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

Abstract

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.

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Acknowledgements

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.

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Prediger, R.D.S., Aguiar, A.S., Matheus, F.C. et al. Intranasal Administration of Neurotoxicants in Animals: Support for the Olfactory Vector Hypothesis of Parkinson’s Disease. Neurotox Res 21, 90–116 (2012). https://doi.org/10.1007/s12640-011-9281-8

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Keywords

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