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Theme: Parkinson's Disease - Review

Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?

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Pages 845-860 | Published online: 09 Jan 2014

References

  • Susilo R, Rommelspacher H. Formation of a β-carboline (1,2,3,4-tetrahydro-1-methyl-β-carboline-1-carboxylic acid) following intracerebroventricular injection of tryptamine and pyruvic acid. Naunyn Schmiedebergs Arch. Pharmacol.335, 70–76 (1987).
  • Herraiz T, Galisteo J. Tetrahydro-β-carboline alkaloids occur in fruits and fruit juices. Activity as antioxidants and radical scavengers. J. Agric. Food Chem.51, 7156–7161 (2003).
  • Gross GA, Turesky RJ, Fay LB, Stillwell WG, Skipper PL, Tannenbaum SR. Heterocyclic aromatic amine formation in grilled bacon, beef and fish and in grill scrapings. Carcinogenesis14, 2313–2318 (1993).
  • Herraiz T, Chaparro C. Analysis of monoamine oxidase enzymatic activity by reversed-phase high performance liquid chromatography and inhibition by β-carboline alkaloids occurring in foods and plants. J. Chromatogr. A.1120, 237–243 (2006).
  • Liao GZ, Wang GY, Xu XL, Zhou GH. Effect of cooking methods on the formation of heterocyclic aromatic amines in chicken and duck breast. Meat Sci.85, 149–154 (2010).
  • Herraiz T, Chaparro C. Human monoamine oxidase is inhibited by tobacco smoke: β-carboline alkaloids act as potent and reversible inhibitors. Biochem. Biophys. Res. Commun.326, 378–386 (2005).
  • Honecker H, Coper H, Fahndrich C, Rommelspacher H. Identification of tetrahydronorharmane (tetrahydro-β-carboline) in human blood platelets. J. Clin. Chem. Clin. Biochem.18, 133–135 (1980).
  • Adachi J, Mizoi Y, Naito T, Ogawa Y, Uetani Y, Ninomiya I. Identification of tetrahydro-β-carboline-3-carboxylic acid in foodstuffs, human urine and human milk. J. Nutr.121, 646–652 (1991).
  • Matsubara K, Kobayashi S, Kobayashi Y et al. β-Carbolinium cations, endogenous MPP+ analogs, in the lumbar cerebrospinal fluid of patients with Parkinson’s disease. Neurology45, 2240–2245 (1995).
  • Herraiz T, Guillen H, Aran VJ. Oxidative metabolism of the bioactive and naturally occurring β-carboline alkaloids, norharman and harman, by human cytochrome P450 enzymes. Chem. Res. Toxicol.21(11), 2172–2189 (2008).
  • Jenner P, Olanow CW. The pathogenesis of cell death in Parkinson’s disease. Neurology66, S24–S36 (2006).
  • Kim YS, Joh TH. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp. Mol. Med.38, 333–347 (2006).
  • Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM. Neuroinflammation and oxidation/nitration of α-synuclein linked to dopaminergic neurodegeneration. J. Neurosci.28, 7687–7698 (2008).
  • Qian L, Flood PM, Hong JS. Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J. Neural Transm.117, 971–979 (2010).
  • McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology38, 1285–1291 (1988).
  • Mastroeni D, Grover A, Leonard B et al. Microglial responses to dopamine in a cell culture model of Parkinson’s disease. Neurobiol. Aging30, 1805–1817 (2009).
  • Gerhard A, Pavese N, Hotton G et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol. Dis.21, 404–412 (2006).
  • Ouchi Y, Yoshikawa E, Sekine Y et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann. Neurol.57, 168–175 (2005).
  • Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C, Peterson DW. Association of circulating TNF-α and IL-6 with ageing and parkinsonism. Acta Neurol. Scand.100, 34–41 (1999).
  • Neafsey EJ, Albores R, Gearhart D et al. Methyl-β-carbolinium analogs of MPP+ cause nigrostriatal toxicity after substantia nigra injections in rats. Brain Res.675, 279–288 (1995).
  • Ostergren A, Fredriksson A, Brittebo EB. Norharman-induced motoric impairment in mice: neurodegeneration and glial activation in substantia nigra. J. Neural Transm.113, 313–329 (2006).
  • Polanski W, Enzensperger C, Reichmann H, Gille G. The exceptional properties of 9-methyl-β-carboline: stimulation, protection and regeneration of dopaminergic neurons coupled with anti-inflammatory effects. J. Neurochem.113, 1659–1675 (2010).
  • Hamann J, Rommelspacher H, Storch A, Reichmann H, Gille G. Neurotoxic mechanisms of 2,9-dimethyl-β-carbolinium ion in primary dopaminergic culture. J. Neurochem.98, 1185–1199 (2006).
  • Hans G, Malgrange B, Lallemend F et al. β-carbolines induce apoptosis in cultured cerebellar granule neurons via the mitochondrial pathway. Neuropharmacology48, 105–117 (2005).
  • Funayama Y, Nishio K, Wakabayashi K et al. Effects of β- and γ-carboline derivatives of DNA topoisomerase activities. Mutat. Res.349, 183–191 (1996).
  • Collins MA, Neafsey EJ, Matsubara K, Cobuzzi RJ, Jr, Rollema H. Indole-N-methylated β-carbolinium ions as potential brain-bioactivated neurotoxins. Brain Res.570, 154–160 (1992).
  • Matsubara K, Collins MA, Akane A et al. Potential bioactivated neurotoxicants, N-methylated β-carbolinium ions, are present in human brain. Brain Res.610, 90–96 (1993).
  • Kuhn W, Muller T, Grosse H, Rommelspacher H. Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients. J. Neural Transm.103, 1435–1440 (1996).
  • Gearhart DA, Collins MA, Lee JM, Neafsey EJ. Increased β-carboline 9N-methyltransferase activity in the frontal cortex in Parkinson’s disease. Neurobiol. Dis.7, 201–211 (2000).
  • Stephens DN, Schneider HH, Kehr W, Jensen LH, Petersen E, Honore T. Modulation of anxiety by β-carbolines and other benzodiazepine receptor ligands: relationship of pharmacological to biochemical measures of efficacy. Brain Res. Bull.19, 309–318 (1987).
  • Aricioglu F, Altunbas H. Harmane induces anxiolysis and antidepressant-like effects in rats. Ann. NY Acad. Sci.1009, 196–201 (2003).
  • Farzin D, Mansouri N. Antidepressant-like effect of harmane and other β-carbolines in the mouse forced swim test. Eur. Neuropsychopharmacol.16, 324–328 (2006).
  • Aricioglu F, Yillar O, Korcegez E, Berkman K. Effect of harmane on the convulsive threshold in epilepsy models in mice. Ann. NY Acad. Sci.1009, 190–195 (2003).
  • Husbands SM, Glennon RA, Gorgerat S et al. β-carboline binding to imidazoline receptors. Drug Alcohol Depend.64, 203–208 (2001).
  • Robinson ES, Anderson NJ, Crosby J, Nutt DJ, Hudson AL. Endogenous β-carbolines as clonidine-displacing substances. Ann. NY Acad. Sci.1009, 157–166 (2003).
  • Musgrave IF, Badoer E. Harmane produces hypotension following microinjection into the RVLM: possible role of I(1)-imidazoline receptors. Br. J. Pharmacol.129, 1057–1059 (2000).
  • Sanchez-Blazquez P, Boronat MA, Olmos G, Garcia-Sevilla JA, Garzon J. Activation of I(2)-imidazoline receptors enhances supraspinal morphine analgesia in mice: a model to detect agonist and antagonist activities at these receptors. Br. J. Pharmacol.130, 146–152 (2000).
  • Aricioglu F, Korcegez E, Ozyalcin S. Effect of harmane on mononeuropathic pain in rats. Ann. NY Acad. Sci.1009, 180–184 (2003).
  • Cao R, Chen Q, Hou X et al. Synthesis, acute toxicities, and antitumor effects of novel 9-substituted β-carboline derivatives. Bioorg. Med. Chem.12, 4613–4623 (2004).
  • Kumar R, Gupta L, Pal P et al. Synthesis and cytotoxicity evaluation of (tetrahydro-β-carboline)-1,3,5-triazine hybrids as anticancer agents. Eur. J. Med. Chem.45, 2265–2276 (2010).
  • Formagio AS, Tonin LT, Foglio MA et al. Synthesis and antitumoral activity of novel 3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-triazol-3-yl) β-carboline derivatives. Bioorg. Med. Chem.16, 9660–9667 (2008).
  • Chen X, Cromer BA, Lynch JW. Molecular determinants of β-carboline inhibition of the glycine receptor. J. Neurochem.110, 1685–1694 (2009).
  • Touiki K, Rat P, Molimard R, Chait A, de Beaurepaire R. Harmane inhibits serotonergic dorsal raphe neurons in the rat. Psychopharmacology (Berl.)182, 562–569 (2005).
  • Yang YJ, Lee JJ, Jin CM, Lim SC, Lee MK. Effects of harman and norharman on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells. Eur. J. Pharmacol.587, 57–64 (2008).
  • Wernicke C, Schott Y, Enzensperger C, Schulze G, Lehmann J, Rommelspacher H. Cytotoxicity of β-carbolines in dopamine transporter expressing cells: structure-activity relationships. Biochem. Pharmacol.74, 1065–1077 (2007).
  • Storch A, Hwang YI, Gearhart DA et al. Dopamine transporter-mediated cytotoxicity of β-carbolinium derivatives related to Parkinson’s disease: relationship to transporter-dependent uptake. J. Neurochem.89, 685–694 (2004).
  • Ho BT, McIsaac WM, Tansey LW, Walker KE. Inhibitors of monoamine oxidase. 3. 9-substituted-β-carbolines. J. Pharm. Sci.58, 219–221 (1969).
  • Rommelspacher H, Meier-Henco M, Smolka M, Kloft C. The levels of norharman are high enough after smoking to affect monoamineoxidase B in platelets. Eur. J. Pharmacol.441, 115–125 (2002).
  • Rook Y, Schmidtke KU, Gaube F et al. Bivalent β-carbolines as potential multitarget anti-Alzheimer agents. J. Med. Chem.53(9), 3611–3617 (2010).
  • Rommelspacher H, May T, Susilo R. β-carbolines and tetrahydroisoquinolines: detection and function in mammals. Planta Med.57, S85–S92 (1991).
  • Musshoff F, Daldrup T, Bonte W, Leitner A, Lesch OM. Formaldehyde-derived tetrahydroisoquinolines and tetrahydro-β-carbolines in human urine. J. Chromatogr. B Biomed. Appl.683, 163–176 (1996).
  • McNaught KS, Carrupt PA, Altomare C et al. Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson’s disease. Biochem. Pharmacol.56, 921–933 (1998).
  • Okuda K, Kotake Y, Ohta S. Neuroprotective or neurotoxic activity of 1-methyl-1,2,3,4-tetrahydroisoquinoline and related compounds. Bioorg. Med. Chem. Lett.13, 2853–2855 (2003).
  • McNaught KS, Thull U, Carrupt PA et al. Inhibition of complex I by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Biochem. Pharmacol.50, 1903–1911 (1995).
  • Kobayashi H, Fukuhara K, Tada-Oikawa S et al. The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson’s disease. J. Neurochem.108, 397–407 (2009).
  • Storch A, Ott S, Hwang YI, Ortmann R et al. Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson’s disease: studies using heterologous expression systems of the dopamine transporter. Biochem. Pharmacol.63, 909–920 (2002).
  • Kotake Y, Tasaki Y, Makino Y, Ohta S, Hirobe M. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline as a Parkinsonism-inducing agent: a novel endogenous amine in mouse brain and Parkinsonian CSF. J. Neurochem.65, 2633–2638 (1995).
  • Lorenc-Koci E, Smialowska M, Antkiewicz-Michaluk L, Golembiowska K, Bajkowska M, Wolfarth S. Effect of acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline on muscle tone, metabolism of dopamine in the striatum and tyrosine hydroxylase immunocytochemistry in the substantia nigra, in rats. Neuroscience95, 1049–1059 (2000).
  • Okuda K, Kotake Y, Ohta S. Parkinsonism-preventing activity of 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives in C57BL mouse in vivo. Biol. Pharm. Bull.29, 1401–1403 (2006).
  • Yamakawa T, Ohta S. Biosynthesis of a parkinsonism-preventing substance, 1-methyl-1,2,3,4-tetrahydroisoquinoline, is inhibited by parkinsonism-inducing compounds in rat brain mitochondrial fraction. Neurosci. Lett.259, 157–160 (1999).
  • Hamann J, Wernicke C, Lehmann J, Reichmann H, Rommelspacher H, Gille G. 9-methyl-β-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture. Neurochem. Int.52, 688–700 (2008).
  • Matsubara K, Gonda T, Sawada H et al. Endogenously occurring β-carboline induces parkinsonism in nonprimate animals: a possible causative protoxin in idiopathic Parkinson’s disease. J. Neurochem.70, 727–735 (1998).
  • Wernicke C, Hellmann J, Zieba B et al. 9-methyl-β-carboline has restorative effects in an animal model of Parkinson’s disease. Pharmacol. Rep.62, 35–53 (2010).
  • Greffard S, Verny M, Bonnet AM et al. Motor score of the Unified Parkinson Disease Rating Scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra. Arch. Neurol.63, 584–588 (2006).
  • Riederer P, Wuketich S. Time course of nigrostriatal degeneration in Parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J. Neural Transm.38, 277–301 (1976).
  • Scherman D, Desnos C, Darchen F, Pollak P, Javoy-Agid F, Agid Y. Striatal dopamine deficiency in Parkinson’s disease: role of aging. Ann. Neurol.26, 551–557 (1989).
  • Ugrumov MV. Non-dopaminergic neurons partly expressing dopaminergic phenotype: distribution in the brain, development and functional significance. J. Chem. Neuroanat.38, 241–256 (2009).
  • Kitahama K, Sakamoto N, Jouvet A, Nagatsu I, Pearson J. Dopamine-β-hydroxylase and tyrosine hydroxylase immunoreactive neurons in the human brainstem. J. Chem. Neuroanat.10, 137–146 (1996).
  • Ikemoto K, Nagatsu I, Nishimura A, Nishi K, Arai R. Do all of human midbrain tyrosine hydroxylase neurons synthesize dopamine? Brain Res.805, 255–258 (1998).
  • Ershov PV, Ugrumov MV, Calas A, Krieger M, Thibault J. Differentiation of tyrosine hydroxylase-synthesizing and/or aromatic L-amino acid decarboxylase-synthesizing neurons in the rat mediobasal hypothalamus: quantitative double-immunofluorescence study. J. Comp. Neurol.446, 114–122 (2002).
  • Hynes M, Porter JA, Chiang C et al. Induction of midbrain dopaminergic neurons by Sonic hedgehog. Neuron15, 35–44 (1995).
  • Prakash N, Brodski C, Naserke T et al. A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo. Development133, 89–98 (2006).
  • Castelo-Branco G, Wagner J, Rodriguez FJ et al. Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proc. Natl Acad. Sci. USA100, 12747–12752 (2003).
  • Simon HH, Saueressig H, Wurst W, Goulding MD, O’Leary DD. Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J. Neurosci.21, 3126–3134 (2001).
  • Saucedo-Cardenas O, Quintana-Hau JD, Le WD et al. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc. Natl Acad. Sci. USA95, 4013–4018 (1998).
  • Maxwell SL, Ho HY, Kuehner E, Zhao S, Li M. Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra and identifies a subgroup of mesencephalic dopaminergic progenitor neurons during mouse development. Dev. Biol.282, 467–479 (2005).
  • Kadkhodaei B, Ito T, Joodmardi E et al. Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J. Neurosci.29, 15923–15932 (2009).
  • Le W, Pan T, Huang M et al. Decreased Nurr1 gene expression in patients with Parkinson’s disease. J. Neurol. Sci.273, 29–33 (2008).
  • Ghee M, Baker H, Miller JC, Ziff EB. AP-1, CREB and CBP transcription factors differentially regulate the tyrosine hydroxylase gene. Brain Res. Mol. Brain Res.55, 101–114 (1998).
  • Kim KS, Lee MK, Carroll J, Joh TH. Both the basal and inducible transcription of the tyrosine hydroxylase gene are dependent upon a cAMP response element. J. Biol. Chem.268, 15689–15695 (1993).
  • Lewis-Tuffin LJ, Quinn PG, Chikaraishi DM. Tyrosine hydroxylase transcription depends primarily on cAMP response element activity, regardless of the type of inducing stimulus. Mol. Cell Neurosci.25, 536–547 (2004).
  • Tsarovina K, Pattyn A, Stubbusch J et al. Essential role of GATA transcription factors in sympathetic neuron development. Development131, 4775–4786 (2004).
  • Hong SJ, Huh Y, Chae H, Hong S, Lardaro T, Kim KS. GATA-3 regulates the transcriptional activity of tyrosine hydroxylase by interacting with CREB. J. Neurochem.98, 773–781 (2006).
  • Kwok RP, Lundblad JR, Chrivia JC et al. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature370, 223–226 (1994).
  • Jiang H, Liu L, Yang S, Tomomi T, Toru N. CREB-binding proteins (CBP) as a transcriptional coactivator of GATA-2. Sci. China C. Life Sci.51, 191–198 (2008).
  • Scherzer CR, Grass JA, Liao Z et al. GATA transcription factors directly regulate the Parkinson’s disease-linked gene α-synuclein. Proc. Natl Acad. Sci. USA105, 10907–10912 (2008).
  • Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW. Tyrosine hydroxylase phosphorylation: regulation and consequences. J. Neurochem.91, 1025–1043 (2004).
  • Cha-Molstad H, Keller DM, Yochum GS, Impey S, Goodman RH. Cell-type-specific binding of the transcription factor CREB to the cAMP-response element. Proc. Natl Acad. Sci. USA101, 13572–13577 (2004).
  • Johannessen M, Delghandi MP, Moens U. What turns CREB on? Cell. Signal.16, 1211–1227 (2004).
  • Hu SC, Chrivia J, Ghosh A. Regulation of CBP-mediated transcription by neuronal calcium signaling. Neuron22, 799–808 (1999).
  • Du X, Iacovitti L. Multiple signaling pathways direct the initiation of tyrosine hydroxylase gene expression in cultured brain neurons. Brain Res. Mol. Brain Res.50, 1–8 (1997).
  • Du X, Iacovitti L. Protein kinase C activators work in synergy with specific growth factors to initiate tyrosine hydroxylase expression in striatal neurons in culture. J. Neurochem.68, 564–569 (1997).
  • Anastasiadis PZ, Kuhn DM, Blitz J, Imerman BA, Louie MC, Levine RA. Regulation of tyrosine hydroxylase and tetrahydrobiopterin biosynthetic enzymes in PC12 cells by NGF, EGF and IFN-γ. Brain Res.713, 125–133 (1996).
  • Fuxe K, Tinner B, Zoli M et al. Computer-assisted mapping of basic fibroblast growth factor immunoreactive nerve cell populations in the rat brain. J. Chem. Neuroanat.11, 13–35 (1996).
  • Ditlevsen DK, Owczarek S, Berezin V, Bock E. Relative role of upstream regulators of Akt, ERK and CREB in NCAM- and FGF2-mediated signalling. Neurochem. Int.53, 137–147 (2008).
  • Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I. Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc. Natl Acad. Sci. USA98, 6074–6079 (2001).
  • Neiiendam JL, Kohler LB, Christensen C et al. An NCAM-derived FGF-receptor agonist, the FGL-peptide, induces neurite outgrowth and neuronal survival in primary rat neurons. J. Neurochem.91, 920–935 (2004).
  • Mograbi B, Bocciardi R, Bourget I et al. Glial cell line-derived neurotrophic factor-stimulated phosphatidylinositol 3-kinase and Akt activities exert opposing effects on the ERK pathway: importance for the rescue of neuroectodermic cells. J. Biol. Chem.276, 45307–45319 (2001).
  • Besset V, Scott RP, Ibanez CF. Signaling complexes and protein–protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase. J. Biol. Chem.275, 39159–39166 (2000).
  • Soler RM, Dolcet X, Encinas M, Egea J, Bayascas JR, Comella JX. Receptors of the glial cell line-derived neurotrophic factor family of neurotrophic factors signal cell survival through the phosphatidylinositol 3-kinase pathway in spinal cord motoneurons. J. Neurosci.19, 9160–9169 (1999).
  • Encinas M, Tansey MG, Tsui-Pierchala BA, Comella JX, Milbrandt J, Johnson EM Jr. c-Src is required for glial cell line-derived neurotrophic factor (GDNF) family ligand-mediated neuronal survival via a phosphatidylinositol-3 kinase (PI-3K)-dependent pathway. J. Neurosci.21, 1464–1472 (2001).
  • Pong K, Xu RY, Baron WF, Louis JC, Beck KD. Inhibition of phosphatidylinositol 3-kinase activity blocks cellular differentiation mediated by glial cell line-derived neurotrophic factor in dopaminergic neurons. J. Neurochem.71, 1912–1919 (1998).
  • Ries V, Cheng HC, Baohan A et al. Regulation of the postnatal development of dopamine neurons of the substantia nigra in vivo by Akt/protein kinase B. J. Neurochem.110, 23–33 (2009).
  • Ries V, Henchcliffe C, Kareva T et al. Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson’s disease. Proc. Natl Acad. Sci. USA103, 18757–18762 (2006).
  • Maurer JA, Wray S. Neuronal dopamine subpopulations maintained in hypothalamic slice explant cultures exhibit distinct tyrosine hydroxylase mRNA turnover rates. J. Neurosci.17, 4552–4561 (1997).
  • Chuang D, Zsilla G, Costa E. Turnover rate of tyrosine hydroxylase during trans-synaptic induction. Mol. Pharmacol.11, 784–794 (1975).
  • Keller S, Reichmann H, Gille G. 9-methyl-β-carboline inhibits monoamine oxidase activity and stimulates the expression of growth factors by astrocytes. Mov. Disord.25, 619 (2010).
  • Martinez R, Gomes FC. Neuritogenesis induced by thyroid hormone-treated astrocytes is mediated by epidermal growth factor/mitogen-activated protein kinase-phosphatidylinositol 3-kinase pathways and involves modulation of extracellular matrix proteins. J. Biol. Chem.277, 49311–49318 (2002).
  • Williams EJ, Walsh FS, Doherty P. Tyrosine kinase inhibitors can differentially inhibit integrin-dependent and CAM-stimulated neurite outgrowth. J. Cell Biol.124, 1029–1037 (1994).
  • Seidenfaden R, Krauter A, Hildebrandt H. The neural cell adhesion molecule NCAM regulates neuritogenesis by multiple mechanisms of interaction. Neurochem. Int.49, 1–11 (2006).
  • Ditlevsen DK, Povlsen GK, Berezin V, Bock E. NCAM-induced intracellular signaling revisited. J. Neurosci. Res.86, 727–743 (2008).
  • Wang DD, Bordey A. The astrocyte odyssey. Prog. Neurobiol.86, 342–367 (2008).
  • Cao JP, Wang HJ, Yu JK, Yang H, Xiao CH, Gao DS. Involvement of NCAM in the effects of GDNF on the neurite outgrowth in the dopamine neurons. Neurosci. Res.61, 390–397 (2008).
  • Zihlmann KB, Ducray AD, Schaller B et al. The GDNF family members neurturin, artemin and persephin promote the morphological differentiation of cultured ventral mesencephalic dopaminergic neurons. Brain Res. Bull.68, 42–53 (2005).
  • Beck KD. Functions of brain-derived neurotrophic factor, insulin-like growth factor-I and basic fibroblast growth factor in the development and maintenance of dopaminergic neurons. Prog. Neurobiol.44, 497–516 (1994).
  • Hyman C, Juhasz M, Jackson C, Wright P, Ip NY, Lindsay RM. Overlapping and distinct actions of the neurotrophins BDNF, NT-3, NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. J. Neurosci.14, 335–347 (1994).
  • Krieglstein K, Strelau J, Schober A, Sullivan A, Unsicker K. TGF-β and the regulation of neuron survival and death. J. Physiol. Paris96, 25–30 (2002).
  • Farkas LM, Dunker N, Roussa E, Unsicker K, Krieglstein K. Transforming growth factor-β(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo. J. Neurosci.23, 5178–5186 (2003).
  • Ben Gedalya T, Loeb V, Israeli E, Altschuler Y, Selkoe DJ, Sharon R. α-synuclein and polyunsaturated fatty acids promote clathrin-mediated endocytosis and synaptic vesicle recycling. Traffic10, 218–234 (2009).
  • Sidhu A, Wersinger C, Vernier P. α-synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson’s disease. FEBS Lett.565, 1–5 (2004).
  • Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ. A role for α-synuclein in the regulation of dopamine biosynthesis. J. Neurosci.22, 3090–3099 (2002).
  • Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL. Substrate-mediated enhancement of phosphorylated tyrosine hydroxylase in nigrostriatal dopamine neurons: evidence for a role of α-synuclein. J. Neurochem.96, 950–959 (2006).
  • Jensen PJ, Alter BJ, O’Malley KL. α-synuclein protects naive but not dbcAMP-treated dopaminergic cell types from 1-methyl-4-phenylpyridinium toxicity. J. Neurochem.86, 196–209 (2003).
  • Yuan Y, Sun J, Zhao M, Hu J, Wang X, Du G, Chen NH. Overexpression of α-synuclein down-regulates BDNF expression. Cell Mol. Neurobiol.30(6), 939–946 (2010).
  • Theodore S, Cao S, McLean PJ, Standaert DG. Targeted overexpression of human α-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol.67, 1149–1158 (2008).
  • Vekrellis K, Xilouri M, Emmanouilidou E, Stefanis L. Inducible over-expression of wild type α-synuclein in human neuronal cells leads to caspase-dependent non-apoptotic death. J. Neurochem.109, 1348–1362 (2009).
  • MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A. The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron52, 587–593 (2006).
  • Imai Y, Gehrke S, Wang HQ et al. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J.27, 2432–2443 (2008).
  • Tong Y, Yamaguchi H, Giaime E et al. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice. Proc. Natl Acad. Sci. USA107, 9879–9884 (2010).
  • Anderson DW, Bradbury KA, Schneider JS. Neuroprotection in Parkinson models varies with toxin administration protocol. Eur. J. Neurosci.24, 3174–3182 (2006).
  • Gao HM, Hong JS, Zhang W, Liu B. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J. Neurosci.22, 782–790 (2002).
  • Schagger H, Pfeiffer K. Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J.19, 1777–1783 (2000).
  • Stroh A, Anderka O, Pfeiffer K et al. Assembly of respiratory complexes I, III, and IV into NADH oxidase supercomplex stabilizes complex I in Paracoccus denitrificans. J. Biol. Chem.279, 5000–5007 (2004).
  • Schafer E, Seelert H, Reifschneider NH, Krause F, Dencher NA, Vonck J. Architecture of active mammalian respiratory chain supercomplexes. J. Biol. Chem.281, 15370–15375 (2006).
  • Radad K, Gille G, Rausch WD. Dopaminergic neurons are preferentially sensitive to long-term rotenone toxicity in primary cell culture. Toxicol. In Vitro22, 68–74 (2008).
  • Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol. Pharmacol.14, 633–643 (1978).
  • Bisaglia M, Tosatto L, Munari F et al. Dopamine quinones interact with α-synuclein to form unstructured adducts. Biochem. Biophys. Res. Commun.394, 424–428 (2010).
  • Hirai H, Pang Z, Bao D et al. Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat. Neurosci.8, 1534–1541 (2005).
  • Kusnoor SV, Muly EC, Morgan JI, Deutch AY. Is the loss of thalamostriatal neurons protective in parkinsonism? Parkinsonism Relat. Disord.15(Suppl. 3), S162–S166 (2009).
  • Jiang Q, Yan Z, Feng J. Neurotrophic factors stabilize microtubules and protect against rotenone toxicity on dopaminergic neurons. J. Biol. Chem.281, 29391–29400 (2006).
  • Bjorklund A, Rosenblad C, Winkler C, Kirik D. Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson’s disease. Neurobiol. Dis.4, 186–200 (1997).
  • Spina MB, Squinto SP, Miller J, Lindsay RM, Hyman C. Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity: involvement of the glutathione system. J. Neurochem.59, 99–106 (1992).
  • Lindholm P, Voutilainen MH, Lauren J et al. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature448, 73–77 (2007).
  • Hagg T. Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostriatal neurons in vivo. Exp. Neurol.149, 183–192 (1998).
  • Li Z, Hu Y, Zhu Q, Zhu J. Neurotrophin-3 reduces apoptosis induced by 6-OHDA in PC12 cells through Akt signaling pathway. Int. J. Dev. Neurosci.26, 635–640 (2008).
  • Kordower JH, Palfi S, Chen EY et al. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann. Neurol.46, 419–424 (1999).
  • Lang AE, Gill S, Patel NK et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol.59, 459–466 (2006).
  • Nutt JG, Burchiel KJ, Comella CL et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology60, 69–73 (2003).
  • Bortolato M, Chen K, Shih JC. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv. Drug Deliv. Rev.60, 1527–1533 (2008).
  • Mallajosyula JK, Kaur D, Chinta SJ et al. MAO-B elevation in mouse brain astrocytes results in Parkinson’s pathology. PLoS One3, e1616 (2008).
  • Malorni W, Giammarioli AM, Matarrese P et al. Protection against apoptosis by monoamine oxidase A inhibitors. FEBS Lett.426, 155–159 (1998).
  • Maruyama W, Youdim MB, Naoi M. Antiapoptotic properties of rasagiline, N-propargylamine-1(R)-aminoindan, and its optical (S)-isomer, TV1022. Ann. NY Acad. Sci.939, 320–329 (2001).
  • Szende B, Bokonyi G, Bocsi J, Keri G, Timar F, Magyar K. Anti-apoptotic and apoptotic action of (-)-deprenyl and its metabolites. J. Neural Transm.108, 25–33 (2001).
  • Zhang X, Zhou JY, Chin MH et al. Region-specific protein abundance changes in the brain of MPTP-induced Parkinson’s disease mouse model. J. Proteome Res.9, 1496–1509 (2010).
  • Collins GG, Youdim MB. Multiple forms of human brain monoamine oxidase: substrate specificities. Biochem. J.117, P43 (1970).
  • Youdim MB, Holman B. The nature of inhibition of cat brain mitochondrial monoamine oxidase by clorgyline. J. Neural Transm.37, 11–24 (1975).
  • Westlund KN, Krakower TJ, Kwan SW, Abell CW. Intracellular distribution of monoamine oxidase A in selected regions of rat and monkey brain and spinal cord. Brain Res.612, 221–230 (1993).
  • Youdim MB, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinson’s disease and depressive illness. Br. J. Pharmacol.147(Suppl. 1), S287–S296 (2006).
  • Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron39, 889–909 (2003).
  • Golbe LI. α-synuclein and Parkinson’s disease. Mov. Disord.14, 6–9 (1999).
  • Henze C, Hartmann A, Lescot T, Hirsch EC, Michel PP. Proliferation of microglial cells induced by 1-methyl-4-phenylpyridinium in mesencephalic cultures results from an astrocyte-dependent mechanism: role of granulocyte macrophage colony-stimulating factor. J. Neurochem.95, 1069–1077 (2005).
  • Duffy HS, John GR, Lee SC, Brosnan CF, Spray DC. Reciprocal regulation of the junctional proteins claudin-1 and connexin43 by interleukin-1β in primary human fetal astrocytes. J. Neurosci.20, RC114 (2000).
  • Wachtel M, Bolliger MF, Ishihara H, Frei K, Bluethmann H, Gloor SM. Down-regulation of occludin expression in astrocytes by tumour necrosis factor (TNF) is mediated via TNF type-1 receptor and nuclear factor-κB activation. J. Neurochem.78, 155–162 (2001).
  • Conti B, Park LC, Calingasan NY et al. Cultures of astrocytes and microglia express interleukin 18. Brain Res. Mol. Brain Res.67, 46–52 (1999).
  • Sugama S, Cho BP, Baker H, Joh TH, Lucero J, Conti B. Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS. Brain Res.958, 1–9 (2002).
  • Prinz M, Hanisch UK. Murine microglial cells produce and respond to interleukin-18. J. Neurochem.72, 2215–2218 (1999).
  • Sugama S, Fujita M, Hashimoto M, Conti B. Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18. Neuroscience146, 1388–1399 (2007).
  • Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Buhrer C, Stahel PF. IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci.28, 487–493 (2005).
  • Flynn G, Maru S, Loughlin J, Romero IA, Male D. Regulation of chemokine receptor expression in human microglia and astrocytes. J. Neuroimmunol.136, 84–93 (2003).
  • Dibaj P, Nadrigny F, Steffens H et al. NO mediates microglial response to acute spinal cord injury under ATP control in vivo. Glia58, 1133–1144 (2010).
  • Caggiano AO, Kraig RP. Eicosanoids and nitric oxide influence induction of reactive gliosis from spreading depression in microglia but not astrocytes. J. Comp. Neurol.369, 93–108 (1996).
  • Ebadi M, Sharma SK. Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson’s disease. Antioxid. Redox Signal.5, 319–335 (2003).
  • Chen S, Brown IR. Neuronal expression of constitutive heat shock proteins: implications for neurodegenerative diseases. Cell Stress Chaperones12, 51–58 (2007).
  • Acarin L, Paris J, Gonzalez B, Castellano B. Glial expression of small heat shock proteins following an excitotoxic lesion in the immature rat brain. Glia38, 1–14 (2002).
  • Kakimura J, Kitamura Y, Takata K et al. Microglial activation and amyloid-β clearance induced by exogenous heat-shock proteins. FASEB J.16, 601–603 (2002).
  • Yoshida M, Xia Y. Heat shock protein 90 as an endogenous protein enhancer of inducible nitric-oxide synthase. J. Biol. Chem.278, 36953–36958 (2003).
  • Clerget M, Polla BS. Erythrophagocytosis induces heat shock protein synthesis by human monocytes-macrophages. Proc. Natl Acad. Sci. USA87, 1081–1085 (1990).
  • Jeon GS, Park SW, Kim D et al. Glial expression of the 90-kDa heat shock protein (HSP90) and the 94-kDa glucose-regulated protein (GRP94) following an excitotoxic lesion in the mouse hippocampus. Glia48, 250–258 (2004).
  • Sriram K, Miller DB, O’Callaghan JP. Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-α. J. Neurochem.96, 706–718 (2006).
  • Trujillo JI, Meyers MJ, Anderson DR et al. Novel tetrahydro-β-carboline-1-carboxylic acids as inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg. Med. Chem. Lett.17, 4657–4663 (2007).
  • Wu JP, Wang J, Abeywardane A et al. The discovery of carboline analogs as potent MAPKAP-K2 inhibitors. Bioorg. Med. Chem. Lett.17, 4664–4669 (2007).
  • Palma JP, Kim BS. The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler’s virus. J. Neuroimmunol.149, 121–129 (2004).
  • Ambrosini E, Remoli ME, Giacomini E et al. Astrocytes produce dendritic cell-attracting chemokines in vitro and in multiple sclerosis lesions. J. Neuropathol. Exp. Neurol.64, 706–715 (2005).
  • Ambrosini E, Aloisi F. Chemokines and glial cells: a complex network in the central nervous system. Neurochem. Res.29, 1017–1038 (2004).
  • Mocco J, Mack WJ, Ducruet AF et al. Complement component C3 mediates inflammatory injury following focal cerebral ischemia. Circ. Res.99, 209–217 (2006).
  • Diez M, Abdelmagid N, Harnesk K et al. Identification of gene regions regulating inflammatory microglial response in the rat CNS after nerve injury. J. Neuroimmunol.212, 82–92 (2009).
  • Gonzalez P, Burgaya F, Acarin L, Peluffo H, Castellano B, Gonzalez B. Interleukin-10 and interleukin-10 receptor-I are upregulated in glial cells after an excitotoxic injury to the postnatal rat brain. J. Neuropathol. Exp. Neurol.68, 391–403 (2009).
  • Kremlev SG, Palmer C. Interleukin-10 inhibits endotoxin-induced pro-inflammatory cytokines in microglial cell cultures. J. Neuroimmunol.162, 71–80 (2005).
  • Strle K, Zhou JH, Shen WH, Broussard SR et al. Interleukin-10 in the brain. Crit. Rev. Immunol.21, 427–449 (2001).
  • LeWitt PA. Deprenyl’s effect at slowing progression of Parkinsonian disability: the DATATOP study. The Parkinson Study Group. Acta Neurol. Scand. Suppl.136, 79–86 (1991).
  • Mandel SA, Sagi Y, Amit T. Rasagiline promotes regeneration of substantia nigra dopaminergic neurons in post-MPTP-induced Parkinsonism via activation of tyrosine kinase receptor signaling pathway. Neurochem. Res.32, 1694–1699 (2007).
  • Mandel S, Maor G, Youdim MB. Iron and α-synuclein in the substantia nigra of MPTP-treated mice: effect of neuroprotective drugs R-apomorphine and green tea polyphenol (-)-epigallocatechin-3-gallate. J. Mol. Neurosci.24, 401–416 (2004).
  • Zhu W, Xie W, Pan T et al. Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators. FASEB J.21, 3835–3844 (2007).
  • Zhu W, Xie W, Pan T et al. Comparison of neuroprotective and neurorestorative capabilities of rasagiline and selegiline against lactacystin-induced nigrostriatal dopaminergic degeneration. J. Neurochem.105, 1970–1978 (2008).
  • Weinreb O, Amit T, Bar-Am O, Youdim MB. Rasagiline; a novel anti-Parkinsonian monoamine oxidase-b inhibitor with neuroprotective activity. Prog. Neurobiol. (2010).
  • Weinreb O, Amit T, Sagi Y, Drigues N, Youdim MB. Genomic and proteomic study to survey the mechanism of action of the anti-Parkinson’s disease drug, rasagiline compared with selegiline, in the rat midbrain. J. Neural Transm.116, 1457–1472 (2009).
  • Sagi Y, Mandel S, Amit T, Youdim MB. Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism. Neurobiol. Dis.25, 35–44 (2007).
  • Weinreb O, Amit T, Bar-Am O, Youdim MB. Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. Ann. NY Acad. Sci.1122, 155–168 (2007).
  • Weinreb O, Amit T, Bar-Am O, Sagi Y, Mandel S, Youdim MB. Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety. J. Neural Transm. Suppl. (70), 457–465 (2006).
  • Ton TG, Heckbert SR, Longstreth WT et al. Nonsteroidal anti-inflammatory drugs and risk of Parkinson’s disease. Mov. Disord.21, 964–969 (2006).
  • Gagne JJ, Power MC. Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology74, 995–1002 (2010).
  • Arib O, Rat P, Molimard R, Chait A, Faure P, de Beaurepaire R. Electrophysiological characterization of harmane-induced activation of mesolimbic dopamine neurons. Eur. J. Pharmacol.629, 47–52 (2010).
  • Ruiz-Durantez E, Ruiz-Ortega JA, Pineda J, Ugedo L. Stimulatory effect of harmane and other β-carbolines on locus coeruleus neurons in anaesthetized rats. Neurosci. Lett.308, 197–200 (2001).
  • Abe A, Yamada H. Harmol induces apoptosis by caspase-8 activation independently of Fas/Fas ligand interaction in human lung carcinoma H596 cells. Anticancer Drugs20, 373–381 (2009).
  • Herraiz T, Gonzalez D, Ancin-Azpilicueta C, Aran VJ, Guillen H. β-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food Chem. Toxicol.48, 839–845 (2010).

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