Neurotoxicity Research

, Volume 21, Issue 1, pp 90–116 | Cite as

Intranasal Administration of Neurotoxicants in Animals: Support for the Olfactory Vector Hypothesis of Parkinson’s Disease

  • Rui D. S. PredigerEmail author
  • Aderbal S. AguiarJr.
  • Filipe C. Matheus
  • Roger Walz
  • Layal Antoury
  • Rita Raisman-Vozari
  • Richard L. Doty


The causes of Parkinson’s disease (PD) are unknown, but there is evidence that exposure to environmental agents, including a number of viruses, toxins, agricultural chemicals, dietary nutrients, and metals, is associated with its development in some cases. The presence of smell loss and the pathological involvement of the olfactory pathways in the early stages of PD are in accord with the tenants of the olfactory vector hypothesis. This hypothesis postulates that some forms of PD may be caused or catalyzed by environmental agents that enter the brain via the olfactory mucosa. In this article, we provide an overview of evidence implicating xenobiotics agents in the etiology of PD and review animal, mostly rodent, studies in which toxicants have been introduced into the nose in an attempt to induce behavioral or neurochemical changes similar to those seen in PD. The available data suggest that this route of exposure results in highly variable outcomes, depending upon the involved xenobiotic, exposure history, and the age and species of the animals tested. Some compounds, such as rotenone, paraquat, and 6-hydroxydopamine, have limited capacity to reach and damage the nigrostriatal dopaminergic system via the intranasal route. Others, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), readily enter the brain via this route in some species and influence the function of the nigrostriatal pathway. Intranasal infusion of MPTP in some rodents elicits a developmental sequence of behavioral and neurochemical changes that closely mimics that seen in PD. For this reason, such an MPTP rodent model appears to be an ecologically valid means for assessing novel palliative treatments for both the motor and non-motor symptoms of PD. More research is needed, however, on this and other ecologically valid models.


Parkinson’s disease Olfactory vector hypothesis Intranasal Neurotoxicants Animal models Review Olfaction 



The authors gratefully acknowledge Dr. Fabrício A. Pamplona for his assistance in some illustrations of this article. Some of the research reviewed in this article was supported by the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Apoio à Pesquisa Científica e Tecnológica do Estado de Santa Catarina (FAPESC) and CAPES-COFECUB (France/Brazil; 681/2010). ASA Jr and FCM are supported by scholarship from CNPq-Brazil. RDSP and RW are supported by research fellowships from CNPq-Brazil. RL Doty is supported by USAMRAA grant W81XWH-09-1-0467. He is President and major shareholder in Sensonics, Inc., a manufacturer and distributor of olfactory and gustatory tests. The other authors have no financial or personal conflicts of interest related to this study.


  1. Albanese A, Bentivoglio M (1982) The organization of dopaminergic and nondopaminergic mesencephalocortical neurons in the rat. Brain Res 238:421–425PubMedGoogle Scholar
  2. Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381PubMedGoogle Scholar
  3. Andersson T, Mohammed AK, Henriksson BG, Wickman C, Norrby E, Schultzberg M, Kristensson K (1993) Immunohistochemical and behaviour pharmacological analysis of rats inoculated intranasally with vesicular stomatitis virus. J Chem Neuroanat 6:7–18PubMedGoogle Scholar
  4. Ansari KA, Johnson A (1975) Olfactory function in patients with Parkinson’s disease. J Chronic Dis 28:493–497PubMedGoogle Scholar
  5. Antunes MB, Bowler R, Doty RL (2007) San-Francisco/Oakland Bay Bridge welder study: olfactory function. Neurology 69:1278–1284PubMedGoogle Scholar
  6. Aronsson F, Robertson B, Ljunggren H, Kristensson K (2003) Invasion and persistence of the neuroadapted influenza virus A/WSN/33 in the mouse olfactory system. Viral Immunol 16:415–423PubMedGoogle Scholar
  7. Baba T, Takeda A, Kikuchi A, Nishio Y, Hosokai Y, Hirayama K, Hasegawa T, Sugeno N, Suzuki K, Mori E, Takahashi S, Fukuda H, Itoyama Y (2011) Association of olfactory dysfunction and brain metabolism in Parkinson’s disease. Mov Disord 26:621–628PubMedGoogle Scholar
  8. Barbeau A (1984) Manganese and extrapyramidal disorders (a critical review and tribute to Dr George C Cotzias). Neurotoxicology 5:13–35PubMedGoogle Scholar
  9. Barnett EM, Perlman S (1993) The olfactory nerve and not the trigeminal nerve is the major site of CNS entry for mouse hepatitis virus, strain JHM. Virology 194:185–191PubMedGoogle Scholar
  10. Barnett EM, Cassell MD, Perlman S (1993) Two neurotropic viruses, Herpes simplex virus type I and mouse hepatitis virus, spread along different neural pathways from the main olfactory bulb. Neuroscience 57:1007–1025PubMedGoogle Scholar
  11. Bazer G, Ebbesson S, Reynolds J, Bailey R (1987) A cobalt-lysine study of primary olfactory projections in king salmon fry (Oncorhynchus-tshawytscha Walbaum). Cell Tissue Res 248:499–503Google Scholar
  12. Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2:325–334PubMedGoogle Scholar
  13. Becker G, Müller A, Braune S, Büttner T, Benecke R, Greulich W, Klein W, Mark G, Rieke J, Thümler R (2002) Early diagnosis of Parkinson’s disease. J Neurol 249(Suppl 3):40–48Google Scholar
  14. Berg D, Hochstrasser H, Schweitzer KJ, Riess O (2006) Disturbance of iron metabolism in Parkinson’s disease—ultrasonography as a biomarker. Neurotox Res 9:1–13PubMedGoogle Scholar
  15. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306PubMedGoogle Scholar
  16. Bezard E, Gross CE, Fournier MC, Dovero S, Bloch B, Jaber M (1999) Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol 155:268–273PubMedGoogle Scholar
  17. Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci 21:6853–6861PubMedGoogle Scholar
  18. Bloch A, Probst A, Bissig H, Adams H, Tolnay M (2006) Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol 32:284–295PubMedGoogle Scholar
  19. Bohnen NI, Müller ML, Kotagal V, Koeppe RA, Kilbourn MA, Albin RL, Frey KA (2010) Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain 133:1747–1754PubMedGoogle Scholar
  20. Bondi MW, Kaszniak AW (1991) Implicit and explicit memory in Alzheimer’s disease and Parkinson’s disease. J Clin Exp Neuropsychol 13:339–358PubMedGoogle Scholar
  21. Boni UD, Otvos A, Scott JW, Crapper DR (1976) Neurofibrillary degeneration induced by systemic aluminum. Acta Neuropathol 35:285–294PubMedGoogle Scholar
  22. Borg-Neczak K, Tjalve H (1996) Uptake of 203Hg2+ in the olfactory system in pike. Toxicol Lett 84:107–112PubMedGoogle Scholar
  23. Bosboom JL, Stoffers D, Ech Wolters (2004) Cognitive dysfunction and dementia in Parkinson’s disease. J Neural Transm 111:1303–1315PubMedGoogle Scholar
  24. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134PubMedGoogle Scholar
  25. Breen EK (1993) Recall and recognition memory in Parkinson’s disease. Cortex 29:91–102PubMedGoogle Scholar
  26. Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823:1–10PubMedGoogle Scholar
  27. Brown RC, Lockwood AH, Sonawane BR (2006) Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect 113:1250–1256Google Scholar
  28. Busenbark KL, Huber SJ, Greer G, Pahwa R, Koller WC (1992) Olfactory function in essential tremor. Neurology 42:1631–1632PubMedGoogle Scholar
  29. Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT (2009) A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis 34:279–290PubMedGoogle Scholar
  30. Cersosimo MG, Koller WC (2006) The diagnosis of manganese-induced parkinsonism. Neurotoxicology 27:340–346PubMedGoogle Scholar
  31. Chaudhuri KR, Healy DG, Schapira AH, National Institute for Clinical Excellence (2006) Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 5:235–245PubMedGoogle Scholar
  32. Chiueh CC, Markey SP, Burns RS, Johannessen JN, Pert A, Kopin IJ (1984) Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat. Eur J Pharmacol 100:189–194PubMedGoogle Scholar
  33. Cicchetti F, Drouin-Ouellet J, Gross RE (2009) Environmental toxins and Parkinson’s disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci 30:475–483PubMedGoogle Scholar
  34. Corasaniti MT, Strongoli MC, Rotiroti D, Bagetta G, Nisticò G (1998) Paraquat: a useful tool for the in vivo study of mechanisms of neuronal cell death. Pharmacol Toxicol 83:1–7PubMedGoogle Scholar
  35. Crapper DR, Dalton AJ (1973) Aluminum induced neurofibrillary degeneration, brain electrical activity and alterations in acquisition and retention. Physiol Behav 10:935–945PubMedGoogle Scholar
  36. Crapper DR, Krishnan SS, De BU, Tomko GJ (1975) Aluminum: a possible neurotoxic agent in Alzheimer’s disease. Trans Am Neurol Assoc 100:154–156PubMedGoogle Scholar
  37. Crossgrove J, Zheng W (2004) Manganese toxicity upon overexposure. NMR Biomed 17:544–553PubMedGoogle Scholar
  38. Cummings JL, Masterman DL (1999) Depression in patients with Parkinson’s disease. Int J Geriatr Psychiatry 14:711–718PubMedGoogle Scholar
  39. Czerniawska A (1970) Experimental investigations on penetration of 198Au from nasal mucous membrane into cerebrospinal fluid. Acta Otolaryngol 70:58–61PubMedGoogle Scholar
  40. Da Cunha C, Gevaerd MS, Vital MA, Miyoshi E, Andreatini R, Silveira R, Takahashi RN, Canteras NS (2001) Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson’s disease amnesia. Behav Brain Res 124:9–18PubMedGoogle Scholar
  41. Da Cunha C, Angelucci ME, Canteras NS, Wonnacott S, Takahashi RN (2002) The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a model for Parkinson’s disease memory disabilities. Cell Mol Neurobiol 22:227–237PubMedGoogle Scholar
  42. Daniel SE, Hawkes CH (1992) Preliminary diagnosis of Parkinson’s disease by olfactory bulb pathology. Lancet 340:186PubMedGoogle Scholar
  43. Dantzer R, Bluthe RM, Koob GF, Le Moal M (1987) Modulation of social memory in male rats by neurohypophyseal peptides. Psychopharmacology 91:363–368PubMedGoogle Scholar
  44. De Lorenzo AJ (1970) The olfactory neuron and the blood-brain barrier. In Ciba foundation symposium—internal secretions of the pancreas (colloquia on endocrinology), anonymous. Wiley, New York, pp 151–176Google Scholar
  45. Dev KK, Hofele K, Barbieri S, Buchman VL, Van der Putten H (2003) Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 45:14–44PubMedGoogle Scholar
  46. Dexter DT, Wells FR, Agid F, Agid Y, Lees AJ, Jenner P, Marsden CD (1987) Increased nigral iron content in postmortem parkinsonian brain. Lancet 2:1219–1220PubMedGoogle Scholar
  47. Di Monte DA (2003) The environment and Parkinson’s disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol 2:531–538PubMedGoogle Scholar
  48. Di Monte D, Sandy MS, Ekström G, Smith MT (1986) Comparative studies on the mechanisms of paraquat and 1-methyl-4-phenylpyridine (MPP+) cytotoxicity. Biochem Biophys Res Commun 137:303–309PubMedGoogle Scholar
  49. Di Monte DA, Lavasani M, Manning-Bog AB (2002) Environmental factors in Parkinson’s disease. Neurotoxicology 23:487–502PubMedGoogle Scholar
  50. Diel DG, Almeida SR, Brum MC, Dezengrini R, Weiblen R, Flores EF (2007) Acute and latent infection by bovine herpesvirus type 5 in experimentally infected goats. Vet Microbiol 121:257–267PubMedGoogle Scholar
  51. Ding X, Dahl AR (2003) Olfactory mucosa: composition, enzymatic localization, and metabolism. In: Doty RL (ed) Handbook of olfaction and gustation, 2nd edn. Marcel Dekker, New York, pp 51–73Google Scholar
  52. Dluzen DE, Kefalas G (1996) The effects of intranasal infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) upon catecholamine concentrations within olfactory bulbs and corpus striatum of male mice. Brain Res 741:215–219PubMedGoogle Scholar
  53. Dluzen DE, Muraoka S, Landgraf R (1998) Olfactory bulb norepinephrine depletion abolishes vasopressin and oxytocin preservation of social recognition responses in rats. Neurosci Lett 254:161–164PubMedGoogle Scholar
  54. Doty RL (2008) The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 63:7–15PubMedGoogle Scholar
  55. Doty RL (2011) Role of environmental factors in Parkinson’s disease. In: Aguiar AS Jr, Prediger RD (eds) Frontiers in Parkinson’s disease research. Nova Science Publishers, New York, in pressGoogle Scholar
  56. Doty RL, Shaman P, Dann M (1984) Development of the University of Pennsylvania smell identification test: a standardized microencapsulated test of olfactory function. Physiol Behav 32:489–502PubMedGoogle Scholar
  57. Doty RL, Deems D, Stellar S (1988a) Olfactory dysfunction in Parkinson’s disease: a general deficit unrelated to neurologic signs, disease state, or disease duration. Neurology 38:1237–1244PubMedGoogle Scholar
  58. Doty RL, Ferguson-Segall M, Lucki I, Kreider M (1988b) Effects of intrabulbar injections of 6-hydroxydopamine on ethyl acetate odor detection in castrate and non-castrate male rats. Brain Res 444:95–103PubMedGoogle Scholar
  59. Doty RL, Singh A, Tetrude J, Langston JW (1992) Lack of olfactory dysfunction in MPTP-induced parkinsonism. Ann Neurol 32:97–100PubMedGoogle Scholar
  60. Doty RL, Golbe LI, McKeown DA, Stern MB, Lehrach CM, Crawford D (1993) Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson’s disease. Neurology 43:962–965PubMedGoogle Scholar
  61. Doty RL, Bromley SM, Stern MB (1995) Olfactory testing as an aid in the diagnosis of Parkinson’s disease: development of optimal discrimination criteria. Neurodegeneration 4:93–97PubMedGoogle Scholar
  62. Dubois B, Pillon B (1997) Cognitive deficits in Parkinson’s disease. J Neurol 244:2–8PubMedGoogle Scholar
  63. Earle KM (1968) Studies on Parkinson’s disease including x-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27:1–14PubMedGoogle Scholar
  64. Esiri M, Tomlinson A (1984) Herpes-simplex encephalitis—immunohistological demonstration of spread of virus via olfactory and trigeminal pathways after infection of facial skin in mice. J Neurol Sci 64:213–217PubMedGoogle Scholar
  65. Evans C (2003) Vomeronasal chemoreception in vertebrates. Imperial College Press, LondonGoogle Scholar
  66. Fall PA, Fredrikson M, Axelson O, Granérus AK (1999) Nutritional and occupational factors influencing the risk of Parkinson’s disease: a case-control study in southeastern Sweden. Mov Disord 14:28–37PubMedGoogle Scholar
  67. Fei Q, Ethell DW (2008) Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members. J Neurochem 105:2091–2097PubMedGoogle Scholar
  68. Ferro MM, Angelucci ME, Anselmo-Franci JA, Canteras NS, Da Cunha C (2007) Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson’s disease. Braz J Med Biol Res 40:89–96PubMedGoogle Scholar
  69. Flexner S, Clark PF (1912) A note on the mode of infection in epidemic poliomyelitis. Proc Soc Expl Biol Med 10:1–2Google Scholar
  70. Flowers KA, Pearce I, Pearce JMS (1984) Recognition memory in Parkinson’s disease. J Neurol Neurosurg Psychiatry 47:1174–1181PubMedGoogle Scholar
  71. Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272PubMedGoogle Scholar
  72. Forno LS, Langston JW, DeLanney LE, Irwin I, Ricaurte GA (1986) Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 20(4):449–455PubMedGoogle Scholar
  73. Forno LS, DeLanney LE, Irwin I, Langston JW (1993) Similarities and differences between MPTP-induced parkinsonsim and Parkinson’s disease. Neuropathologic considerations. Adv Neurol 60:600–608PubMedGoogle Scholar
  74. Franco J, Prediger RD, Pandolfo P, Takahashi RN, Farina M, Dafre AL (2007) Antioxidant responses and lipid peroxidation following intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats: increased susceptibility of olfactory bulb. Life Sci 80:1906–1914PubMedGoogle Scholar
  75. Freyaldenhoven TE, Cadet JL, Ali SF (1996) The dopamine-depleting effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in CD-1 mice are gender-dependent. Brain Res 735:232–238PubMedGoogle Scholar
  76. Gal S, Zheng H, Fridkin M, Youdim MB (2010) Restoration of nigrostriatal dopamine neurons in post-MPTP treatment by the novel multifunctional brain-permeable iron chelator-monoamine oxidase inhibitor drug, M30. Neurotox Res 17:15–27PubMedGoogle Scholar
  77. Gerlach M, Riederer P (1996) Animal models of Parkinson’s disease: an empirical comparison with the phenomenology of the disease in man. J Neural Transm 103:987–1041PubMedGoogle Scholar
  78. Giovanni A, Sieber BA, Heikkila RE, Sonsalla PK (1994) Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine part 1: systemic administration. J Pharmacol Exp Ther 270:1000–1007PubMedGoogle Scholar
  79. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346–1350PubMedGoogle Scholar
  80. Gorell JM, Rybicki BA, Cole JC, Peterson EL (1999) Occupational metal exposures and the risk of Parkinson’s disease. Neuroepidemiology 18:303–308PubMedGoogle Scholar
  81. Goto A (1962) A long duration follow-up study of Japanese encephalitis. Folia Psychiatr Neurol Jpn 64:236–266PubMedGoogle Scholar
  82. Graff CL, Pollack GM (2005) Nasal drug administration: potential for targeted central nervous system delivery. J Pharm Sci 94:1187–1195PubMedGoogle Scholar
  83. Guan X, Blank J, Dluzen DE (1993) Depletion of olfactory bulb norepinephrine by 6-OHDA disrupts chemical cue but not social recognition responses in male rats. Brain Res 622:51–57PubMedGoogle Scholar
  84. Halász N, Shepherd GM (1983) Neurochemistry of the vertebrate olfactory bulb. Neuroscience 10:579–619PubMedGoogle Scholar
  85. Halász N, Ljungdahl A, Hökfelt T, Johansson O, Goldstein M, Park D, Biberfeld P (1977) Transmitter histochemistry of the rat olfactory bulb. I. Immunohistochemical localization of monoamine synthesizing enzymes. Support for intrabulbar, periglomerular dopamine neurons. Brain Res 126:455–474PubMedGoogle Scholar
  86. Hamaue N, Ogata A, Terado M, Ohno K, Kikuchi S, Sasaki H et al (2006) Brain catecholamine alterations and pathological features with aging in Parkinson disease model rat induced by Japanese encephalitis virus. Neurochem Res 31:1451–1455PubMedGoogle Scholar
  87. Hanson LR, Frey WH 2nd (2008) Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 9:Suppl S3:S5Google Scholar
  88. Harik SI, Schmidley JW, Iacofano LA, Blue P, Arora PK, Sayre LM (1987) On the mechanisms underlying 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity: the effect of perinigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, its metabolite and their analogs in the rat. J Pharmacol Exp Ther 241:669–676PubMedGoogle Scholar
  89. Hasegawa E, Kang D, Sakamoto K, Mitsumoto A, Nagano T, Minakami S, Takeshige K (1997) A dual effect of 1-methyl-4-phenylpyridinium (MPP +)-analogs on the respiratory chain of bovine heart mitochondria. Arch Biochem Biophys 337:69–74PubMedGoogle Scholar
  90. Hastings L, Evans JE (1988) Transaxonal transport of cadmium in the olfactory system. Chem Senses 13:696Google Scholar
  91. Hastings L, Evans JE (1991) Olfactory primary neurons as a route of entry for toxic agents into the CNS. Neurotoxicology 12:707–714PubMedGoogle Scholar
  92. Hastings TG, Lewis DA, Zigmond MJ (1996) Reactive dopamine metabolites and neurotoxicity: implications for Parkinson’s disease. Adv Exp Med Biol 387:97–106PubMedGoogle Scholar
  93. Hawkes CH, Doty RL (2009) The neurology of olfaction. Cambridge University Press, CambridgeGoogle Scholar
  94. Hawkes CH, Shephard BC (1993) Selective anosmia in Parkinson's disease? Lancet 341:435–436Google Scholar
  95. Hawkes CH, Shephard BC, Daniel SE (1999) Is Parkinson’s disease a primary olfactory disorder? QJM 92:473–480PubMedGoogle Scholar
  96. Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual hit hypothesis. Neuropathol Appl Neurobiol 33:599–614PubMedGoogle Scholar
  97. Hayek R, Waite PME (1991) The olfactory pathway as a possible route for aluminum entry to the brain. J Neurochem 57:S113Google Scholar
  98. He Y, Imam SZ, Dong Z, Jankovic J, Ali SF, Appel SH, Le W (2003) Role of nitric oxide in rotenone-induced nigro-striatal injury. J Neurochem 86:1338–1345PubMedGoogle Scholar
  99. Heikkila RE, Nicklas WJ, Vyas I, Duvoisin RC (1985) Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett 62:389–394PubMedGoogle Scholar
  100. Henriksson J, Tjalve H (1998) Uptake of inorganic mercury in the olfactory bulbs via olfactory pathways in rats. Environ Res 77:130–140PubMedGoogle Scholar
  101. Henriksson J, Tjälve H (2000) Manganese taken up into the CNS via the olfactory pathway in rats affects astrocytes. Toxicol Sci 55:392–398PubMedGoogle Scholar
  102. Henriksson J, Tallkvist J, Tjalve H (1999) Transport of manganese via the olfactory pathway in rats: dosage dependency of the uptake and subcellular distribution of the metal in the olfactory epithelium and the brain. Toxicol Appl Pharmacol 156:119–128PubMedGoogle Scholar
  103. Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopamine neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334:345–348PubMedGoogle Scholar
  104. Hirsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y (1991) Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 56:446–451PubMedGoogle Scholar
  105. Inden M, Kitamura Y, Takeuchi H, Yanagida T, Takata K, Kobayashi Y, Taniguchi T, Yoshimoto K, Kaneko M, Okuma Y, Taira T, Ariga H, Shimohama S (2007) Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone. J Neurochem 101:1491–1504PubMedGoogle Scholar
  106. Jang H, Boltz D, Sturm-Ramierz K, Shepherd KR, Jian Y, Webster R, Smeyne RJ (2009) Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci USA 106:14063–14068PubMedGoogle Scholar
  107. Johnson CC, Gorell JM, Rybicki BA, Sanders K, Peterson EL (1999) Adult nutrient intake as a risk factor for Parkinson’s disease. Int J Epidemiol 28:1102–1109PubMedGoogle Scholar
  108. Jonsson G, Sachs C (1975) Actions of 6-hydroxydopamine quinones on catecholamine neurons. J Neurochem 25:509–516PubMedGoogle Scholar
  109. Kalaria RN, Mitchell MJ, Harik SI (1987) Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood-brain barrier monoamine oxidase activity. Proc Natl Acad Sci USA 84:3521–3525PubMedGoogle Scholar
  110. Kamel F, Tanner C, Umbach D, Hoppin J, Alavanja M, Blair A, Comyns K, Goldman S, Korell M, Langston J, Ross G, Sandler D (2007) Pesticide exposure and self-reported Parkinson’s disease in the agricultural health study. Am J Epidemiol 165:364–374PubMedGoogle Scholar
  111. Kawano T, Margolis FL (1982) Transsynaptic regulation of olfactory bulb catecholamines in mice and rats. J Neurochem 39:342–348PubMedGoogle Scholar
  112. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608PubMedGoogle Scholar
  113. Koutsilieri E, Sopper S, Scheller C, Ter MV, Riederer P (2002) Parkinsonism in HIV dementia. J Neural Transm 109:767–775PubMedGoogle Scholar
  114. Lafay F, Coulon P, Astic L, Saucier D, Riche D, Holley A, Flamand A (1991) Spread of the CVS strain of rabies virus and of the avirulent mutant AvO1 along the olfactory pathways of the mouse after intranasal inoculation. Virology 183:320–330PubMedGoogle Scholar
  115. Lan J, Jiang DH (1997) Excessive iron accumulation in the brain: a possible potential risk of neurodegeneration in Parkinson’s disease. J Neural Transm 104:649–660PubMedGoogle Scholar
  116. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980PubMedGoogle Scholar
  117. Levenson CW, Cutler RG, Ladenheim B, Cadet JL, Hare J, Mattson MP (2004) Role of dietary iron restriction in a mouse model of Parkinson’s disease. Exp Neurol 190:506–514PubMedGoogle Scholar
  118. Lewis SJG, Dove A, Robbins TW, Barker RA, Owen AM (2003) Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry. J Neurosci 23:6351–6356PubMedGoogle Scholar
  119. Lewy FH (1912) Paralysis agitans. Pathologische Anatomie. In: Lewandowski M (ed) Handbuch der Neurologie. Springer, Berlin Heidelberg New York, pp 920–933Google Scholar
  120. Lucchini RG, Martin CJ, Doney BC (2009) From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure. Neuromolecular Med 11:311–332PubMedGoogle Scholar
  121. Lundh B, Love A, Kristensson K, Norrby E (1988) Non-lethal infection of aminergic reticular core neurons: age-dependent spread of ts mutant vesicular stomatitis virus from the nose. J Neuropathol Exp Neurol 47:497–506PubMedGoogle Scholar
  122. Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277:1641–1644PubMedGoogle Scholar
  123. Marttila RJ, Rinne UK (1978) Herpes simplex virus antibodies in patients with Parkinson’s disease. J Neurol Sci 35:375–379PubMedGoogle Scholar
  124. Marttila RJ, Arstila P, Nikoskelainen J, Halonen PE, Rinne UK (1977) Viral antibodies in the sera from patients with Parkinson disease. Eur Neurol 15:25–33PubMedGoogle Scholar
  125. Marttila RJ, Rinne UK, Halonen P, Madden DL, Sever JL (1981) Herpesviruses and parkinsonism Herpes simplex virus types 1 and 2, and cytomegalovirus antibodies in serum and CSF. Arch Neurol 38:19–21PubMedGoogle Scholar
  126. Martyn CN (1997) Infection in childhood and neurological diseases in adult life. Br Med Bull 53:24–39PubMedGoogle Scholar
  127. Martyn CN, Osmond C (1995) Parkinson’s disease and the environment in early life. J Neurol Sci 132:201–206PubMedGoogle Scholar
  128. Mayeux R (2003) Epidemiology of neurodegeneration. Annu Rev Neurosci 26:81–104PubMedGoogle Scholar
  129. Meissner W, Hill MO, Tison F, Gross CE, Bezard E (2004) Neuroprotective strategies for Parkinson’s disease: conceptual limits of animal models and clinical trials. Trends Pharmacol Sci 25:249–253PubMedGoogle Scholar
  130. Menco BPH, Morrison EE (2003) Morphology of the mammalian olfactory epithelium: form, fine structure, function, and pathology. In: Doty RL (ed) Handbook of olfaction and gustation, 2nd edn. Marcel Dekker, New York, pp 17–49Google Scholar
  131. Meredith M (2001) Human vomeronasal organ function: a critical review of best and worst cases. Chem Senses 26:433–445PubMedGoogle Scholar
  132. Merkus FW, Van den Berg MP (2007) Can nasal drug delivery bypass the blood-brain barrier?: questioning the direct transport theory. Drugs R D 8:133–144PubMedGoogle Scholar
  133. Misra UK, Kalita J, Pandey S, Khanna VK, Babu GN (2005) Cerebrospinal fluid catecholamine levels in Japanese encephalitis patients with movement disorders. Neurochem Res 30:1075–1078PubMedGoogle Scholar
  134. Monath T, Cropp C, Harrison A (1983) Mode of entry of a neurotropic arbovirus into the central nervous system—reinvestigation of an old controversy. Lab Invest 48:399–410PubMedGoogle Scholar
  135. Monnet-Tschudi F, Zurich MG, Boschat C, Corbaz A, Honegger P (2006) Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases. Rev Environ Health 21:105–117PubMedGoogle Scholar
  136. Moore G (1977) Influenza and Parkinson’s disease. Public Health Rep 92:79–80PubMedGoogle Scholar
  137. Morales JA, Herzog S, Kompter C, Frese K, Rott R (1988) Axonal transport of Borna disease virus along olfactory pathways in spontaneously and experimentally infected rats. Med Microbiol Immunol 177:51–68PubMedGoogle Scholar
  138. Moreira EL, Rial D, Aguiar AS Jr, Figueiredo CP, Siqueira JM, DalBó S, Horst H, de Oliveira J, Mancini G, dos Santos TS, Villarinho JG, Pinheiro FV, Marino-Neto J, Ferreira J, De Bem AF, Latini A, Pizzolatti MG, Ribeiro-do-Valle RM, Prediger RD (2010) Proanthocyanidin-rich fraction from Croton celtidifolius Baill confers neuroprotection in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rat model of Parkinson’s disease. J Neural Transm 117:1337–1351PubMedGoogle Scholar
  139. Mori I, Komatsu T, Takeuchi K, Nakakuki K, Sudo M, Kimura Y (1995) Parainfluenza virus type-1 infects olfactory neurons and establishes long-term persistence in the nerve-tissue. J Gen Virol 76:1251–1254PubMedGoogle Scholar
  140. Morris RG, Garrud P, Rawlins JN, O’keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683PubMedGoogle Scholar
  141. Mulder W, Pol J, Kimman T, Kok G, Priem J, Peeters B (1996) Glycoprotein D-negative pseudorabies virus can spread transneuronally via direct neuron-to-neuron transmission in its natural host, the pig, but not after additional inactivation of gE or gI. J Virol 70:2191–2200PubMedGoogle Scholar
  142. Murgod UA, Muthane UB, Ravi V, Radhesh S, Desai A (2001) Persistent movement disorders following Japanese encephalitis. Neurology 57:2313–2315PubMedGoogle Scholar
  143. Narita M, Uchimura A, Kawanabe M, Fukushi H, Hirai K (2001) Invasion and spread of equine herpesvirus 9 in the olfactory pathway of pigs after intranasal inoculation. J Comp Pathol 124:265–272PubMedGoogle Scholar
  144. O’Brien JA, Ward A, Michels SL, Tzivelekis S, Brandt NJ (2003) Economic burden associated with Parkinson disease. Drug Benefit Trends 21:179–190Google Scholar
  145. Ogata A, Tashiro K, Nukuzuma S, Nagashima K, Hall WW (1997) A rat model of Parkinson’s disease induced by Japanese encephalitis virus. J Neurovirol 3:141–147PubMedGoogle Scholar
  146. Ogata A, Tashiro K, Pradhan S (2000) Parkinsonism due to predominant involvement of substantia nigra in Japanese encephalitis. Neurology 55:602PubMedGoogle Scholar
  147. Olanow CW (2007) The pathogenesis of cell death in Parkinson’s disease. Mov Disord Suppl 17:S335–S342Google Scholar
  148. Oliver KR, Fazakerley J (1998) Transneuronal spread of Semliki Forest virus in the developing mouse olfactory system is determined by neuronal maturity RID A-7352–2008. Neuroscience 82:867–877PubMedGoogle Scholar
  149. Oliver KR, Scallan MF, Dyson H, Fazakerley JK (1997) Susceptibility to a neurotropic virus and its changing distribution in the developing brain is a function of CNS maturity. J Neurovirol 3:38–48PubMedGoogle Scholar
  150. Owen AM, Iddon JL, Hodges JR, Summers BA, Robbins TW (1997) Spatial and non-spatial working memory at different stages of Parkinson’s disease. Neuropsychologia 35:519–532PubMedGoogle Scholar
  151. Packard MG, Knowlton BJ (2002) Learning and memory functions of the basal ganglia. Annu Rev Neurosci 25:563–593PubMedGoogle Scholar
  152. Pardridge WM (1997) Drug delivery to the brain. J Cereb Blood Metab 17:713–731Google Scholar
  153. Passingham D, Sakai K (2004) The prefrontal cortex and working memory: physiology and brain imaging. Curr Opin Neurobiol 14:163–168PubMedGoogle Scholar
  154. Perl D, Good P (1987) Uptake of aluminum into central nervous system along nasal-olfactory pathways. Lancet 1:1028PubMedGoogle Scholar
  155. Perl DP, Olanow CW (2007) The neuropathology of manganese-induced parkinsonism. J Neuropathol Exp Neurol 66:675–682PubMedGoogle Scholar
  156. Persson E, Henriksson J, Tallkvist J, Rouleau C, Tjalve H (2003) Transport and subcellular distribution of intranasally administered zinc in the olfactory system of rats and pikes. Toxicology 191:97–108PubMedGoogle Scholar
  157. Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS (2001) Mouse model of parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 106:589–601PubMedGoogle Scholar
  158. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedGoogle Scholar
  159. Poser CM, Huntley CJ, Poland JD (1969) Para-encephalitic parkinsonism report of an acute case due to coxsackie virus type B 2 and re-examination of the etiologic concepts of postencephalitic parkinsonism. Acta Neurol Scand 45:199–215PubMedGoogle Scholar
  160. Poskanzer DC, Schwab RS (1963) Cohort analysis of Parkinson’s syndrome: evidence for a single etiology related to subclinical infection about 1920. J Chronic Dis 16:961–973PubMedGoogle Scholar
  161. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2003) Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology 60:1761–1766PubMedGoogle Scholar
  162. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2009) Dietary fats, cholesterol and iron as risk factors for Parkinson’s disease. Parkinsonism Relat Disord 15:47–52PubMedGoogle Scholar
  163. Pranzatelli MR, Mott SH, Pavlakis SG, Conry JA, Tate ED (1994) Clinical spectrum of secondary parkinsonism in childhood: a reversible disorder. Pediatr Neurol 10:131–140PubMedGoogle Scholar
  164. Prediger RD, Batista LC, Medeiros R, Pandolfo P, Florio JC, Takahashi RN (2006) The risk is in the air: intranasal administration of MPTP to rats reproducing clinical features of Parkinson’s disease. Exp Neurol 202:391–403PubMedGoogle Scholar
  165. Prediger RD, Rial D, Medeiros R, Figueiredo CP, Doty RL, Takahashi RN (2009a) Risk is in the air: an intranasal MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) rat model of Parkinson’s disease. Ann N Y Acad Sci 1170:629–636PubMedGoogle Scholar
  166. Prediger RD, Rial D, Medeiros R, Figueiredo CP, Doty RL, Takahashi RN (2009b) Risk is in the air: an intranasal MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) rat model of Parkinson’s disease. Ann N Y Acad Sci 1170:629–636PubMedGoogle Scholar
  167. Prediger RD, Aguiar AS Jr, Rojas-Mayorquin AE, Figueiredo CP, Matheus FC, Ginestet L, Chevarin C, Bel ED, Mongeau R, Hamon M, Lanfumey L, Raisman-Vozari R (2010) Single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson’s disease. Neurotox Res 17:114–129PubMedGoogle Scholar
  168. Prediger RD, Aguiar AS Jr, Moreira EL, Matheus FC, Castro AA, Walz R, De Bem AF, Latini A, Tasca CI, Farina M, Raisman-Vozari R (2011) The intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a new rodent model to test palliative and neuroprotective agents for Parkinson’s disease. Curr Pharm Des 17:489–507PubMedGoogle Scholar
  169. Reiss C, Plakhov I, Komatsu T (1998) Viral replication in olfactory receptor neurons and entry into the olfactory bulb and brain. In: Olfaction and taste XII: an international symposium, vol 855, pp 751–761Google Scholar
  170. Richardson JR, Quan Y, Sherer TB, Greenamyre JT, Miller GW (2005) Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci 88:193–201PubMedGoogle Scholar
  171. Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in Parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm 38:277–301PubMedGoogle Scholar
  172. Rieger B, Markowitsch HJ (1996) Implicit and explicit mnestic performance of patients with prefrontal, medial temporal, and basal ganglia damage. Neurol Psychiatry Brain Res 4:53–74Google Scholar
  173. Roberts J (1962) Histopathogenesis of Mousepox. I. Respiratory Infection. Br J Exp Pathol 43:451–461PubMedGoogle Scholar
  174. Robinson RL, Shahida S, Madan N, Rao S, Khardori N (2003) Transient parkinsonism in West Nile virus encephalitis. Am J Med 115:252–253PubMedGoogle Scholar
  175. Rojo AI, Montero C, Salazar M, Close RM, Fernández-Ruiz J, Sánchez-González MA, de Sagarra MR, Jackson-Lewis V, Cavada C, Cuadrado A (2006) Persistent penetration of MPTP through the nasal route induces Parkinson’s disease in mice. Eur J Neurosci 24:1874–1884PubMedGoogle Scholar
  176. Rojo AI, Cavada C, de Sagarra MR, Cuadrado A (2007) Chronic inhalation of rotenone or paraquat does not induce Parkinson’s disease symptoms in mice or rats. Exp Neurol 208:120–126PubMedGoogle Scholar
  177. Ross CA, Smith WW (2007) Gene-environment interactions in Parkinson’s disease. Parkinsonism Relat Disord Suppl 13:S309–S315Google Scholar
  178. Royet JP, Gervais R, Araneda S (1983) Effect of local 6-OHDA and 5,6-DHT injections into the rat olfactory bulb on neophobia and learned aversion to a novel food. Behav Brain Res 10:297–309PubMedGoogle Scholar
  179. Rudd PA, Cattaneo R, von Messling V (2006) Canine distemper virus uses both the anterograde and the hematogenous pathway for neuroinvasion. J Virol 80:9361–9370PubMedGoogle Scholar
  180. Ryzhikov A, Ryabchikova E, Sergeev A, Tkacheva N (1995) Spread of Venezuelan equine encephalitis virus in mice olfactory tract. Arch Virol 140:2243–2254PubMedGoogle Scholar
  181. Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, Duyckaerts C, Sazdovitch V, Zhao L, Garrick LM, Nunez MT, Garrick MD, Raisman-Vozari R, Hirsch EC (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Nat Acad Sci USA 105:18578–18583PubMedGoogle Scholar
  182. Santin R, Fonseca VF, Bleil CB, Rieder CR, Hilbig A (2010) Olfactory function and Parkinson’s disease in Southern Brazil. Arq Neuropsiquiatr 68:252–257PubMedGoogle Scholar
  183. Sasco AJ, Paffenbarger RS (1985) Measles infection and Parkinson’s disease. Am J Epidemiol 122:1017–1031PubMedGoogle Scholar
  184. Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401–415PubMedGoogle Scholar
  185. Schapira AH (2008) Neurobiology and treatment of Parkinson’s disease. Trends Pharmacol Sci 30:41–47PubMedGoogle Scholar
  186. Schapira AH, Mann VM, Cooper JM, Dexter D, Daniel SE, Jenner P, Clark JB, Marsden CD (1990) Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 55:2142–2145PubMedGoogle Scholar
  187. Schmidt N, Ferger B (2001) Neurochemical findings in the MPTP model of Parkinson’s disease. J Neural Transm 108:1263–1282PubMedGoogle Scholar
  188. Schuler F, Casida JE (2001) The insecticide target in the PSST subunit of complex I. Pest Manag Sci 57:932–940PubMedGoogle Scholar
  189. Sedelis M, Hofele K, Auburger GW, Morgan S, Huston JP, Schwarting RK (2000) MPTP susceptibility in the mouse: behavioral, neurochemical, and histological analysis of gender and strain differences. Behav Genet 30:171–182PubMedGoogle Scholar
  190. Semchuk KM, Love EJ, Lee RG (1992) Parkinson’s disease and exposure to agricultural work and pesticide chemicals. Neurology 42:1328–1335PubMedGoogle Scholar
  191. Sherer TB, Kim JH, Betarbet R, Greenamyre JT (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol 179:9–16PubMedGoogle Scholar
  192. Shimizu K, Ohtaki K, Matsubara K, Aoyama K, Uezono T, Saito O, Suno M, Ogawa K, Hayase N, Kimura K, Shiono H (2001) Carrier-mediated processes in blood–brain barrier penetration and neural uptake of paraquat. Brain Res 906:135–142PubMedGoogle Scholar
  193. Shipley MT, Halloran FJ, de la Torre J (1985) Surprisingly rich projection from locus coeruleus to the olfactory bulb in the rat. Brain Res 329:294–299PubMedGoogle Scholar
  194. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedGoogle Scholar
  195. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95:6469–6473PubMedGoogle Scholar
  196. Stebbins GT, Gabrieli JD, Masciari F, Monti L, Goetz CG (1999) Delayed recognition memory in Parkinson’s disease: a role for working memory? Neuropsychologia 37:503–510PubMedGoogle Scholar
  197. Stephenson R, Houghton D, Sundarararjan S, Doty RL, Stern M, Xie SX, Siderowf A (2010) Odor identification deficits are associated with increased risk of neuropsychiatric complications in patients with Parkinson’s disease. Mov Disord 25:2099–2104PubMedGoogle Scholar
  198. Stroop W, Rock D, Fraser N (1984) Localization of herpes simplex virus in the trigeminal and olfactory systems of the mouse central nervous system during acute and latent infections by insitu hybridization. Lab Invest 51:27–38PubMedGoogle Scholar
  199. Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ (2006) Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology 66:968–975PubMedGoogle Scholar
  200. Takahashi N, Miner LL, Sora I, Ujike H, Revay RS, Kostic V, Jackson-Lewis V, Przedborski S, Uhl GR (1997) VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci USA 94:9938–9943PubMedGoogle Scholar
  201. Tallkvist J, Henriksson J, d’Argy R, Tjalve H (1998) Transport and subcellular distribution of nickel in the olfactory system of pikes and rats. Toxicol Sci 43:196–203PubMedGoogle Scholar
  202. Tallkvist J, Persson E, Henriksson J, Tjalve H (2002) Cadmium-metallothionein interactions in the olfactory pathways of rats and pikes. Toxicol Sci 67:108–113PubMedGoogle Scholar
  203. Tanner CM (1989) The role of environmental toxins in the etiology of Parkinson’s disease. Trends Neurosci 12:49–54PubMedGoogle Scholar
  204. Tanner CM (2010) Advances in environmental epidemiology. Mov Disord 25(Suppl 1):S58–S62PubMedGoogle Scholar
  205. Thiruchelvam M, Brockel BJ, Richfield EK, Baggs RB, Cory-Slechta DA (2000a) Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease? Brain Res 873:225–234PubMedGoogle Scholar
  206. Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA (2000b) The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson’s disease. J Neurosci 20:9207–9214PubMedGoogle Scholar
  207. Thiruchelvam M, Richfield EK, Goodman BM, Baggs RB, Cory-Slechta DA (2002) Developmental exposure to the pesticides paraquat and maneb and the Parkinson’s disease phenotype. Neurotoxicology 23:621–633PubMedGoogle Scholar
  208. Thiruchelvam M, McCormack A, Richfield EK, Baggs RB, Tank AW, Di Monte DA, Cory-Slechta DA (2003) Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson’s disease phenotype. Eur J Neurosci 18:589–600PubMedGoogle Scholar
  209. Thompson K, Molina RM, Donaghey T, Schwob JE, Brain JD, Wessling-Resnick M (2007) Olfactory uptake of manganese requires DMT1 and is enhanced by anemia. FASEB J 21:223–230PubMedGoogle Scholar
  210. Thor DH, Holloway WR (1982) Social memory of the male laboratory rat. J Comp Physiol Psychol 96:1000–1006Google Scholar
  211. Tissingh G, Berendse HW, Bergmans P, DeWaard R, Drukarch B, Stoof JC, Wolters EC (2001) Loss of olfaction in de novo and treated Parkinson’s disease: possible implications for early diagnosis. Mov Disord 16:41–46PubMedGoogle Scholar
  212. Tjalve H, Mejare C, Borg-Neczak K (1995) Uptake and transport of manganese in primary and secondary olfactory neurones in pike. Pharmacol Toxicol 77:23–31PubMedGoogle Scholar
  213. Tolosa E, Compta Y, Gaig C (2007) The premotor phase of Parkinson’s disease. Parkinsonism Relat Disord 13(Suppl):S2–S7PubMedGoogle Scholar
  214. Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5:107–110PubMedGoogle Scholar
  215. Uversky VN (2004) Neurotoxicant-induced animal models of Parkinson’s disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration. Cell Tissue Res 318:225–241PubMedGoogle Scholar
  216. Vanacore N, Nappo A, Gentile M, Brustolin A, Palange S, Liberati A, Di Rezze S, Caldora G, Gasparini M, Benedetti F, Bonifati V, Forastiere F, Quercia A, Meco G (2002) Evaluation of risk of Parkinson’s disease in a cohort of licensed pesticide users. Neurol Sci 23(Suppl 2):S119–S120PubMedGoogle Scholar
  217. Varastet M, Riche D, Maziere M, Hantraye P (1994) Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson’s disease. Neuroscience 63:47–56PubMedGoogle Scholar
  218. Vila M, Przedborski S (2003) Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci 4:365–375PubMedGoogle Scholar
  219. Wang XF, Li S, Chou AP, Bronstein JM (2006) Inhibitory effects of pesticides on proteasome activity: implication in Parkinson’s disease. Neurobiol Dis 23:198–205PubMedGoogle Scholar
  220. Wang B, Feng WY, Wang M, Shi JW, Zhang F, Ouyang H, Zhao YL, Chai ZF, Huang YY, Xie YN, Wang HF, Wang J (2007) Transport of intranasally instilled fine Fe2O3 particles into the brain: micro-distribution, chemical states, and histopathological observation RID B-1461-2009. Biol Trace Elem Res 118:233–243PubMedGoogle Scholar
  221. Ward CD, Hess WA, Calne DB (1983) Olfactory impairment in Parkinson’s disease. Neurology 33:943–946PubMedGoogle Scholar
  222. White NM, McDonald RJ (2002) Multiple parallel memory systems in the brain of the rat. Neurobiol Learn Mem 77:125–184PubMedGoogle Scholar
  223. Wright JM, Wall RA, Perry TL, Paty DW (1984) Chronic parkinsonism secondary to intranasal administration of a product of meperidine-analogue synthesis. N Engl J Med 310:325PubMedGoogle Scholar
  224. Wu H, Hu K, Jiang X (2008) From nose to brain: understanding transport capacity and transport rate of drugs. Expert Opin Drug Deliv 5:1159–1168PubMedGoogle Scholar
  225. Yasui M, Kihira T, Ota K (1992) Calcium, magnesium and aluminum concentrations in Parkinson’s disease. Neurotoxicology 13:593–600PubMedGoogle Scholar
  226. Youdim MB, Ben-Shachar D, Riederer P (1993) The possible role of iron in the etiopathology of Parkinson’s disease. Mov Disord 8:1–12PubMedGoogle Scholar
  227. Zatta P, Favarato M, Nicolini M (1993) Deposition of aluminum in brain-tissues of rats exposed to inhalation of aluminum acetylacetonate. Neuroreport 4:1119–1122PubMedGoogle Scholar
  228. Zhao H, Otaki J, Firestein S (1996) Adenovirus-mediated gene transfer in olfactory neurons in vivo. J Neurobiol 30:521–530PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Rui D. S. Prediger
    • 1
    • 2
    Email author
  • Aderbal S. AguiarJr.
    • 1
  • Filipe C. Matheus
    • 1
  • Roger Walz
    • 2
    • 3
  • Layal Antoury
    • 4
  • Rita Raisman-Vozari
    • 5
  • Richard L. Doty
    • 4
  1. 1.Departamento de Farmacologia, Centro de Ciências BiológicasUniversidade Federal de Santa Catarina, UFSCFlorianópolisBrazil
  2. 2.Centro de Neurociências Aplicadas (CeNAp)Hospital Universitário, Universidade Federal de Santa Catarina, UFSCFlorianópolisBrazil
  3. 3.Departamento de Clínica MédicaHospital Universitário, Universidade Federal de Santa Catarina, UFSCFlorianópolisBrazil
  4. 4.Smell & Taste Center and Department of Otorhinolaryngology: Head and Neck SurgeryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  5. 5.UMR 975 INSERM-Université Pierre et Marie Curie, Centre de Recheche de l’Institut du cerveau et de la moelle épinière-CRICM Thérapeutique Expérimentale de La neurodégénérescence, Hôpital de la SalpêtrièreParisFrance

Personalised recommendations