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dc.contributor.authorKadigamuwa, Chamila C.
dc.contributor.authorMapa, Mapa S.T.
dc.contributor.authorWimalasena, Kandatege
dc.identifier.citationChamila C. Kadigamuwa, Mapa S. T. Mapa, and Kandatege Wimalasena, Lipophilic Cationic Cyanines Are Potent Complex I Inhibitors and Specific in Vitro Dopaminergic Toxins with Mechanistic Similarities to Both Rotenone and MPP+, Chemical Research in Toxicology, 2016 29 (9) 1468-1479en_US
dc.descriptionClick on the DOI link to access the article (may not be free).en_US
dc.description.abstractWe have recently reported that simple lipophilic cationic cyanines are specific and potent dopaminergic toxins with a mechanism of toxicity similar to that of the Parkinsonian toxin MPP+. In the present study, a group of fluorescent lipophilic cyanines have been used to further exploit the structure activity relationship of the specific dopaminergic toxicity of cyanines. Here, we report that all cyanines tested were highly toxic to dopaminergic MN9D cells with IC(50)s in the range of 60-100 nM and not toxic to non-neuronal HepG2 cells parallel to that previously reported for 2,2'- and 4,4'-cyanines. All cyanines nonspecifically accumulate in the mitochondria of both MN9D and HepG2 cells at high concentrations, inhibit the mitochondrial complex I with the inhibition potencies similar to the potent complex I inhibitor, rotenone. They increase the reactive oxygen species (ROS) production specifically in dopaminergic cells causing apoptotic cell death. These and other findings suggest that the complex I inhibition, the expression of low levels of antioxidant enzymes, and presence of high levels of oxidatively labile radical propagator, dopamine, could be responsible for the specific increase in ROS production in dopaminergic cells. Thus, the predisposition of dopaminergic cells to produce high levels of ROS in response to mitochondrial toxins together with their inherent greater demand for energy may contribute to their specific vulnerability toward these toxins. The novel findings that cyanines are an unusual class of potent mitochondrial toxins with specific dopaminergic toxicity suggest that their presence in the environment could contribute to the etiology of PD similar to that of MPP+ and rotenone.en_US
dc.description.sponsorshipNational Institutes of Health National Center for Research Resources INBRE Program [Grant P20 RR016475] (to K.W.).en_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofseriesChemical Research in Toxicology;v.29:no.9
dc.subject1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTPen_US
dc.subjectMonoamine transporteren_US
dc.subjectRat hepatocytesen_US
dc.subjectOrganic cationsen_US
dc.titleLipophilic cationic cyanines are potent complex I inhibitors and specific in vitro dopaminergic toxins with mechanistic similarities to both rotenone and MPP+en_US
dc.rights.holderCopyright © 2016 American Chemical Societyen_US

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