ToxSci Advance Access originally published online on February 27, 2008
Toxicological Sciences 2008 103(1):219-221; doi:10.1093/toxsci/kfn028
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Response to "Paraquat: The Red Herring of Parkinson's Disease Research"
* Department of Anesthesiology, Albert Einstein College of Medicine
Department of Chemistry, Iona College
Received January 15, 2008; accepted January 18, 2008
This communication is in response to the editorial by G. W. Miller entitled "Paraquat: The Red Herring of Parkinson's Disease Research" (Toxicol. Sci. 100(1–2), 2007). The author has suggested that research based on the structural similarities between N-N'-dimethyl-4,4'-bipyridinium dichloride (paraquat) and the 1-methyl-4-phenylpyridinium ion (MPP+) is a red herring that has derailed progress in the search for the neuropathogenic mechanism of Parkinson's disease (PD). In support of this, Dr Miller cites several studies from his laboratory that presumably demonstrate the mechanistic independence of paraquat (PQ) and MPP+. However, the author does not recognize the critical role of chemical structure in determining the toxicokinetic and toxicodynamic characteristics of a neurotoxicant. Consequently, the structural similarities between PQ and MPP+ could indicate a common neurodegenerative mechanism. Furthermore, the editorial is based on an underlying assumption that the neurotoxicological actions of MPP+ are an accurate representation of PD molecular pathogenesis. The validity of this assumption has not been established conclusively. Nonetheless, the author focuses on the presumed mechanistic differences among pyridinium toxicants and concludes that PQ models generate misleading information. The editorial did not, however, accurately portray existing controversies in the PQ and MPP+ databases and, as a result, did not provide a balanced discussion. The conflicted nature of the databases and a growing awareness of pyridinium mechanistic complexity effectively preclude conclusions regarding neuropathogenic distinctions between PQ and MPP+. Finally, based on relatively low in vitro potency, Dr Miller states that "paraquat cannot be considered ... a physiologically relevant complex I inhibitor." The author, however, does not consider the possible cumulative toxic actions of PQ with respect to this and other molecular parameters. The purpose of this response is to provide a brief discussion of these concerns.
PQ and MPP+ are structural analogs and, consequently, it is rational to suggest that they produce nerve terminal toxicity by a similar mechanism of action. Clearly, the noted differences in dopaminergic toxicity following systemic intoxication can be attributed to the relative toxicokinetic differences imposed by the dicationic nature of PQ and corresponding requirement for blood–brain barrier transport (e.g., see McCormack and Di Monte, 2003
; Shimizu et al., 2001). However, at the molecular level, there is no conclusive evidence that PQ and MPP+ differ mechanistically. Thus, although the author has provided data that, unlike MPP+, PQ is not a substrate for membrane dopamine transport (DAT) and does not affect mitochondrial complex I activity (Ramachandiran et al., 2007; Richardson et al., 2005), the results of other research contradict these findings (e.g., Cochene and Murphy, 2007; Fuchushima et al., 1993, 1994; Ossowska et al., 2005a; Tawara et al., 1996; Yang and Tiffany-Castiglioni, 2005). In fact, it has not been established conclusively that complex I is the primary site of action for MPP+; for example, whereas Richardson et al. (2007) recently published evidence suggesting that an obligatory role for complex I in MPP+ neurotoxicity, other findings do not support these data (Bates et al., 1994; Espino et al., 1994; Nakamura et al., 2000; Obata, 2002). In fact, alternative, even nonmitochondrial, mechanisms of MPP+ neurotoxicity have been proposed (e.g., Gerlach et al., 1996; Klaidman et al., 1993; Lotharius and O'Malley, 2000; Obata, 2006). The contradictory nature of the PQ/MPP+ database likely reflects a multicomponent mechanism of pyridinium neurotoxicity that involves a complex interplay between DAT transport, vesicular sequestration, mitochondrial damage and cytosolic enzyme inhibition (e.g., see Lotharius and O'Malley, 2000; McCormack et al., 2005; Nakamura et al., 2000; Yang and Tiffany-Castiglioni, 2005; reviewed in Dauer and Prezedborski, 2003). Whether the multiple neurotoxic possibilities of the pyridiniums are mediated by mitochondrial superoxide production, direct toxicant–protein interactions (adduct formation) or both has not been determined. Regardless, given the ambiguity of the pyridinium database and evolving mechanistic complexity, it is premature to conclude that PQ and MPP+ operate via different molecular mechanisms. In contrast to the author's contention, structural similarities are important and, therefore, defining structure–toxicity relationships among congeners (e.g., PQ, MPP+, diquat, putrescine) could provide mechanistic insight. Structure–toxicity studies have significantly improved our understanding of the neurotoxicity associated with other chemical classes; e.g., the 
,β-unsaturated carbonyl derivatives and polychlorinated biphenyls (LoPachin et al., 2008; Mariussen et al., 2001).
Also disconcerting was the author's cavalier dismissal of PQ as a "physiologically" (toxicologically?) relevant inhibitor of mitochondrial complex I. This comment was based on the relatively low in vitro potency of PQ; that is, the IC50 for PQ inhibition of complex 1 was 7 mM compared with an IC50 of 30 µM for MPP+. Although the role of complex 1 inhibition in PQ dopaminergic toxicity has not been resolved (see above), exclusion of a possible neurotoxic effect based on in vitro potency is shortsighted. For example, acrylamide (ACR) intoxication is associated with nerve terminal dysfunction and delayed degeneration in the peripheral and central nervous systems (reviewed in LoPachin et al., 2003). ACR is a weak soft electrophile that slowly forms adducts with soft biological nucleophiles, primarily cysteine sulfhydryl groups. Despite exhibiting relatively low in vitro potency; for example, the ACR IC50 for inhibition of vesicular 3H-DA transport is 243 mM versus an IC50 of 213 µM for acrolein, there is now substantial evidence from animal models that ACR produces presynaptic toxicity by disrupting vesicular neurotransmitter storage and membrane fusion. This toxicity is mediated by adduction of functionally critical proteins that turnover slowly and consequently accumulate. The build-up of adducted, dysfunctional proteins in nerve terminal is likely responsible for the cumulative (progressive) neurotoxicity that characterizes experimental and environmental ACR exposure (reviewed in LoPachin et al., 2008). There is evidence that subchronic PQ exposure produces cumulative nigrostriatal toxicity associated with parallel CNS retention of the pyridinium (McCormack et al., 2002; Ossowska et al., 2005b; Prasad et al., 2007). This toxicodynamic might indicate that, like ACR, PQ produces cumulative neurotoxicity by forming irreversible protein adducts that subsequently accumulate. Therefore, the relatively low potency of PQ in several in vitro models (Ramachandiran et al., 2007; Richardson et al., 2005) does not necessarily exclude the corresponding parameter from mechanistic consideration.
In his role as provocateur, Dr Miller has succeeded in generating discussion, which is always scientifically beneficial. Clearly, resolving data discrepancies and establishing the similar/dissimilar molecular mechanisms of PQ and MPP+ will require systematic determinations of structure–toxicity relationships. The results of such research would provide a rational basis for the application (or not) of these chemicals as PD models. In addition, understanding how pyridinium chemical structure affects toxicity (dopaminergic damage) could be used to predict the neurotoxic potential of existing and newly developed agricultural and industrial chemicals. Finally, although redox cycling through mitochondria appears to be neurotoxicologically important, it might be helpful to determine how PQ and MPP+ interact with nerve terminal proteins and membranes.
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