbalance between the intracellular production of free radicals and the cellular defense mechanisms. An excess availability of free radicals accompanied with a reduction of the capacity of the natural anti-oxidant systems lead to cellular dysfunction and death. Superoxide, hydroxyl radical species and nitric oxide (NO) are the predominant cellular free radicals, while hydrogen peroxide and peroxynitrite, although not themselves free radicals, aid substantially to the cellular redox state [15]. The cytotoxicity of free radicals is related to the ability of these molecules to oxidize cell constituents, particularly lipids and nucleic acids. An array of cellular defense systems exists to counterbalance free radicals. These include enzymatic and nonenzymatic antioxidants that lower the steady-state concentrations of free radical species, oppose sources that generate cellular oxidants and limit the likelihood that oxidative damage will occur. Cellular antioxidant defense mechanisms include low-molecular weight molecules such as glutathione (GSH) and vitamins

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C and E and antioxidant enzymes such as superoxide dismutase, glutathion peroxidase and catalase [8,16]. A discussion of general issues on oxidative stress is beyond the scope of this chapter, further reading is advised [17 –21]. 2.1. Role of oxidative stress in neuronal cell death The cascade of events which leads to neuronal death share common mechanisms of pathogenecity and links oxidative stress with mitochondrial dysfunctions and glutamate excitotoxicity accompanied with increased intracellular Ca2þ concentrations [22 – 24]. The central nervous system (CNS) is highly susceptible to damage because neuronal cells with few exceptions do not renew themselves thus, a gradual reduction throughout life is unavoidable. Cell death associated with oxidative stress can be either apoptotic or necrotic. Apoptotic cell death is characterized by caspase cleavage [25], chromatin condensation, DNA fragmentation [26], cellular shrinkage and formation of apoptotic bodies [27]. Neighboring cells are not affected by cells dying from apoptosis. In contrast, necrotic cell death is characterized by a rapid loss of membrane integrity as a consequence of a breakdown of the membrane potential [28]. The loss of membrane integrity leads to swelling of the organelles and to rupture of the cell membrane which results in release of cellular proteins into the neighboring tissue. As a consequence, necrotic cell death is accompanied by signs of inflammation. Apoptotic processes triggered by various stimuli are often associated with changes in the cellular redox state [29]. For example, TNF-a, that triggers apoptosis in susceptible cells, induces endogenous ROS production by mitochondria [30]. Although oxidative stress is not a general prerequisite for apoptotic cell death, it can trigger apoptosis; NO-dependent apoptosis has been observed in several experimental models and certain pathologies [31] and is associated with decreased activity in mitochondrial electron transport chain, and release of mitochondrial cytochrome c into the cytoplasm [32]. Moreover, it can be inhibited by elevated intracellular glutathione concentration [33]. In general, only high levels of oxidative stress cause acute necrotic cell death whereas, mild alterations in redox state lead to modulation of intracellular signaling cascades. 2.2. Alterations of cellular signaling and gene transcription due to oxidative stress The redox state of a cell affects the biochemistry of cellular proteins. For example, cysteine residues in proteins are converted into cysteine sulfenic acid (Cys-SOH) by millimolar concentrations of hydogen peroxide [34]. Alternatively, the redox sensitive cysteine may react with glutathione to form a mixed disulfide [35]. If the modified cysteine residues are a part of the active center of an enzyme, both modifications lead to an inactivation of enzymatic activity as demonstrated with three distinct

protein tyrosine phosphatases [34]. Tyrosine phosphatase inhibition results in increased phosphorylation of various cellular proteins involved in cellular signaling [36] and may therefore affect cellular gene transcription. One prominent target for alterations of the cellular redox state is the transcription factor NF-kB. Activation of NF-kB is implicated in a variety of cellular reactions, such as inflammation, growth control, or apoptosis [37]. In nonactivated cells, NF-kB is bound to its inhibitor IkB which is located in the cytoplasm. Phosphorylation of IkB leads to ubiquitinylation of IkB and subsequent degradation at the proteasome, resulting in release of NF-kB, which in turn translocates into the nucleus to activate its target genes (Fig. 1). NF-kB is the first eukaryotic transcription factor shown to respond to oxidative stress in a variety of cells [38]. At least two mechanisms contribute to redox-dependent activation of NF-kB. The first one involves a ROS-mediated increase in IkB degradation [39], the second involves an oxidative enhancement of upstream signaling pathways that lead to phosphorylation of IkB [40]. Moreover, antioxidants such as cysteine inhibit IkB degradation and therefore block NF-kB activation [41]. Oxidative stress in neurodegenerative disorders is associated with NF-kB, however, it is still unclear whether NF-kB activation is related to neuronal repair or contributes to the observed neurodegeneration. Both views are supported by experimental data; NF-kB inhibition by acetylsalicylic acid was protective in glutamateinduced neurotoxicity, suggesting that NF-kB activation is a key event in glutamate-induced cell death [42]. In contrast, in another study NF-kB activation appeared neuroprotective in oxidative stress-induced apoptosis [43]. Further experiments are needed to address the causative role of NF-kB in oxidative stress and neurodegeneration.

3. Microglial contribution to oxidative stress Interestingly, almost all degenerative CNS disorders, including multiple sclerosis [44], AD [45], PD [46,47] are associated with signs of CNS inflammation. Consequently, microglia, the resident CNS immune cells, have been discussed as contributors in chronic neurodegeneration and oxidative stress [48]. Particularly, the main abilities of microglia to produce and release a variety of cytoactive factors as well as reactive oxygen and nitrogen species, including superoxide anion and NO but also glutamate [49] increase the likelihood that microglia contribute to the neurodegenerative process [50]. Microglia actually serve major homeostatic and reparative functions in CNS as evidenced by their prompt response to physiological and stress stimuli as well as by their ability to secrete cytokines and neurotrophic factors and become phagocytic when neurons are damaged [51]. However, the immune reaction can be self-destructive or it may be inadequate and too prolonged, as in the cases of neurodegenerative disorders [1]. Within a few hours after neuronal injury, microglia

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oxidative stress

P phosphorylation

P I-κB

IKKα I-κB

I-κB

U ubiquitinylation

NF-κB degradation

NF-κB

nucleus

NF-κB

DNA binding

proteasome activation of target genes

neurodegeneration

neuroprotection

Fig. 1. The influence of oxidative stress on NF-kB signaling. Oxidative stress activates different cellular kinases, such as IKKa, that is directly involved in NFkB activation. In nonactivated cells, NF-kB is located in the cytoplasm and it is bound to its inhibitor IkB. Phosphorylation of IkB by IKKa allows NF-kB to dissociate from the protein complex and to enter the nucleus. The phosphorylated IkB is ubiquitinylated and degraded at the proteasome. Degradation of IkB is enhanced by oxidative stress. After translocation into the nucleus, NF-kB binds to the cellular DNA and activates its target genes.

show increased expression of immune-related receptors [51]. Their motility is then increased and they migrate to lesioned neurons [52]. Neuronal cell death leads to the transformation of microglia into phagocytotic cells that remove cellular debris. They express inducible NO synthase and release reactive oxygen intermediates and proteinases [53], promoting in some cases cellular death in the nearby region. In vitro it has been shown that the net effect of microglial-secreted factors can be neurotoxic [54]. It is an astrocyte-microglia communication, through transforming growth factor b, which determines the control of the potentially dangerous properties of activated microglia by exerting a negative feed-back on the microglial production of NO [55]. This communication is based on the release of various cytokines, including TNF-a, IL-6, and IL-1b which influence the activation of microglia and the profile of their secreted products [56]. Finally, we can speak about a rivalry between astrocytes and microglia cytokine stimulation, the outcome of which determines the fate of nearby neurons [54]. Reactive microglia seem to be a major source for the generation of ROS in the brain. In AD, the microglia

surrounding the senile plaques express major histocompatibility complex class II (MHC class II) [57], a marker of activated macrophage-type cells. Several studies [58] have shown that Ab peptides or fragments of amyloid precursor protein, increase superoxide anion production in rat peritoneal macrophages and in cultured rat microglia [59]. Interestingly, Ab peptides among other factors have also been reported to increase NO in a mouse microglial cell line [60]. Evidence for a pathogenetic role for activated microglia in dopaminergic cell injury in PD is primarily circumstantial and is based on the presence of elevated levels of cytokines. IL-1b, interferon-g, and TNF-a are increased by 7-15-fold in the substantia nigra of PD patients [61,62]. Moreover, there is induction of MHC class II [63]. In a recent article [64] it was shown that NO and hydrogen peroxide released by microglia mediated neuronal cell injury and that dopaminergic cells appeared to be the most susceptible neuronal type. Microglial activation and oxidative stress seem to be significant components of the pathology of neurodegenerative disorders and imply that suppression of the inflammatory response may improve therapeutic strategies in the future.

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4. Therapeutic approaches

Acknowledgments

The implication of oxidative stress in a wide range of disorders lead to several attempts to ameliorate or attenuate the progression of neurodegenerative disease by antioxidant treatment [65]. Such studies have yielded mildly beneficial results with regard to slowing disease progression. A great disadvantage is that the neurorescue effects of antioxidants are achieved in the early phase of degenerative process and thus, antioxidative treatment has a limitation in slowing the clinical progression in advanced degenerative brain disorders. Recently, administration of neuronal NO synthase inhibitors showed some beneficial results in PD and Huntington’s disease models [66,67]. Potential therapeutic strategies rely upon downregulation of proinflammatory and prooxidative genes or the activation of cytoprotective genes involved in cell death [68,69]. We mentioned above that inflammatory events leading to oxidative stress in the brain contribute to the neurodegenerative processes. In this context, the role of activated microglia is of central value. A series of attempts have been performed in order to inhibit microglia effects, expecting that suppressive microglia regulators would result in a reduction of inflammation and subsequent neurotoxicity; IL-10 suppressed microglia [70, 71]. The same was observed with CD45, a membrane-bound protein tyrosine phosphatase [72,73]. The inhibition of microglia activation blocked TNF-a release, NO production and neuronal injury [72,73]. Treatment with anti-inflammatory drugs reduced both in vitro and in vivo microglia activation [74,75] and inhibited neurotoxin production [75,76]. Estrogen was shown to attenuate microglial superoxide anion release and phagocytic activity [77]. Further, several studies emphasize the importance of molecules that interfere at the second messenger cross-talk level. NO generation was markedly depressed when microglia had been pre-treated with dibutyryl-cAMP, a membranepermeable cAMP analog, before LPS stimulation [78] and ROS were significantly inhibited by cAMP agonists in cultured rat microglia [79]. Such treatments resulted also in an inhibition of IL-1b and TNF-a release [79]. Thus, a reinforced cAMP signaling induced by pharmaka may limit glia-related oxidative damage of neuronal cells.

E.K. is a recipient of the HWP ‘Programm Chancengleichheit fu¨r Frauen in Forschung und Lehre’. This study was supported by a grant from the Bundesministerium fu¨r Bildung, Wissenschaft, Forschung und Technologie, Germany (BMBF 01 KI 9762/5).

5. Conclusions Microglial activation and promotion of oxidative stress in CNS is implicated in the pathogenesis of neurodegenerative diseases such as multiple sclerosis, AD and PD. In terms of therapeutic strategies to fight the diseases mentioned earlier it is crucial to further understand the sequential mechanisms associated with microglia activation on the molecular level and the impact of this activation on the development of the neuronal damage.

References [1] Neumann H. Control of glial immune function by neurons. Glia 2001; 36:191–9. [2] Westendorp MO, Shatrov VA, Schulze-Osthoff K, Frank R, Kraft M, Los M, Krammer PH, Droge W, Lehmann V. HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. EMBO J 1995;14:546–54. [3] Keaney Jr JF, Vita JA. Atherosclerosis, oxidative stress, and antioxidant protection in endothelium-derived relaxing factor action. Prog Cardiovasc Dis 1995;38:129 –54. [4] Adelman R, Saul RL, Ames BN. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci USA 1988; 85:2706–8. [5] Oliver CN, Ahn BW, Moerman EJ, Goldstein S, Stadtman ER. Agerelated changes in oxidized proteins. J Biol Chem 1987;262:5488–91. [6] Spina MB, Cohen G. Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA 1989;86: 1398–400. [7] Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 1989;52:515–20. [8] Fahn S, Cohen G. The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 1992;32:804–12. [9] Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990;54:823–7. [10] Cohen G. Monoamine oxidase and oxidative stress at dopaminergic synapses. J Neural Transm Suppl 1990;32:229–38. [11] Benzi G, Moretti A. Are reactive oxygen species involved in Alzheimer’s disease? Neurobiol Aging 1995;16:661–74. [12] Gsell W, Conrad R, Hickethier M, Sofic E, Frolich L, Wichart I, Jellinger K, Moll G, Ransmayr G, Beckmann H, Riederer P. Decreased catalase activity but unchanged superoxide dismutase activity in brains of patients with dementia of Alzheimer type. J Neurochem 1995;64:1216–23. [13] Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M, Wu JF, Floyd RA, Butterfield DA. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA 1994;91: 3270–4. [14] Bergeron C. Oxidative stress: its role in the pathogenesis of amyotrophic lateral sclerosis. J Neurol Sci 1995;129:81–4. [15] Albers DS, Beal MF. Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J Neural Transm Suppl 2000; 59:133–54. [16] Sagara Y, Dargusch R, Chambers D, Davis J, Schubert D, Maher P. Cellular mechanisms of resistance to chronic oxidative stress. Free Radic Biol Med 1998;24:1375– 89. [17] Olanow CW. A radical hypothesis for neurodegeneration. Trends Neurosci 1993;16:439–44. [18] Simonian NA, Coyle JT. Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol 1996;36:83–106. [19] Halliwell B. Oxidants and the central nervous system: some fundamental questions. Is oxidant damage relevant to Parkinson’s

E. Koutsilieri et al. / Parkinsonism and Related Disorders 8 (2002) 401–406

[20] [21]

[22]

[23] [24] [25] [26]

[27]

[28] [29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37] [38]

[39]

[40]

disease, Alzheimer’s disease, traumatic injury or stroke? Acta Neurol Scand Suppl 1989;126:23– 33. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47 –95. Gotz ME, Kunig G, Riederer P, Youdim MB. Oxidative stress: free radical production in neural degeneration. Pharmacol Ther 1994;63: 37–122. Zamzami N, Hirsch T, Dallaporta B, Petit PX, Kroemer G. Mitochondrial implication in accidental and programmed cell death: apoptosis and necrosis. J Bioenerg Biomembr 1997;29:185–93. Calne DB, Hochberg FH, Snow BJ, Nygaard T. Theories of neurodegeneration. Ann NY Acad Sci 1992;648:1–5. Cohen G, Kesler N. Monoamine oxidase and mitochondrial respiration. J Neurochem 1999;73:2310–5. Salvesen GS, Dixit VM. Caspases: intracellular signaling by proteolysis. Cell 1997;91:443–6. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998;391:43–50. Hale AJ, Smith CA, Sutherland LC, Stoneman VE, Longthorne V, Culhane AC, Williams GT. Apoptosis: molecular regulation of cell death. Eur J Biochem 1996;237:884. Murphy MP. Nitric oxide and cell death. Biochim Biophys Acta 1999; 1411:401–14. Esteve JM, Mompo J, Garcia de la Asuncion J, Sastre J, Asensi M, Boix J, Vina JR, Vina J, Pallardo FV. Oxidative damage to mitochondrial DNA and glutathione oxidation in apoptosis: studies in vivo and in vitro. FASEB J 1999;13:1055– 64. Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 1992; 267:5317–23. Adamson DC, Wildemann B, Sasaki M, Glass JD, McArthur JC, Christov VI, Dawson TM, Dawson VL. Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science 1996;274:1917–21. Ushmorov A, Ratter F, Lehmann V, Droge W, Schirrmacher V, Umansky V. Nitric-oxide-induced apoptosis in human leukemic lines requires mitochondrial lipid degradation and cytochrome C release. Blood 1999;93:2342–52. Umansky V, Rocha M, Breitkreutz R, Hehner S, Bucur M, Erbe N, Droge W, Ushmorov A. Glutathione is a factor of resistance of Jurkat leukemia cells to nitric oxide-mediated apoptosis. J Cell Biochem 2000;78:578– 87. Denu JM, Tanner KG. Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 1998;37:5633 –42. Barrett WC, DeGnore JP, Keng YF, Zhang ZY, Yim MB, Chock PB. Roles of superoxide radical anion in signal transduction mediated by reversible regulation of protein–tyrosine phosphatase 1B. J Biol Chem 1999;274:34543–6. Hardwick JS, Sefton BM. Activation of the Lck tyrosine protein kinase by hydrogen peroxide requires the phosphorylation of Tyr-394. Proc Natl Acad Sci USA 1995;92:4527 –31. Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell 1996;87: 13–20. Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 1991;10:2247– 58. Kretz-Remy C, Bates EE, Arrigo AP. Amino acid analogs activate NF-kappa B through redox-dependent IkappaB-alpha degradation by the proteasome without apparent IkappaB-alpha phosphorylation, Consequence on HIV-1 long terminal repeat activation. J Biol Chem 1998;273:3180–91. Schoonbroodt S, Ferreira V, Best-Belpomme M, Boelaert JR,

[41]

[42]

[43]

[44]

[45] [46]

[47]

[48] [49]

[50]

[51] [52]

[53] [54] [55]

[56]

[57]

[58]

[59]

[60]

405

Legrand-Poels S, Korner M, Piette J. Crucial role of the aminoterminal tyrosine residue 42 and the carboxyl—terminal PEST domain of IkappaB alpha in NF-kappa; B activation by an oxidative stress. J Immunol 2000;164:4292–300. Meyer M, Schreck R, Baeuerle PA. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 1993;12: 2005– 15. Grilli M, Pizzi M, Memo M, Spano P. Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation. Science 1996;274:1383–5. Mattson MP, Goodman Y, Luo H, Fu W, Furukawa K. Activation of NF-kappaB protects hippocampal neurons against oxidative stressinduced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J Neurosci Res 1997;49:681–97. Windhagen A, Newcombe J, Dangond F, Strand C, Woodroofe MN, Cuzner ML, Hafler DA. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med 1995;182:1985– 96. McGeer EG, McGeer PL. The importance of inflammatory mechanisms in Alzheimer disease. Exp Gerontol 1998;33:371–8. McGeer PL, McGeer EG. Glial cell reactions in neurodegenerative diseases: pathophysiology and therapeutic interventions. Alzheimer Dis Assoc Disord 1998;12(Suppl. 2):S1–S6. Youdim MB, Lavie L. Selective MAO-A and B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson’s disease. Life Sci 1994;55:2077–82. Gebicke-Haerter PJ. Microglia in neurodegeneration: molecular aspects. Microsc Res Technol 2001;54:47–58. Koutsilieri E, Sopper S, Heinemann T, Scheller C, Lan J, StahlHennig C, ter Meulen V, Riederer P, Gerlach M. Involvement of microglia in cerebrospinal fluid glutamate increase in SIV-infected rhesus monkeys (Macaca mulatta). AIDS Res Hum Retroviruses 1999;15:471 –7. Colton CA, Chernyshev ON, Gilbert DL, Vitek MP. Microglial contribution to oxidative stress in Alzheimer’s disease. Ann NY Acad Sci 2000;899:292 –307. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996;19:312– 8. Heppner FL, Skutella T, Hailer NP, Haas D, Nitsch R. Activated microglial cells migrate towards sites of excitotoxic neuronal injury inside organotypic hippocampal slice cultures. Eur J Neurosci 1998; 10:3284–90. Banati RB, Gehrmann J, Schubert P, Kreutzberg GW. Cytotoxicity of microglia. Glia 1993;7:111–8. Giulian D. Reactive glia as rivals in regulating neuronal survival. Glia 1993;7:102 –10. Vincent VA, Tilders FJ, Van Dam AM. Inhibition of endotoxininduced nitric oxide synthase production in microglial cells by the presence of astroglial cells: a role for transforming growth factor beta. Glia 1997;19:190–8. Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 1995;20: 269–87. McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG. Microglia in degenerative neurological disease. Glia 1993;7:84–92. Van Muiswinkel FL, Veerhuis R, Eikelenboom P. Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity. J Neurochem 1996;66:2468 –76. Klegeris A, Walker DG, McGeer PL. Activation of macrophages by Alzheimer beta amyloid peptide. Biochem Biophys Res Commun 1994;199:984 –91. Meda L, Cassatella MA, Szendrei GI, Otvos Jr L, Baron P, Villalba M,

406

[61]

[62] [63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

E. Koutsilieri et al. / Parkinsonism and Related Disorders 8 (2002) 401–406 Ferrari D, Rossi F. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995;374:647–50. Hirsch EC, Hunot S, Damier P, Faucheux B. Glial cells and inflammation in Parkinson’s disease: a role in neurodegeneration? Ann Neurol 1998;44:S115 –20. Nagatsu T, Mogi M, Ichinose H, Togari A, Riederer P. Cytokines in Parkinson’s disease. NeuroSci News 1999;2:88–90. Yamada T, McGeer PL, McGeer EG. Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol (Berl) 1992;84:100–4. Le W, Rowe D, Xie W, Ortiz I, He Y, Appel SH. Microglial activation and dopaminergic cell injury: an in vitro model relevant to Parkinson’s disease. J Neurosci 2001;21:8447 –55. Shoulson I. DATATOP: a decade of neuroprotective inquiry. Parkinson Study Group. Deprenyl and tocopherol antioxidative therapy of parkinsonism. Ann Neurol 1998;44:S160–6. Matthews RT, Yang L, Beal MF. S-Methylthiocitrulline a neuronal nitric oxide synthase inhibitor, protects against malonate and MPTP neurotoxicity. Exp Neurol 1997;143:282–6. Maragos WF, Silverstein FS. Inhibition of nitric oxide synthase activity attenuates striatal malonate lesions in rats. J Neurochem 1995; 64:2362–5. Sabate O, Barkats M, Buc-Caron MH, Castel-Barthe MN, Finiels F, Horellou P, Revah F, Mallet J. Adenovirus for neurodegenerative diseases: in vivo strategies and ex vivo gene therapy using human neural progenitors. Clin Neurosci 1995–1996;3:317– 21. Bordet T, Lesbordes JC, Rouhani S, Castelnau-Ptakhine L, Schmalbruch H, Haase G, Kahn A. Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice. Hum Mol Genet 2001;10:1925–33. O’Keefe GM, Nguyen VT, Benveniste EN. Class II transactivator and class II MHC gene expression in microglia: modulation by the

[71]

[72]

[73]

[74] [75]

[76]

[77]

[78]

[79]

cytokines TGF-beta, IL-4, IL-13 and IL-10. Eur J Immunol 1999;29: 1275–85. Tan J, Town T, Saxe M, Paris D, Wu Y, Mullan M. Ligation of microglial CD40 results in p44/42 mitogen-activated protein kinasedependent TNF-alpha production that is opposed by TGF-beta 1 and IL-10. J Immunol 1999;163:6614–21. Tan J, Town T, Mori T, Wu Y, Saxe M, Crawford F, Mullan M. CD45 opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase. J Neurosci 2000;20:7587–94. Tan J, Town T, Mullan M. CD45 inhibits CD40L-induced microglial activation via negative regulation of the Src/p44/42 MAPK pathway. J Biol Chem 2000;275:37224–31. Mackenzie IR, Munoz DG. Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology 1998;50:986 –90. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE. Inflammatory mechanisms in Alzheimer’s disease: inhibition of betaamyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci 2000;20:558–67. Klegeris A, Walker DG, McGeer PL. Toxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal anti-inflammatory drugs (NSAIDs). Neuropharmacology 1999;38: 1017–25. Bruce-Keller AJ, Keeling JL, Keller JN, Huang FF, Camondola S, Mattson MP. Antiinflammatory effects of estrogen on microglial activation. Endocrinology 2000;141:3646–56. Schubert P, Ogata T, Marchini C, Ferroni S. Glia-related pathomechanisms in Alzheimer’s disease: a therapeutic target? Mech Ageing Dev 2001;123:47–57. Si Q, Nakamura Y, Ogata T, Kataoka K, Schubert P. Differential regulation of microglial activation by propentofylline via cAMP signaling. Brain Res 1998;812:97 –104.