ReviewParaquat exposure as an etiological factor of Parkinson's disease
Introduction
Parkinson's disease (PD), first described by James Parkinson in 1817, is a chronic progressive neurodegenerative disease, affecting at least 1% of the population over the age of 55 (Rajput, 1992). It is the second most common neurodegenerative disorder after Alzheimer's disease, with new 5–24 cases per 100,000 population diagnosed every year (Rajput, 1992).
Fully developed PD comprises motor symptoms such as resting tremor on one or both sides of the body, rigidity, bradykinesia, hypokinesia, and postural reflex impairment (Marsden, 1994). The pathology of PD is not fully understood. In normal brains the number of nigral cells is reduced by 4.7–6% per decade between the fifth and the ninth decade of life (Gibb and Lees, 1991), but this loss is not sufficient to cause PD (McGeer et al., 1977). The common feature of PD is the degeneration of the neural connection between the substantia nigra (SN) and the striatum (Wooten, 1997), two essential brain regions in maintaining normal motor function (Fig. 1). The striatum receives its dopaminergic input from neurons of substantia nigra pars compacta (SNpc) via the nigrostriatal pathway (Moore et al., 1971). Progressive degeneration of the nigrostriatal dopaminergic pathway results in profound striatal dopamine (DA) deficiency (Albin et al., 1989, Crossman, 1989, DeLong, 1990, Greenamyre, 1993, Klockgether and Turski, 1989). By the time that the clinical manifestations of PD are fully developed, a large proportion (80%) of dopaminergic neurons in the SN are already lost, resulting in reduced synthesis and release of DA from the striatal nerve terminals (Lang and Lozano, 1998).
Besides the loss of SN neurons, another important pathological feature of PD is the presence of neuronal cytoplasmatic inclusions known as Lewy bodies (LBs) (Gibb and Lees, 1988, Marsden, 1994) in some surviving nigral dopaminergic neurons. In PD, LBs are present in the dopaminergic neurons of SN, as well as in other brain regions such as the cortex and magnocellular basal forebrain nuclei (Braak et al., 1995). A major component of the LBs is the α-synuclein protein (thioflavin S-positive staining), and LBs seem to derive from α-synuclein aggregation (Spillantini et al., 1997, Spillantini et al., 1998, Uversky, 2003). However, several other clinical syndromes are also associated with intracellular α-synuclein inclusions (synucleinopathies) (Mukaetova-Ladinska and McKeith, 2006).
Considerable evidence suggests a multifactorial etiology for PD, involving genetic and environmental factors. The contribution of genetic predisposition to PD has been investigated in twin studies (Piccini et al., 1999), case-control studies (Gasser, 1998, Gasser, 2001, Sveinbjornsdottir et al., 2000), and in studies identifying mutations in genes encoding α-synuclein (Kruger et al., 1998, Polymeropoulos et al., 1997, Zarranz et al., 2004), parkin (Kitada et al., 1998), PINK1 (Valente et al., 2004), dardarin (Hernandez et al., 2005) and DJ-1 (Bonifati et al., 2003).
However, inheritance cannot fully explain all PD cases. In fact, a comprehensive study of over 19,000 white male twins showed that inheritance is not the cause of sporadic PD (Tanner et al., 1999). In addition, α-synuclein is found in all LBs, even in the majority of the idiopathic PD cases without α-synuclein mutations (Spillantini et al., 1997), thus indicating that additional mechanisms may lead to conformational changes and consequent protein aggregation.
Numerous environmental risk factors have been associated with the PD as causative agents, either in the modulation of the disease onset and/or on its progression (Di Monte, 2001, Di Monte, 2003, Di Monte et al., 2002, McCormack et al., 2002, Tanner, 1989, Tanner and Ben-Shlomo, 1999). Several environmental agents are known to cause nigrostriatal damage, and may thus contribute to PD, namely: (i) metals (Altschuler, 1999, Good et al., 1992, Gorell et al., 1999, Hellenbrand et al., 1996, Hirsch et al., 1991, Tanner, 1989, Yasui et al., 1992), (ii) solvents (Davis and Adair, 1999, Hageman et al., 1999, Pezzoli et al., 1996, Seidler et al., 1996, Uitti et al., 1994), and (iii) carbon monoxide (Klawans et al., 1982). Additionally, data from epidemiological studies point to an association between increased PD risk and specific environmental factors such as rural residence (Liou et al., 1997, Marder et al., 1998, Morano et al., 1994), farming (Fall et al., 1999, Gorell et al., 1998, Liou et al., 1997, Semchuk et al., 1992), drinking water from wells (Marder et al., 1998, Morano et al., 1994), and exposure to agricultural chemicals, including paraquat (PQ) (Fall et al., 1999, Gorell et al., 1998, Liou et al., 1997, Semchuk et al., 1992, Semchuk et al., 1993, Vanacore et al., 2002).
Given the public health implications concerning risk factors for the development of PD, the study of the environmental factors involved in the etiology of PD has gained renewed interest of the scientific and medical community as well as of the regulatory governmental agencies. In the present review the recent evidence from epidemiological, clinical, and experimental work linking the widely used herbicide, PQ, to PD pathology is discussed.
Section snippets
Paraquat toxicity mechanism
The cellular toxicity of PQ is essentially due to its redox cycle (Fig. 2). Paraquat is reduced, mainly by NADPH-cytochrome P-450 reductase (Clejan and Cederbaum, 1989), NADPH-cytochrome c reductase (Fernandez et al., 1995), and the mitochondrial complex I also known as NADH: ubiquinone oxidoreductase (Fukushima et al., 1993, Yamada and Fukushima, 1993), to form a PQ monocation free radical (PQ+). It is generally accepted that PQ uses cellular diaphorases, which are a class of enzymes that
Paraquat induces long-lasting dopamine overflow and reduction of dopamine synthesis
The excitotoxicity induced by N-methyl-d-aspartate (NMDA) receptor activation, associated to Ca2+ penetration into the cells by activation of non-NMDA receptors, is a central mechanism of neurodegeneration in several neurological diseases (Dugan and Choi, 1999). There is also increasing evidence that the excitotoxic injury plays a critical role in progressive degeneration of DA neurons in PD (Beal, 1998). In vivo studies on the mechanisms of PQ-induced toxicity in the striatum, indicated that
Permeability of blood-brain barrier to paraquat and putative uptake by the dopamine transporter
Another important feature of PQ toxicity is related to its ability to permeate the blood-brain barrier (BBB) into the CNS. Paraquat is a charged molecule, with a hydrophilic structure, low partition coefficient and does not readily cross membranes. Thus, it is unlikely that the passive entry of PQ across the BBB leads to a significant accumulation of the compound in the brain. In accordance, it was previously shown that the structurally related dopaminergic neurotoxin
The inherent susceptibility of dopaminergic neurons contributes to the paraquat-induced damage
Comparing to other neuronal cell types, dopaminergic cells are much more sensitive to oxidative injury due to the participation of DA in harmful oxidative reactions (Fitsanakis et al., 2002, Graham, 1978). The activity of MAO, which is involved in DA metabolism, produces H2O2 as a normal byproduct. Moreover, autoxidation of DA results in the formation of ROS (Lotharius and O’Malley, 2000). Nevertheless, the toxicological implications of the inherent vulnerability of the nigrostriatal DA system
Epidemiological studies
A study performed with 120 patients in Taiwan, where the herbicide PQ is commonly sprayed over rice fields, showed a strong association between PQ exposure and PD risk. The hazard increased by more than six times in individuals who had been exposed to PQ for more than 20 years (Liou et al., 1997). These observations were consistent with a dose-dependent effect and increased with duration of pesticide use in agricultural workers (Liou et al., 1997, Petrovitch et al., 2002). Occupational PQ
Paraquat as a tool for animal models of Parkinson's disease
Animal models are an invaluable tool for studying the pathogenesis and therapeutic intervention strategies of human disease, including PD and in particular, toxicant-induced Parkinsonism. Since PD does not develop spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. Although an ideal model should reproduce the characteristic clinical and pathological features of PD (i.e., animals should develop progressive loss of dopaminergic neurons, show
Two insults are more effective than one: paraquat + maneb
The hypothesis that a combination of environmental risk factors may result in more severe nigrostriatal injury is supported by several lines of experimental evidence. These observations are of special interest, since humans are likely to be exposed to a complex mixture of chemical agents in their residential and occupational environments. PQ is a member of only one class of agricultural chemicals known to have adverse effects in the nigrostriatal DA system. Complex mixtures of several
Concluding remarks
A number of clinical and experimental studies have increased the interest in the possibility that environmental chemicals, including PQ, may be related to the development of PD (Brooks et al., 1999, Corasaniti et al., 1998, Liou et al., 1996). PQ seems to be one of the most eligible herbicides that may contribute for the development of PD, given that the incidence and development of the disease and the extent of PQ exposure strongly correlate. (Brooks et al., 1999, Corasaniti et al., 1998, Liou
Acknowledgement
Ricardo Dinis, acknowledges FCT for his PhD grant (SFRH/BD/13707/2003).
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