Title page for ETD etd-11302005-154325


Type of Document Dissertation
Author Kou, Jinghong
Author's Email Address jkou@vt.edu
URN etd-11302005-154325
Title The Neurotoxicity of Insecticides to Striatal Dopaminergic Pathway
Degree PhD
Department Entomology
Advisory Committee
Advisor Name Title
Bloomquist, Jeffrey R. Committee Chair
Castagnoli, Kay P. Committee Member
Ehrich, Marion F. Committee Member
Klein, Bradley G. Committee Member
Paulson, Sally L. Committee Member
Keywords
  • neurotoxicity testing
  • neurotoxicology
  • environmental neurotoxicant
  • neurodegeneration
  • toxicology
  • neuroscience
Date of Defense 2005-11-18
Availability unrestricted
Abstract

Parkinson's disease (PD) is an age-related neurodegenerative disease, which is characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and consequent dopamine depletion in its projecting area. In this dissertation, I evaluated the neurotoxicity of several classes of insecticides/drugs/neurotoxins to the striatal dopaminergic pathway and their potential relationship to Parkinsonism in the C57BL/6 mouse model, using biochemical and molecular biology methods.

In the first objective, I investigated the neurotoxicity in striatal dopaminergic pathways following co-application of permethrin (PM), chlorpyrifos (CPF) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The study was done because pyrethroid and organophosphorus compounds are widely used insecticides and they have been implicated in Gulf War Syndrome. We found that short-term, high-dose exposure to PM or CPF had no significant effects on the expression of dopamine transporter (DAT), tyrosine hydroxylase (TH), or α-synuclein protein in striatal nerve terminals, but the insecticides slightly enhanced the neurotoxicity of MPTP in C57BL/6 mice at 28 days post-treatment. This finding indicates a slowly developing neurotoxicity may occur after termination of high-dose exposure. Long-term, low-dose exposure to PM did not show significant neurotoxicity to striatal dopaminergic pathways when given alone, nor did this injection of PM enhance the neutotoxicity of MPTP in C57BL/6 mice. In addition, experiments with pure cis or trans isomers of permethrin showed that both cis and trans isomers contributed equally to the neurotoxicity of PM in the short-term high dose study.

Previous studies demonstrated a deficiency in mitochondrial function in PD, and a high density of K+ATP channels are present in substantia nigra, which play an important role in the maintenance of the membrane potential under metabolic stress. Therefore, in the second objective, I investigated the effect of K+ATP channel blockage on the neurotoxicity of mitochondrial-directed neurotoxins to striatal dopaminergic pathways. I found that mitochondrial inhibitors are potent releasers of preloaded dopamine from striatal nerve terminals, with the most potent compounds active in the nanomolar range. Co-application of the K+ATP channel blocker glibenclamide selectively increased the dopamine-releasing effect by complex I inhibitors in vitro, and potentiated the neurotoxicity of MPTP (a complex I inhibitor) on DAT and TH expression, in vivo. Mechanistic studies demonstrated that mitochondrial inhibitor-induced dopamine release is Ca2+-dependent. In addition, the selectivity of glibenclamide is not correlated to ATP depletion, but associated with the generation of excessive reactive oxygen species at the site of complex I.

In the third objective, I conducted comparative studies on the mode of action of rotenone-/reserpine-/tetrabenzaine (TBZ)-induced depletion, in vitro, as these three compounds share some similarities in their chemical structures. I found that rotenone, reserpine and TBZ selectively released preloaded dopamine and serotonin (5-HT), with the rank order as rotenone>reserpine>TBZ. Mechanistic studies demonstrated more than one mechanism was involved in both rotenone- and reserpine-induced neurotransmitter release. Ca2+-stimulated vesicular release and neurotransmitter transporter-mediated release are the common mechanisms involved in rotenone- and reserpine-induced dopamine release.

Overall, the insecticides/drugs/neurotoxins tested in the above experiments all exhibited some effect on the nigrastrital dopaminergic pathway, either alone or by enhancing the toxicity of other chemicals in combination treatment.

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