Advertisement

Organic Cation Transporters as Modulators of Neurodegeneration and Neuroprotection in the Brain

  • Kim TieuEmail author
Chapter
  • 453 Downloads

Abstract

The organic cation transporters have emerged as important regulators in human health and diseases. This chapter will discuss the latest studies demonstrating how a sub-group of these transporters, the organic cation transporter-3 (OCT3), would modulate neurodegeneration and neuroprotection in the brain. These roles of OCT3 have been documented in the dopaminegic nigrostriatal system, a pathway that is affected in Parkinson’s disease (PD). Three experimental models of nigrostriatal neurotoxicity will be discussed to illustrate how OCT3 modulate cell viability. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, previously discovered to cause parkinsonism in a group of drug addicts) mouse model, blocking OCT3 function is neuroprotective. However, OCT3 deletion enhances neurotoxicity in the paraquat (a herbicide that increases the risk of developing PD) and methamphetamine mouse models. These observations are consistent with the ability of OCT3 to bi-directionally transport these toxins and consistent with the expression pattern of OCT3 in the brain. Polymorphisms of OCT3 have been reported in humans and this transporter is suggested to be a susceptibility gene contributing to PD.

Keywords

Parkinson’s disease Neurodegeneration Neurotoxicity Neuroprotection Organic cation transporter-3 Astrocytes Paraquat MPTP Methamphetamine Dopamine 

References

  1. 1.
    Sprowl JA, Ciarimboli G, Lancaster CS, Giovinazzo H, Gibson AA, Du G, et al. Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci U S A. 2013;110(27):11199–204.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Cui M, Aras R, Christian WV, Rappold PM, Hatwar M, Panza J, et al. The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci U S A. 2009;106(19):8043–8.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Rappold PM, Cui M, Chesser AS, Tibbett J, Grima JC, Duan L, et al. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci U S A. 2011;108(51):20766–71.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39(6):889–909.PubMedCrossRefGoogle Scholar
  5. 5.
    Krusz JC, Koller WC, Ziegler DK. Historical review: abnormal movements associated with epidemic encephalitis lethargica. Mov Disord. 1987;2(3):137–41.PubMedCrossRefGoogle Scholar
  6. 6.
    Calne DB, Lees AJ. Late progression of post-encephalitic Parkinson’s syndrome. Can J Neurol Sci. 1988;15(2):135–8.PubMedGoogle Scholar
  7. 7.
    Langston JW, Ballard P, Irwin I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219:979–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Bowman AB, Kwakye GF, Herrero Hernández E, Aschner M. Role of manganese in neurodegenerative diseases. J Trace Elem Med Biol. 2011;25(4):191–203.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Tanner CM. Epidemiology of Parkinson’s disease. Neurol Clin. 1992;10(2):317–29.PubMedGoogle Scholar
  10. 10.
    Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, et al. Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology. 1997;48(6):1583–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Hertzman C, Wiens M, Bowering D, Snow B, Calne D. Parkinson’s disease: a case-control study of occupational and environmental risk factors. Am J Ind Med. 1990;17(3):349–55.PubMedCrossRefGoogle Scholar
  12. 12.
    Ritz BR, Manthripragada AD, Costello S, Lincoln SJ, Farrer MJ, Cockburn M, et al. Dopamine transporter genetic variants and pesticides in Parkinson’s disease. Environ Health Perspect. 2009;117(6):964–9.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Gatto NM, Cockburn M, Bronstein J, Manthripragada AD, Ritz B. Well-water consumption and Parkinson’s disease in rural California. Environ Health Perspect. 2009;117(12):1912–8.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, et al. Rotenone, paraquat and Parkinson’s Disease. Environ Health Perspect. 2011;119(6):866–72.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, et al. Chronic parkinsonism secondary to intravenous injection of meperidine analogs. Psychiatry Res. 1979;1:249–54.PubMedCrossRefGoogle Scholar
  16. 16.
    Tieu K. A guide to neurotoxic animal models of Parkinson’s Disease. Cold Spring Harb Perspect Med. 2011;1:a009316.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Rappold PM, Tieu K. Astrocytes and therapeutics for Parkinson’s disease. Neurotherapeutics. 2010;7(4):413–23.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridinium by dopamine neurons explain selective toxicity. Proc Natl Acad Sci U S A. 1985;82:2173–7.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Bezard E, Gross CE, Fournier MC, Dovero S, Bloch B, Jaber M. Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol. 1999;155(2):268–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Miller GW, Gainetdinov RR, Levey AI, Caron MG. Dopamine transporters and neuronal injury. Trends Pharmacol Sci. 1999;20(10):424–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Namura I, Douillet P, Sun CJ, Pert A, Cohen RM, Chiueh CC. MPP+ (1-methyl-4-phenylpyridine) is a neurotoxin to dopamine-, norepinephrine- and serotonin-containing neurons. Eur J Pharmacol. 1987;136(1):31–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res. 2007;24(7):1227–51.PubMedCrossRefGoogle Scholar
  23. 23.
    Courousse T, Gautron S. Role of organic cation transporters (OCTs) in the brain. Pharmacol Ther. 2014;14:10.Google Scholar
  24. 24.
    Grundemann D, Schechinger B, Rappold GA, Schomig E. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci. 1998;1(5):349–51.PubMedCrossRefGoogle Scholar
  25. 25.
    Wu X, Kekuda R, Huang W, Fei YJ, Leibach FH, Chen J, et al. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem. 1998;273(49):32776–86.PubMedCrossRefGoogle Scholar
  26. 26.
    Slitt AL, Cherrington NJ, Hartley DP, Leazer TM, Klaassen CD. Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab Dispos. 2002;30(2):212–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Gasser PJ, Lowry CA, Orchinik M. Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J Neurosci. 2006;26(34):8758–66.PubMedCrossRefGoogle Scholar
  28. 28.
    Vialou V, Balasse L, Callebert J, Launay JM, Giros B, Gautron S. Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem. 2008;106(3):1471–82.PubMedGoogle Scholar
  29. 29.
    Takeda H, Inazu M, Matsumiya T. Astroglial dopamine transport is mediated by norepinephrine transporter. Naunyn Schmiedebergs Arch Pharmacol. 2002;366(6):620–3.PubMedCrossRefGoogle Scholar
  30. 30.
    Shang T, Uihlein AV, Van Asten J, Kalyanaraman B, Hillard CJ. 1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. J Neurochem. 2003;85(2):358–67.PubMedCrossRefGoogle Scholar
  31. 31.
    Inazu M, Takeda H, Matsumiya T. Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes. J Neurochem. 2003;84(1):43–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Russ H, Staust K, Martel F, Gliese M, Schomig E. The extraneuronal transporter for monoamine transmitters exists in cells derived from human central nervous system glia. Eur J Neurosci. 1996;8(6):1256–64.PubMedCrossRefGoogle Scholar
  33. 33.
    Schomig E, Russ H, Staudt K, Martel F, Gliese M, Grundemann D. The extraneuronal monoamine transporter exists in human central nervous system glia. Adv Pharmacol. 1998;42:356–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH, et al. Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem. 1998;273(26):15971–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Grundemann D, Liebich G, Kiefer N, Koster S, Schomig E. Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol. 1999;56(1):1–10.PubMedGoogle Scholar
  36. 36.
    Martel F, Keating E, Calhau C, Grundemann D, Schomig E, Azevedo I. Regulation of human extraneuronal monoamine transporter (hEMT) expressed in HEK293 cells by intracellular second messenger systems. Naunyn Schmiedebergs Arch Pharmacol. 2001;364(6):487–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Russ H, Gliese M, Sonna J, Schomig E. The extraneuronal transport mechanism for noradrenaline (uptake2) avidly transports 1-methyl-4-phenylpyridinium (MPP+). Naunyn Schmiedebergs Arch Pharmacol. 1992;346(2):158–65.PubMedCrossRefGoogle Scholar
  38. 38.
    Clejan L, Cederbaum AI. Synergistic interactions between NADPH-cytochrome P-450 reductase, paraquat, and iron in the generation of active oxygen radicals. Biochem Pharmacol. 1989;38(11):1779–86.PubMedCrossRefGoogle Scholar
  39. 39.
    Bus JS, Gibson JE. Paraquat: model for oxidant-initiated toxicity. Environ Health Perspect. 1984;55:37–46.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Day BJ, Patel M, Calavetta L, Chang LY, Stamler JS. A mechanism of paraquat toxicity involving nitric oxide synthase. Proc Natl Acad Sci U S A. 1999;96(22):12760–5.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Smith JG. Paraquat poisoning by skin absorption: a review. Hum Toxicol. 1988;7(1):15–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Grant H, Lantos PL, Parkinson C. Cerebral damage in paraquat poisoning. Histopathology. 1980;4(2):185–95.PubMedCrossRefGoogle Scholar
  43. 43.
    Hughes JT. Brain damage due to paraquat poisoning: a fatal case with neuropathological examination of the brain. Neurotoxicology. 1988;9(2):243–8.PubMedGoogle Scholar
  44. 44.
    Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ. Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res. 1999;823(1–2):1–10.PubMedCrossRefGoogle Scholar
  45. 45.
    McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, et al. Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis. 2002;10(2):119–27.PubMedCrossRefGoogle Scholar
  46. 46.
    Thiruchelvam M, McCormack A, Richfield EK, Baggs RB, Tank AW, Di Monte DA, et al. Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson’s disease phenotype. Eur J Neurosci. 2003;18(3):589–600.PubMedCrossRefGoogle Scholar
  47. 47.
    Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem. 2002;277(3):1641–4.PubMedCrossRefGoogle Scholar
  48. 48.
    Shimizu K, Ohtaki K, Matsubara K, Aoyama K, Uezono T, Saito O, et al. Carrier-mediated processes in blood--brain barrier penetration and neural uptake of paraquat. Brain Res. 2001;906(1–2):135–42.PubMedCrossRefGoogle Scholar
  49. 49.
    McCormack AL, Di Monte DA. Effects of L-dopa and other amino acids against paraquat-induced nigrostriatal degeneration. J Neurochem. 2003;85(1):82–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Barlow BK, Thiruchelvam MJ, Bennice L, Cory-Slechta DA, Ballatori N, Richfield EK. Increased synaptosomal dopamine content and brain concentration of paraquat produced by selective dithiocarbamates. J Neurochem. 2003;85(4):1075–86.PubMedCrossRefGoogle Scholar
  51. 51.
    Richardson JR, Quan Y, Sherer TB, Greenamyre JT, Miller GW. Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci. 2005;88:193–201.PubMedCrossRefGoogle Scholar
  52. 52.
    Miller GW. Paraquat: the red herring of Parkinson’s disease research. Toxicol Sci. 2007;100(1):1–2.PubMedCrossRefGoogle Scholar
  53. 53.
    Cory-Slechta DA, Thiruchelvam M, Di Monte DA. Letter regarding: “Paraquat: the red herring of Parkinson’s disease research”. Toxicol Sci. 2008;103(1):215–6.PubMedCrossRefGoogle Scholar
  54. 54.
    LoPachin RM, Gavin T. Response to “Paraquat: the red herring of Parkinson’s disease research”. Toxicol Sci. 2008;103(1):219–21.PubMedCrossRefGoogle Scholar
  55. 55.
    Zaczek R, Culp S, Goldberg H, Mccann DJ, De Souza EB. Interactions of [3H]amphetamine with rat brain synaptosomes. I. Saturable sequestration. J Pharmacol Exp Ther. 1991;257(2):820–9.PubMedGoogle Scholar
  56. 56.
    Zaczek R, Culp S, De Souza EB. Interactions of [3H]amphetamine with rat brain synaptosomes. II. Active transport. J Pharmacol Exp Ther. 1991;257(2):830–5.PubMedGoogle Scholar
  57. 57.
    Fumagalli F, Gainetdinov RR, Valenzano KJ, Caron MG. Role of dopamine transporter in methamphetamine-induced neurotoxicity: evidence from mice lacking the transporter. J Neurosci. 1998;18(13):4861–9.PubMedGoogle Scholar
  58. 58.
    Sulzer D, Chen T-K, Lau YY, Kristensen H, Rayport S, Ewing A. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci. 1995;15:4102–8.PubMedGoogle Scholar
  59. 59.
    Sulzer D, Maidment NT, Rayport S. Amphetamine and other weak bases act to promote reverse transport of dopamine in ventral midbrain neurons. J Neurochem. 1993;60(2):527–35.PubMedCrossRefGoogle Scholar
  60. 60.
    Scorza MC, Carrau C, Silveira R, Zapata-Torres G, Cassels BK, Reyes-Parada M. Monoamine oxidase inhibitory properties of some methoxylated and alkylthio amphetamine derivatives: structure-activity relationships. Biochem Pharmacol. 1997;54(12):1361–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Clausing P, Bowyer JF. Time course of brain temperature and caudate/putamen microdialysate levels of amphetamine and dopamine in rats after multiple doses of d-amphetamine. Ann N Y Acad Sci. 1999;890:495–504.PubMedCrossRefGoogle Scholar
  62. 62.
    Kita T, Matsunari Y, Saraya T, Shimada K, O’Hara K, Kubo K, et al. Methamphetamine-induced striatal dopamine release, behavior changes and neurotoxicity in BALB/c mice. Int J Dev Neurosci. 2000;18(6):521–30.PubMedCrossRefGoogle Scholar
  63. 63.
    Segal DS, Kuczenski R. Behavioral pharmacology of amphetamine. In: Cho AK, Segal DS, editors. Amphetamine and its analogs, Psychopharmacology, toxicology, and abuse. New York: Academic; 1994. p. 115–50.Google Scholar
  64. 64.
    Ricaurte GA, Sabol KE, Seiden LS. Functional consequences of neurotoxic amphetamine exposure. In: Cho AK, Segal DS, editors. Amphetamine and its analogs, Psychopharmacology, toxicology, and abuse. New York: Academic; 1994. p. 297–313.Google Scholar
  65. 65.
    Cubells JF, Rayport S, Rajendran G, Sulzer D. Methamphetamine neurotoxicity involves vacuolation of endocytic organelles and dopamine-dependent intracellular oxidative stress. J Neurosci. 1994;14:2260–71.PubMedGoogle Scholar
  66. 66.
    Fumagalli F, Gainetdinov RR, Wang YM, Valenzano KJ, Miller GW, Caron MG. Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice. J Neurosci. 1999;19(7):2424–31.PubMedGoogle Scholar
  67. 67.
    Cadet JL, Krasnova IN, Jayanthi S, Lyles J. Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms. Neurotox Res. 2007;11(3–4):183–202.PubMedCrossRefGoogle Scholar
  68. 68.
    Amphoux A, Vialou V, Drescher E, Bruss M, La Cour CM, Rochat C, et al. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006;50(8):941–52.PubMedCrossRefGoogle Scholar
  69. 69.
    Nakayama H, Kitaichi K, Ito Y, Hashimoto K, Takagi K, Yokoi T, et al. The role of organic cation transporter-3 in methamphetamine disposition and its behavioral response in rats. Brain Res. 2007;1184:260–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Kitayama S, Mitsuhata C, Davis S, Wang JB, Sato T, Morita K, et al. MPP+ toxicity and plasma membrane dopamine transporter: study using cell lines expressing the wild-type and mutant rat dopamine transporters. Biochim Biophys Acta. 1998;1404(3):305–13.PubMedCrossRefGoogle Scholar
  71. 71.
    Itokawa M, Lin Z, Uhl GR. Dopamine efflux via wild-type and mutant dopamine transporters: alanine substitution for proline-572 enhances efflux and reduces dependence on extracellular dopamine, sodium and chloride concentrations. Brain Res Mol Brain Res. 2002;108(1–2):71–80.PubMedCrossRefGoogle Scholar
  72. 72.
    Lazar A, Grundemann D, Berkels R, Taubert D, Zimmermann T, Schomig E. Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet. 2003;48(5):226–30.PubMedCrossRefGoogle Scholar
  73. 73.
    Aoyama N, Takahashi N, Kitaichi K, Ishihara R, Saito S, Maeno N, et al. Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder. Alcohol Clin Exp Res. 2006;30(10):1644–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, Pugh EW, et al. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet. 2009;124(6):593–605.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Clinical Neurobiology, Institute of Translational and Stratified MedicinePlymouth UniversityPlymouthUK

Personalised recommendations