Paraquat (PQ) is a cationic non-selective bipyridyl herbicide widely used in
agriculture to control weeds and grasses. Epidemiologic studies indicate that exposure to
pesticides can be a risk factor in the incidence of Parkinson`s disease (PD). A strong
correlation has been reported between exposure to paraquat and PD incidence in Canada,
Taiwan, and United States. This correlation is supported by animal studies showing that
paraquat produces toxicity in dopaminergic neurons of the rat and mouse brain. However,
it is unclear how paraquat triggers toxicity in dopaminergic neurons. Based on the
previous reports, it was hypothesized that paraquat may induce oxidative stress and
proteasomal dysfunction-mediated toxicity in dopaminergic neurons. To explore this
possibility, dopaminergic SH-SY5Y human neuroblastoma cells were treated with
paraquat, and several biomarkers of oxidative stress or proteasomal dysfunction were
investigated. First, a specific dopamine transporter inhibitor GBR12909 significantly
protected SY5Y cells against the toxicity of paraquat, indicating that paraquat exerts its
toxicity by a mechanism involving the dopamine transporter (DAT). Second, paraquat increased the levels of reactive oxygen species (ROS) in SY5Y cells, but decreased the
levels of glutathione. Third, paraquat inhibited glutathione peroxidase activity, but did
not affect glutathione reductase activity. On the other hand, paraquat increased GST
activity by 24 hr, after which GST activity returned to the control value at 48 hr. Fourth,
paraquat decreased mitochondrial transmembrane potential (MTP). Fifth, paraquat
produced the increases in malondialdehyde (MDA) and protein carbonyls, as well as
DNA fragmentation, indicating oxidative damage to major cellular components. Sixth,
paraquat decreased proteasomal activity, the activities of mitochondrial complex I and V,
and intracellular ATP levels, but increased the activities of caspase 3 and 9, indicating
that proteasomal inhibition is linked to mitochondrial dysfunction accompanied by the
activation of apoptotic signaling pathway. Seventh, paraquat increased the protein levels
of heme oxygenase-1 (HO-1), p53, Bax, ñ-synuclein and ubiquitinated proteins. Eighth,
paraquat induced nuclear condensation. Taken together, these findings support the
hypothesis that paraquat produces oxidative stress and proteasomal dysfunctionmediated
toxicity in SY5Y cells. Thus, current findings suggest that paraquat may
induce the pathogenesis of dopaminergic neurons through oxidative stress and
proteasomal dysfunction.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/4384 |
| Date | 30 October 2006 |
| Creators | Yang, Wonsuk |
| Contributors | Tiffany-Castiglioni, Evelyn |
| Publisher | Texas A&M University |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Dissertation, text |
| Format | 1633882 bytes, electronic, application/pdf, born digital |
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