Altered Brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease)

Sleep Medicine

Volumn 15, Issue 11, 2014, Pages 1288-1301

  Earley, Christopher J ^a   Connor, James ^b   Garcia Borreguero, Diego ^c   Jenner, Peter ^d   Winkelman, John ^e   Zee, Phyllis C ^f   Allen, Richard ^a  

^a JOHNS HOPKINS BAYVIEW MEDICAL CENTER   (United States)

^b PENN STATE COLLEGE OF MEDICINE   (United States)

^c SLEEP RESEARCH INSTITUTE   (Spain)

^d KING'S COLLEGE LONDON   (United Kingdom)

^e BRIGHAM AND WOMEN S HOSPITAL   (United States)

^f NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Animal models; Dopamine; Hypoxia inducible factor; Imaging; Iron deficiency; Sleep disorders

Indexed keywords

DOPAMINE 1 RECEPTOR; DOPAMINE 2 RECEPTOR; DOPAMINE TRANSPORTER; FERRITIN; FERROPORTIN; HYPOXIA INDUCIBLE FACTOR 1BETA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; IRON REGULATORY PROTEIN 1; IRON REGULATORY PROTEIN 2; MESSENGER RNA; TRANSFERRIN RECEPTOR; VASCULOTROPIN; IRON;

AUTOPSY; BRAIN LEVEL; BTBD9 GENE; DISEASE ASSOCIATION; DOPAMINE METABOLISM; DOPAMINERGIC ACTIVITY; DOPAMINERGIC TRANSMISSION; GENE; GENETIC ASSOCIATION; HUMAN; IRON BALANCE; IRON DEFICIENCY; IRON METABOLISM; IRON RESPONSIVE ELEMENT; MEIS1 GENE; NEUROIMAGING; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOLOGY; POSITRON EMISSION TOMOGRAPHY; RESTLESS LEGS SYNDROME; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; SYNAPTIC TRANSMISSION; ANIMAL; BRAIN; DEFICIENCY; DOPAMINERGIC NERVE CELL; HOMEOSTASIS; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; BRAIN; DOPAMINERGIC NEURONS; HOMEOSTASIS; HUMANS; IRON; RESTLESS LEGS SYNDROME;

EID: 84908463653     PISSN: 13899457     EISSN: 18785506     Source Type: Journal    
DOI: 10.1016/j.sleep.2014.05.009     Document Type: Review

References (152)

1. Hening W.A., Walters A.S., Wagner M., Rosen R., Chen V., Kim S., et al. Circadian rhythm of motor restlessness and sensory symptoms in the idiopathic restless legs syndrome. Sleep 1999, 22:901-912.
2. Earley C.J., Allen R.P., Hening W. Restless legs syndrome and periodic leg movements in sleep. Handbook Clin Neurol 2011, 99:913-948.
3. Garcia-Borreguero D., Stillman P., Benes H., Buschmann H., Chaudhuri K.R., Gonzalez Rodriguez V.M., et al. Algorithms for the diagnosis and treatment of restless legs syndrome in primary care. BMC Neurol 2011, 11:28.
4. Trenkwalder C., Hening W.A., Montagna P., Oertel W.H., Allen R.P., Walters A.S., et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord 2008, 23:2267-2302.
5. Trenkwalder C., Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010, 6:337-346.
6. Winkelman J.W., Allen R.P., Tenzer P., Hening W. Restless legs syndrome: nonpharmacologic and pharmacologic treatments. Geriatrics 2007, 62:13-16.
7. Nordlander N.B. Therapy in restless legs. Acta Med Scand 1953, 145:453-457.
8. Allen R.P., Earley C.J. The role of iron in restless legs syndrome. Mov Disord 2007, 22(Suppl. 18):S440-S448.
9. Allen R.P., Auerbach S., Bahrain H., Auerbach M., Earley C.J. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013, 88:261-264.
10. Allen R.P., Walters A.S., Montplaisir J., Hening W., Myers A., Bell T.J., et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005, 165:1286-1292.
11. Nordlander N.B. Restless legs. Br J Phys Med 1954, 17:160-162.
12. Beard J. Iron deficiency alters brain development and functioning. J Nutr 2003, 133:1468S-1472S.
13. Beard J.L. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr 2001, 131:568S-579S. discussion 580S.
14. Beard J.L., Connor J.R., Jones B.C. Iron in the brain. Nutr Rev 1993, 51:157-170.
15. Fishman J.B., Rubin J.B., Handrahan J.V., Connor J.R., Fine R.E. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J Neurosci Res 1987, 18:299-304.
16. Connor J.R., Ponnuru P., Wang X.S., Patton S.M., Allen R.P., Earley C.J. Profile of altered brain iron acquisition in restless legs syndrome. Brain 2011, 134:959-968.
17. Gulyani S., Earley C.J., Camandola S., Maudsley S., Ferre S., Mughal M.R., et al. Diminished iron concentrations increase adenosine A(2A) receptor levels in mouse striatum and cultured human neuroblastoma cells. Exp Neurol 2009, 215:236-242.
18. Walters A.S., Ondo W.G., Zhu W., Le W. Does the endogenous opiate system play a role in the Restless Legs Syndrome? A pilot post-mortem study. J Neurol Sci 2009, 279:62-65.
19. Allen R.P., Barker P.B., Horska A., Earley C.J. Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. Neurology 2013, 80:2028-2034. Epub 2013/04/30.
20. Beard J.L., Chen Q., Connor J., Jones B.C. Altered monamine metabolism in caudate-putamen of iron-deficient rats. Pharmacol Biochem Behav 1994, 48:621-624.
21. Bianco L.E., Unger E.L., Earley C.J., Beard J.L. Iron deficiency alters the day-night variation in monoamine levels in mice. Chronobiol Int 2009, 26:447-463.
22. Bianco L.E., Wiesinger J., Earley C.J., Jones B.C., Beard J.L. Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats. J Neurochem 2008, 106:205-215.
23. Connor J.R., Wang X.S., Allen R.P., Beard J.L., Wiesinger J.A., Felt B.T., et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 2009, 132:2403-2412.
24. Erikson K.M., Jones B.C., Beard J.L. Iron deficiency alters dopamine transporter functioning in rat striatum. J Nutr 2000, 130:2831-2837.
25. Erikson K.M., Jones B.C., Hess E.J., Zhang Q., Beard J.L. Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav 2001, 69:409-418.
26. Glover J., Jacobs A. Activity pattern of iron-deficient rats. Br Med J 1972, 2:627-628.
27. Nelson C., Erikson K., Pinero D.J., Beard J.L. In vivo dopamine metabolism is altered in iron-deficient anemic rats. J Nutr 1997, 127:2282-2288.
28. Ondo W.G., Zhao H.R., Le W.D. Animal models of restless legs syndrome. Sleep Med 2007, 8:344-348.
29. Unger E.L., Earley C.J., Beard J.L. Diurnal cycle influences peripheral and brain iron levels in mice. J Appl Physiol 2009, 106:187-193.
30. Unger E.L., Earley C.J., Thomsen L.L., Jones B.C., Allen R.P. Effects of IV iron isomaltoside-1000 treatment on regional brain iron status in an iron-deficient animal. Neuroscience 2013, 246:179-185.
31. Mefford I.N. Application of high performance liquid chromatography with electrochemical detection to neurochemical analysis: measurement of catecholamines, serotonin and metabolites in rat brain. J Neurosci Methods 1981, 3:207-224.
32. Refshauge C., Kissinger P.T., Dreiling R., Blank L., Freeman R., Adams R.N. New high performance liquid chromatographic analysis of brain catecholamines. Life Sci 1974, 14:311-322.
33. Bungay P.M., Newton-Vinson P., Isele W., Garris P.A., Justice J.B. Microdialysis of dopamine interpreted with quantitative model incorporating probe implantation trauma. J Neurochem 2003, 86:932-946.
34. Chefer V.I., Zapata A., Shippenberg T.S., Bungay P.M. Quantitative no-net-flux microdialysis permits detection of increases and decreases in dopamine uptake in mouse nucleus accumbens. J Neurosci Methods 2006, 155:187-193.
35. Unger E.L., Wiesinger J.A., Hao L., Beard J.L. Dopamine D2 receptor expression is altered by changes in cellular iron levels in PC12 cells and rat brain tissue. J Nutr 2008, 138:2487-2494.
36. Zhao H., Zhu W., Pan T., Xie W., Zhang A., Ondo W.G., et al. Spinal cord dopamine receptor expression and function in mice with 6-OHDA lesion of the A11 nucleus and dietary iron deprivation. J Neurosci Methods 2007, 85:1065-1076.
37. Barraud Q., Obeid I., Aubert I., Barriere G., Contamin H., McGuire S., et al. Neuroanatomical study of the A11 diencephalospinal pathway in the non-human primate. PLoS ONE 2010, 5:e13306.
38. Baier P.C., Ondo W.G., Winkelmann J. Animal studies in restless legs syndrome. Mov Disord 2007, 22(Suppl. 18):S459-S465.
39. Clemens S., Rye D., Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006, 67:125-130.
40. Qu S., Ondo W.G., Zhang X., Xie W.J., Pan T.H., Le W.D. Projections of diencephalic dopamine neurons into the spinal cord in mice. Exp Brain Res 2006, 168:152-156.
41. Ondo W.G., He Y., Rajasekaran S., Le W.D. Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord 2000, 15:154-158.
42. Earley C.J., Allen R.P., Connor J.R., Ferrucci L., Troncoso J. The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal. Sleep Med 2009, 10:1155-1157.
43. Collado-Seidel V., Kohnen R., Samtleben W., Hillebrand G.F., Oertel W.H., Trenkwalder C. Clinical and biochemical findings in uremic patients with and without restless legs syndrome. Am J Kidney Dis 1998, 31:324-328.
44. Araujo S.M., de Bruin V.M., Nepomuceno L.A., Maximo M.L., Daher Ede F., Correia Ferrer D.P., et al. Restless legs syndrome in end-stage renal disease: clinical characteristics and associated comorbidities. Sleep Med 2010, 11:785-790.
45. Hogl B., Kiechl S., Willeit J., Saletu M., Frauscher B., Seppi K., et al. Restless legs syndrome: a community-based study of prevalence, severity, and risk factors. Neurology 2005, 64:1920-1924.
46. Earley C.J., Connor J.R., Beard J.L., Malecki E.A., Epstein D.K., Allen R.P. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000, 54:1698-1700.
47. Earley C.J., Connor J.R., Beard J.L., Clardy S.L., Allen R.P. Ferritin levels in the cerebrospinal fluid and restless legs syndrome: effects of different clinical phenotypes. Sleep 2005, 28:1069-1075.
48. Eisenstein R.S. Iron regulatory proteins and the molecular control of mammalian iron metabolism. Annu Rev Nutr 2000, 20:627-662.
49. Mizuno S., Mihara T., Miyaoka T., Inagaki T., Horiguchi J. CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 2005, 14:43-47.
50. Clardy S.L., Wang X., Boyer P.J., Earley C.J., Allen R.P., Connor J.R. Is ferroportin-hepcidin signaling altered in restless legs syndrome?. J Neurol Sci 2006, 247:173-179.
51. Ganz T., Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta 2012, 1823:1434-1443.
52. Earley C.J., Hyland K., Allen R.P. CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome. Mov Disord 2001, 16:144-149.
53. Earley C.J., Hyland K., Allen R.P. Circadian changes in CSF dopaminergic measures in restless legs syndrome. Sleep Med 2006, 7:263-268.
54. Lovenberg W., Levine R.A., Robinson D.S., Ebert M., Williams A.C., Calne D.B. Hydroxylase cofactor activity in cerebrospinal fluid of normal subjects and patients with Parkinson's disease. Science 1979, 204:624-626.
55. Williams A., Ballenger J., Levine R., Lovenberg W., Calne D. Aging and CSF hydroxylase cofactor. Neurology 1980, 30:1244-1246.
56. Stiasny-Kolster K., Moller J.C., Zschocke J., Bandmann O., Cassel W., Oertel W.H., et al. Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients. Mov Disord 2004, 19:192-196.
57. Allen R.P., Connor J.R., Hyland K., Earley C.J. Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis. Sleep Med 2009, 10:123-128.
58. Connor J.R., Boyer P.J., Menzies S.L., Dellinger B., Allen R.P., Ondo W.G., et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003, 61:304-309.
59. Connor J.R., Wang X.S., Patton S.M., Menzies S.L., Troncoso J.C., Earley C.J., et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 2004, 62:1563-1567.
60. Todorich B., Zhang X., Slagle-Webb B., Seaman W.E., Connor J.R. Tim-2 is the receptor for H-ferritin on oligodendrocytes. J Neurochem 2008, 107:1495-1505.
61. Connor J.R., Menzies S.L., St Martin S.M., Mufson E.J. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res 1990, 27:595-611.
62. Pantopoulos K. Iron metabolism and the IRE/IRP regulatory system: an update. Ann N Y Acad Sci 2004, 1012:1-13.
63. Sanchez M., Galy B., Muckenthaler M.U., Hentze M.W. Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat Struct Mol Biol 2007, 14:420-426.
64. Snyder A.M., Wang X., Patton S.M., Arosio P., Levi S., Earley C.J., et al. Mitochondrial ferritin in the substantia nigra in restless legs syndrome. J Neuropathol Exp Neurol 2009, 68:1193-1199.
65. Ye H., Rouault T.A. Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 2010, 49:4945-4956.
66. Allen R.P., Barker P.B., Wehrl F., Song H.K., Earley C.J. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001, 56:263-265.
67. Astrakas L.G., Konitsiotis S., Margariti P., Tsouli S., Tzarouhi L., Argyropoulou M.I. T2 relaxometry and fMRI of the brain in late-onset restless legs syndrome. Neurology 2008, 71:911-916.
68. Earley C.J., B Barker P., Horska A., Allen R.P. MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med 2006, 7:458-461.
69. Godau J., Klose U., Di Santo A., Schweitzer K., Berg D. Multiregional brain iron deficiency in restless legs syndrome. Mov Disord 2008, 23:1184-1187.
70. Godau J., Schweitzer K.J., Liepelt I., Gerloff C., Berg D. Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome. Mov Disord 2007, 22:187-192.
71. Lee B.-L., Farace E., Vesek J., Wang J., Connor J.R., Yang Q. In vivo measurement of iron deficiency in restless legs syndrome (RLS) with voxel-based R2 relaxometry. Proc Int Soc Mag Reson Med 2007, 427. Abstract 2170.
72. Knake S., Heverhagen J., Menzler K., Keil B., Oertel W., Stiasny-Kolster K. Normal regional brain iron concentration in restless legs syndrome measured by MRI. Nat Sci Sleep 2010, 2:19-22.
73. Haba-Rubio J., Staner L., Petiau C., Erb G., Schunck T., Macher J.P. Restless legs syndrome and low brain iron levels in patients with haemochromatosis. J Neurol Neurosurg Psychiatry 2005, 76:1009-1010.
74. Schmidauer C., Sojer M., Seppi K., Stockner H., Hogl B., Biedermann B., et al. Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann Neurol 2005, 58:630-634.
75. Vymazal J., Brooks R.A., Zak O., McRill C., Shen C., Di Chiro G. T1 and T2 of ferritin at different field strengths: effect on MRI. Magn Reson Med 1992, 27:368-374.
76. Rizzo G., Manners D., Testa C., Tonon C., Vetrugno R., Marconi S., et al. Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging. Mov Disord 2013, 28:1886-1890.
77. Zheng W., Nichol H., Liu S., Cheng Y.C., Haacke E.M. Measuring iron in the brain using quantitative susceptibility mapping and X-ray fluorescence imaging. Neuroimage 2013, 78:68-74.
78. Zecca L., Berg D., Arzberger T., Ruprecht P., Rausch W.D., Musicco M., et al. In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage. Mov Disord 2005, 20:1278-1285.
79. Eisensehr I., Wetter T.C., Linke R., Noachtar S., von Lindeiner H., Gildehaus F.J., et al. Normal IPT and IBZM SPECT in drug-naive and levodopa-treated idiopathic restless legs syndrome. Neurology 2001, 57:1307-1309.
80. Michaud M., Soucy J.P., Chabli A., Lavigne G., Montplaisir J. SPECT imaging of striatal pre- and postsynaptic dopaminergic status in restless legs syndrome with periodic leg movements in sleep. J Neurol 2002, 249:164-170.
81. Mrowka M., Jobges M., Berding G., Schimke N., Shing M., Odin P. Computerized movement analysis and beta-CIT-SPECT in patients with restless legs syndrome. J Neural Transm 2005, 112:693-701.
82. Earley C.J., Kuwabara H., Wong D.F., Gamaldo C., Salas R., Brasic J., et al. The dopamine transporter is decreased in the striatum of subjects with restless legs syndrome. Sleep 2011, 34:341-347.
83. Wiesinger J.A., Buwen J.P., Cifelli C.J., Unger E.L., Jones B.C., Beard J.L. Down-regulation of dopamine transporter by iron chelation in vitro is mediated by altered trafficking, not synthesis. J Neurochem 2007, 100:167-179.
84. Trenkwalder C., Earley C.J. Neuroimaging in restless legs syndrome restless legs syndrome. 2007.
85. Earley C.J., Kuwabara H., Wong D.F., Gamaldo C., Salas R.E., Brasic J.R., et al. Increased synaptic dopamine in the putamen in restless legs syndrome. Sleep 2013, 36:51-57.
86. Ferre S. Heteromerization of G-protein-coupled receptors. Implications for central nervous system function and dysfunction. ScientificWorldJournal 2007, 7:46-47.
87. Kvernmo T., Hartter S., Burger E. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther 2006, 28:1065-1078.
88. Lohse M.J., Maiellaro I., Calebiro D. Kinetics and mechanism of G protein-coupled receptor activation. Curr Opin Cell Biol 2014, 27C:87-93.
89. Metaye T., Gibelin H., Perdrisot R., Kraimps J.L. Pathophysiological roles of G-protein-coupled receptor kinases. Cell Signal 2005, 17:917-928.
90. Larsson B.W., Kadi F., Ulfberg J., Aulin K.P. Skeletal muscle morphology in patients with restless legs syndrome. Eur Neurol 2007, 58:133-137.
91. Wahlin-Larsson B., Ulfberg J., Aulin K.P., Kadi F. The expression of vascular endothelial growth factor in skeletal muscle of patients with sleep disorders. Muscle Nerve 2009, 40:556-561.
92. Semenza G.L. Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta 2011, 1813:1263-1268.
93. Semenza G.L. Oxygen sensing, homeostasis, and disease. N Engl J Med 2011, 365:537-547.
94. Semenza G.L. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood 2009, 114:2015-2019.
95. Patton S.M., Ponnuru P., Snyder A.M., Podskalny G.D., Connor J.R. Hypoxia-inducible factor pathway activation in restless legs syndrome patients. Eur J Neurol 2011, 18:1329-1335.
96. Benediktsdottir B., Janson C., Lindberg E., Arnardottir E.S., Olafsson I., Cook E., et al. Prevalence of restless legs syndrome among adults in Iceland and Sweden: lung function, comorbidity, ferritin, biomarkers and quality of life. Sleep Med 2010, 11:1043-1048.
97. Kaplan Y., Inonu H., Yilmaz A., Ocal S. Restless legs syndrome in patients with chronic obstructive pulmonary disease. Can J Neurol Sci 2008, 35:352-357.
98. Lo Coco D., Mattaliano A., Lo Coco A., Randisi B. Increased frequency of restless legs syndrome in chronic obstructive pulmonary disease patients. Sleep Med 2009, 10:572-576.
99. Ohayon M.M., Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002, 53:547-554.
100. Phillips B., Hening W., Britz P., Mannino D. Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll. Chest 2006, 129:76-80.
101. Phillips B., Young T., Finn L., Asher K., Hening W.A., Purvis C. Epidemiology of restless legs symptoms in adults. Arch Intern Med 2000, 160:2137-2141.
102. Pearson V.E., Gamaldo C.E., Allen R.P., Lesage S., Hening W.A., Earley C.J. Medication use in patients with restless legs syndrome compared with a control population. Eur J Neurol 2008, 15:16-21.
103. Ulfberg J., Nystrom B., Carter N., Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001, 16:1159-1163.
104. Winkelman J.W., Finn L., Young T. Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med 2006, 7:545-552.
105. Winkelman J.W., Shahar E., Sharief I., Gottlieb D.J. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology 2008, 70:35-42.
106. Mastrogiannaki M., Matak P., Keith B., Simon M.C., Vaulont S., Peyssonnaux C. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest 2009, 119:1159-1166.
107. Oktay Y., Dioum E., Matsuzaki S., Ding K., Yan L.J., Haller R.G., et al. Hypoxia-inducible factor 2alpha regulates expression of the mitochondrial aconitase chaperone protein frataxin. J Biol Chem 2007, 282:11750-11756.
108. Nie G., Sheftel A.D., Kim S.F., Ponka P. Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 2005, 105:2161-2167.
109. Centers for Disease Control and Prevention Iron deficiency - United States, 1999-2000. MMWR Morb Mortal Wkly Rep 2002, 51:897-899.
110. Pantaleo N.P., Hening W.A., Allen R.P., Earley C.J. Pregnancy accounts for most of the gender difference in prevalence of familial RLS. Sleep Med 2010, 11:310-313.
111. Neau J.P., Marion P., Mathis S., Julian A., Godeneche G., Larrieu D., et al. Restless legs syndrome and pregnancy: follow-up of pregnant women before and after delivery. Eur Neurol 2010, 64:361-366.
112. Schormair B., Kemlink D., Roeske D., Eckstein G., Xiong L., Lichtner P., et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 2008, 40:946-948.
113. Stefansson H., Rye D.B., Hicks A., Petursson H., Ingason A., Thorgeirsson T.E., et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007, 357:639-647.
114. Vilarino-Guell C., Farrer M.J., Lin S.C. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2008, 358:425-427.
115. Winkelmann J., Schormair B., Lichtner P., Ripke S., Xiong L., Jalilzadeh S., et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007, 39:1000-1006.
116. Catoire H., Dion P.A., Xiong L., Amari M., Gaudet R., Girard S.L., et al. Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Ann Neurol 2011, 70:170-175.
117. Silver N., Allen R.P., Earley C.J. MEIS1 as a potential mediator of the RLS-iron patholology. Mov Disord 2010, 25:S513-S514.
118. Oexle K., Schormair B., Ried J.S., Czamara D., Heim K., Frauscher B., et al. Dilution of candidates: the case of iron-related genes in restless legs syndrome. Eur J Hum Genet 2013, 21:410-414.
119. Sorensen E., Grau K., Berg T., Simonsen A.C., Magnussen K., Erikstrup C., et al. A genetic risk factor for low serum ferritin levels in Danish blood donors. Transfusion 2012, 52:2585-2589.
120. Freeman A., Pranski E., Miller R.D., Radmard S., Bernhard D., Jinnah H.A., et al. Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome. Curr Biol 2012, 22:1142-1148.
121. De Ponti C., Carini R., Alchera E., Nitti M.P., Locati M., Albano E., et al. Adenosine A2a receptor-mediated, normoxic induction of HIF-1 through PKC and PI-3 K-dependent pathways in macrophages. J Leukoc Biol 2007, 82:392-402.
122. Bianchi L., Tacchini L., Cairo G. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic Acids Res 1999, 27:4223-4227.
123. Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004, 5:385-391.
124. Simsek T., Kocabas F., Zheng J., Deberardinis R.J., Mahmoud A.I., Olson E.N., et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 2010, 7:380-390.
125. Mastroberardino P.G., Hoffman E.K., Horowitz M.P., Betarbet R., Taylor G., Cheng D., et al. A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease. Neurobiol Dis 2009, 34:417-431.
126. Barros S.P., Offenbacher S. Epigenetics: connecting environment and genotype to phenotype and disease. J Dent Res 2009, 88:400-408.
127. Watson J.A., Watson C.J., McCann A., Baugh J. Epigenetics, the epicenter of the hypoxic response. Epigenetics 2010, 5:293-296.
128. Loenarz C., Schofield C.J. Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 2008, 4:152-156.
129. Pollard P.J., Loenarz C., Mole D.R., McDonough M.A., Gleadle J.M., Schofield C.J., et al. Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha. Biochem J 2008, 416:387-394.
130. Silva P.F., Garcia V.A., Dornelles Ada S., Silva V.K., Maurmann N., Portal B.C., et al. Memory impairment induced by brain iron overload is accompanied by reduced H3K9 acetylation and ameliorated by sodium butyrate. Neuroscience 2012, 200:42-49.
131. Bateman D.N., Dutta D.K., McClelland H.A., Rawlins M.D. Metoclopramide and haloperidol in tardive dyskinesia. Br J Psychiatry 1979, 135:505-508.
132. Winkelmann J., Schadrack J., Wetter T.C., Zieglgansberger W., Trenkwalder C. Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients. Sleep Med 2001, 2:57-61.
133. Cooper J.R., Bloom F.E., Roth R.H. The biochemical basis of neuropharmacology 2008, Oxford University Press, New York.
134. Cote S.R., Kuzhikandathil E.V. In vitro and in vivo characterization of the agonist-dependent D3 dopamine receptor tolerance property. Neuropharmacology 2014, 79:359-367. Epub 2013/12/10.
135. Amara S.G., Kuhar M.J. Neurotransmitter transporters: recent progress. Ann Rev Neurosci 1993, 16:73-93.
136. Bolan E.A., Kivell B., Jaligam V., Oz M., Jayanthi L.D., Han Y., et al. D2 receptors regulate dopamine transporter function via an extracellular signal-regulated kinases 1 and 2-dependent and phosphoinositide 3 kinase-independent mechanism. Mol Pharm 2007, 71:1222-1232.
137. Zapata A., Kivell B., Han Y., Javitch J.A., Bolan E.A., Kuraguntla D., et al. Regulation of dopamine transporter function and cell surface expression by D3 dopamine receptors. J Biol Chem 2007, 282:35842-35854.
138. Walters A.S. Review of receptor agonist and antagonist studies relevant to the opiate system in restless legs syndrome. Sleep Med 2002, 3:301-304.
139. Silver N., Allen R.P., Senerth J., Earley C.J. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 2011, 12:440-444.
140. Trenkwalder C., Benes H., Grote L., Garcia-Borreguero D., Hogl B., Hopp M., et al. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension. Lancet Neurol 2013, 12:1141-1150. Epub 2013/10/22.
141. Pert A., DeWald L., Gallager D. Effects of opiates on nigrostriatal dopaminergic activity: electrophysiological and behavioral analysis. Catachoamines: basic and clinical frontiers 1979, 1041-1043. Pergamon, New York. E. Usdin, I. Kopin, J. Barchas (Eds.).
142. Allen R.P., Chen C., Garcia-Borreguero D., Polo O., DuBrava S., Miceli J., et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014, 370:621-631. Epub 2014/02/14.
143. Ellenbogen A.L., Thein S.G., Winslow D.H., Becker P.M., Tolson J.M., Lassauzet M.L., et al. A 52-week study of gabapentin enacarbil in restless legs syndrome. Clin Neuropharmacol 2011, 34:8-16.
144. Hoppa M.B., Lana B., Margas W., Dolphin A.C., Ryan T.A. alpha2delta expression sets presynaptic calcium channel abundance and release probability. Nature 2012, 486:122-125.
145. Coderre T.J., Kumar N., Lefebvre C.D., Yu J.S. A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain. J Neurochem 2007, 100:1289-1299.
146. Inturrisi C.E. Pharmacology of methadone and its isomers. Minerva Anestesiol 2005, 71:435-437.
147. Akhisaroglu M., Kurtuncu M., Manev H., Uz T. Diurnal rhythms in quinpirole-induced locomotor behaviors and striatal D2/D3 receptor levels in mice. Pharmacol Biochem Behav 2005, 80:371-377.
148. Ellender T.J., Huerta-Ocampo I., Deisseroth K., Capogna M., Bolam J.P. Differential modulation of excitatory and inhibitory striatal synaptic transmission by histamine. J Neurosci 2011, 31:15340-15351.
149. Rivest R.W., Schulz P., Lustenberger S., Sizonenko P.C. Differences between circadian and ultradian organization of cortisol and melatonin rhythms during activity and rest. J Clin Endocrinol Metab 1989, 68:721-729.
150. Veldhuis J.D., Johnson M.L. Operating characteristics of the hypothalamo-pituitary-gonadal axis in men: circadian, ultradian, and pulsatile release of prolactin and its temporal coupling with luteinizing hormone. J Clin Endocrinol Metab 1988, 67:116-123.
151. Wetter T.C., Collado-Seidel V., Oertel H., Uhr M., Yassouridis A., Trenkwalder C. Endocrine rhythms in patients with restless legs syndrome. J Neurol 2002, 249:146-151.
152. Trenkwalder C., Stiasny K., Pollmacher T., Wetter T., Schwarz J., Kohnen R., et al. L-dopa therapy of uremic and idiopathic restless legs syndrome: a double-blind, crossover trial. Sleep 1995, 18:681-688.