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A Guide to Neurotoxic Animal Models of Parkinson’s Disease

Kim Tieu

Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York 14625 Correspondence: [email protected]

Parkinson’s disease (PD) is a neurological movement disorder primarily resulting from damage to the nigrostriatal dopaminergic pathway. To elucidate the pathogenesis, mechan- isms of cell death, and to evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. The primary objectives of this article are twofold: First, to assist new investigators who are contemplating embarking on PD research to navigate through the available animal models. Emphasis will be placed on common neurotoxic murine models in which toxic molecules are used to lesion the nigrostriatal dopaminergic system. And second, to provide an overview of basic technical requirements for assessing the pathology, structure, and function of the nigrostriatal pathway.

arkinson’s disease (PD) is the second most PD, or a combination of both, have been created Pcommon chronic neurodegenerative disor- to study PD and to screen therapeutic strategies. der, after Alzheimer’s disease. Currently, there The success rate of translating this basic research is no cure for PD and additional effective treat- into clinical relevance for PD relies heavily on ments for this devastating disease are urgently the extent to which these experimental models needed. To achieve this goal, it is critical to accurately recapitulate the pathology, symp- understand its etiology and the underlying toms, and pathogenic mechanism as seen in

www.perspectivesinmedicine.org mechanisms of neurodegeneration and neuro- PD patients. nal dysfunction. However, the cause(s) of the Pathologically, the hallmarks of PD are the majority of PD cases remains unknown. Less loss of dopaminergic neurons in the substantia than 10% of PD cases can be directly linked to nigra pars compacta and the presence of cyto- monogenic mutations. Environmental factors, plasmic protein aggregates, known as Lewy or a combination of both environment and bodies, in remaining dopaminergic cells (Dauer genetic susceptibility, have been proposed to and Przedborski 2003). When degeneration in play a role in sporadic PD. Accordingly, experi- these neurons results in a threshold reduction mental models utilizing exposure to exogenous of 80% dopamine in the striatum (Dauer neurotoxicants, mutations in genes linked to and Przedborski 2003), motor symptoms of

Editor: Serge Przedborski Additional Perspectives on Parkinson’s Disease available at www.perspectivesinmedicine.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a009316 Cite this article as Cold Spring Harb Perspect Med 2011;1:a009316

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K. Tieu

PD emerge. Mechanistically, the death of different molecules are used to damage the dopaminergic neurons has been linked to mi- nigrostriatal pathway. Faced with a wide variety tochondrial dysfunction, oxidative stress, neu- of PD models, a new investigator may find roinflammation, and insufficient autophagic selecting the appropriate one to be a daunting or proteasomal protein degradation (Dauer task. Another challenging step is knowing and Przedborski 2003; Hirsch and Hunot what basic techniques and equipment are re- 2009; Martin et al. 2010). In addition to the quired for assessing neurodegeneration and loss of nigrostriatal dopaminergic structures dysfunction in these models. To address these and function, PD also affects many other areas issues, this article will provide both an overview of the central nervous system, such as the dorsal of the strengths and limitations of some com- motor nucleus of the vagus, the nucleus basalis monly used animal models, as well as a general of Meynert, the locus coeruleus, and the hypo- guide to assessing nigrostriatal damage. Because thalamus (Hornykiewicz and Kish 1987; Braak genetic models of PD and other vertebrate spe- et al. 2004). Furthermore, the pathology of PD cies such as nonhuman primates are discussed extends well beyond the central nervous system by Dawson and Bezard, respectively, elsewhere because Lewy bodies have been detected in the in this collection, this article will focus on neu- myenteric plexus (Kupsky et al. 1987). Together, rotoxic rodent models. these extranigrostriatal regions may account for the observed nonmotor symptoms such as sleep disturbances, depression, cognitive im- 6-HYDROXYDOPAMINE pairment, anosmia, constipation, incontinence, 6-Hydroxydopamine (6-OHDA), a hydroxy- and autonomic dysfunctions (Chaudhuri et al. lated analog of dopamine (Fig. 1; see also 2005; Langston 2006; Jain 2011). Table 1), was first identified more than 50 years An ideal model of PD should consist of ago (Senoh and Witkop 1959; Senoh et al. pathological and clinical features of PD involv- 1959). Initially, 6-OHDA was reported to cause ing both dopaminergic and nondopaminer- depletion of noradrenaline in the mouse heart gic systems, the central and peripheral nervous (Porter et al. 1963, 1965). The subsequent dis- systems, plus motor and nonmotor symptoms. covery that 6-OHDA could induce selective Additionally, the age-dependent onset and degeneration in sympathetic adrenergic nerve progressive nature of PD should be reflected. terminals (Tranzer and Thoenen 1968, 1973) Unfortunately, none of the current models led to the novel concept of “chemical denerva- displays all of these PD features. Despite these tion” in neurobiology, in which a neurotoxic limitations, animal models have contributed molecule is used to target a specific cell popula- www.perspectivesinmedicine.org significantly to our current understanding of tion (Jonsson 1980). Todate, 6-OHDA is widely the disease processes and potential therapeutic targets in PD. Current animal models of PD can be broadly 6-OHDA MPTP

divided into two categories: genetic and neuro- HO NH2 H3C N toxic models. Each group has strengths and HO OH weaknesses. One strength of the genetic mod- MPP+ els is that they are created primarily based on + H C N identified targets associated with potential Rotenone 3 H O O mechanisms known to cause PD in humans O Paraquat (Meredith et al. 2008; Bezard and Przedborski H + O + 2011). However, currently available models do H3CO H3C N N CH3 OCH not display appreciable neurodegeneration and 3 phenotypes (Dawson et al. 2010). This limita- Figure 1. Structures of neurotoxic molecules used tion of genetic models, however, can be comple- to induce nigrostriatal damage in some common mented by the neurotoxic models in which animal models of PD.

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Toxic Animal Models of Parkinson’s Disease

Table 1. Key features of common neurotoxic models of PD Models Pathology Behavioral phenotypes

Nigrostriatal damage Motor (L-dopa SN cell Str. Str. Extranigral or apomorphine body terminals DA pathology LB responsive) Nonmotor 6-OHDA Rat Stereotactic injection Yes Yes Yes No No Yes Cognitive, psychiatric, to SN, MFB, and GI disorders striatum MPTP Nonhuman primates i.p, i.m, intracarotid Yes Yes Yes LC Yes Yes Numerous (see Fox infusion and Brotchie 2010; Bezard 2011) Mouse Acute, subacute (i.p.) Yes Yes Yes No No Yes Transient colon motility Chronic (osmotic Yes Yes Yes LC Yes Yes ND minipumps) PQ Mouse i.p. Yes Conflicting No LC Yes ND ND PQ/Maneb Mouse i.p. Yes ND Yes ND Yes ND ND Rotenone Rat Infusion via osmotic Yes Yes Yes ND Yes Yes GI motility minipumps i.p. injection Yes Yes Yes GI Yes Yes GI motility Abbreviations: SN, substantia nigra; Str., striatal; LB, Lewy bodies; LC, locus coeruleus; GI, gastrointestinal; MFB, medial forebrain bundle; ND, not determined. www.perspectivesinmedicine.org used to lesion the nigrostriatal dopaminergic 6-OHDA accumulates in the cytosol where it system as a model of PD. The evidence that is readily oxidized leading to the generation this molecule can be found endogenously in of reactive oxygen species and ultimately, oxida- human brain (Curtius et al. 1974) and urine tive stress-related cytotoxicity (Saner and Thoe- samples (Andrew et al. 1993) lends additional nen 1971; Graham 1978; Jonsson 1983; Cohen credence to this model. and Werner 1994; Blum et al. 2001). Accord- In the brain, 6-OHDA is capable of in- ingly, the locus coeruleus and the nigrostriatal ducing degeneration of both dopaminergic region are highly sensitive to this neurotoxin and noradrenergic neurons (Ungerstedt 1968). (Jonsson 1980). To target specific neurons and These types of neurons are particularly vulner- to bypass the blood–brain barrier, 6-OHDA is able to 6-OHDA because their plasma mem- typically injected stereotactically into the brain brane transporters, the dopamine transporter region of interest. Because of the difficulty in and noradrenergic transporter, respectively, targeting small brain structures such as the have high affinity for this molecule (Luthman substantia nigra or medial forebrain bundle, et al. 1989). Once taken up into neurons, 6-OHDA is more commonly used in rats than

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K. Tieu

in mice to model PD (Jonsson 1983). Although Subsequent to this unilateral lesioning, sys- uncommon, 6-OHDA has also been used in temic injection of dopamine receptor agonists cats, guinea pigs, dogs, and monkeys (Bezard (such as apomorphine), L-3,4-dihydroxyphe- et al. 1998; Bezard and Przedborski 2011). nylalanine (L-dopa, a dopamine precursor), The magnitude and characteristics of neu- or dopamine releasing compounds (such as rodegeneration induced by 6-OHDA are signif- amphetamine) induces asymmetrical rotation icantly affected by the site of injection (Agid (Ungerstedt and Arbuthnott 1970; Hefti et al. et al. 1973; Przedborski et al. 1995; Przedborski 1980). The magnitude of nigrostriatal lesions and Tieu 2006). 6-OHDA is most commonly correlates with the circling motor behavior injected unilaterally to the substantia nigra, (Ungerstedt 1968; Ungerstedt and Arbuthnott medial forebrain bundle, or striatum. Although 1970; Hefti et al. 1980; Przedborski et al. generally the nerve terminals are more sensi- 1995). Overall, the unilateral 6-OHDA rat tive to 6-OHDA toxicity than the axon and model has been used extensively as a preclinical cell body (Malmfors and Sachs 1968; Jonsson model to assess the antiparkinsonian effects and 1983), when injected into the nigra or the neuroprotection of new pharmacological thera- medial forebrain bundle, 6-OHDA produces a pies (Jiang et al. 1993; Chan et al. 2010; Ilijic complete and rapid lesion in the nigrostriatal et al. 2011), as well as the clinical improvement pathway. When injected into the nigra, degener- of cell transplantation (Bjorklund et al. 2002; ation of dopaminergic neurons takes place Kirik et al. 2002; Roy et al. 2006). However, within 12 h preceding a significant loss of stria- like many other neurotoxic models of PD, tal terminals, which occurs 2–3 d later (Faull the acute neurodegenerative property of the and Laverty 1969; Jeon et al. 1995). When 6-OHDA model lacks the progressive, age- injected into the medial forebrain bundle, how- dependent effects of PD. Additionally, Lewy ever, 6-OHDA induces degeneration in striatal bodies are not present in this model. terminals before dopaminergic cell death occurs (Sarre et al. 2004). In contrast to the nigra and 1-METHYL-4-PHENYL-1,2,3,6- medial forebrain bundle, when delivered to TETRAHYDROPYRIDINE the striatum, 6-OHDA induces slow, progres- sive, and partial damage to the nigrostriatal The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri- structure in a retrograde fashion over a period dine (MPTP) model originates from discoveries of up to 3 weeks (Sauer and Oertel 1994; Przed- in the early 1980s when several Californian borski et al. 1995). This latter route of ad- intravenous drug users were admitted to hospi- ministration offers three advantages: First, the tals showing severe symptoms similar to PD www.perspectivesinmedicine.org progressive and less extensive lesion is more (Davis et al. 1979; Langston et al. 1983). Further relevant to PD. Second, this regimen has been investigations uncovered that these patients shown to produce nonmotor symptoms of had self-administered synthetic meperidine PD, including cognitive, psychiatric, and gas- contaminated with MPTP (Langston et al. trointestinal dysfunction (Branchi et al. 2008; 1983). The movement abnormalities in these Tadaiesky et al. 2008; Cannon and Greenamyre patients were successfully treated with L-dopa, 2010). Third, the ease of stereotactically inject- a cornerstone treatment of PD, suggesting sim- ing a large structure such as the striatum enhan- ilar underlying neuropathological and bio- ces the likelihood of success in mice. chemical features to those seen in PD patients. The major advantage of using the 6-OHDA Postmortem studies confirmed the loss of model is its rather unique effect on quantifi- nigrostriatal structures in these patients (Davis able circling motor abnormality in animals et al. 1979; Langston et al. 1999). Recently, one (Ungerstedt and Arbuthnott 1970). Typically, of the surviving patients showed a significant unilateral injection into one hemisphere clinical improvement when treated with deep (hemiparkinsonian model) is performed, leav- brain stimulation (Christine et al. 2009), further ing the unlesioned side as an internal control. affirming the damage induced by MPTP in the

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Toxic Animal Models of Parkinson’s Disease

basal ganglia resembles that in human PD. Since In both monkeys and mice, MPTP primar- its discovery, MPTP has drastically altered the ily causes damage to the nigrostriatal dopami- course of PD research by providing insights nergic pathway (Forno et al. 1993; Dauer and into potential pathogenesis and mechanisms Przedborski 2003; Fox and Brotchie 2010). for cell death in PD. Studies using this model This specific and reproducible neurotoxic effect have led to the concepts such as environmental to the nigrostriatal system is a strength of this toxicity as a potential culprit in sporadic PD, model. Although intraneuronal inclusions and mitochondrial dysfunction as a potential reminiscent of Lewy bodies have been described pathogenic mechanism. Additionally, work in MPTP-injected monkeys (Forno et al. 1986), with this model has enabled the development in general, this pathological feature is absent in of some current treatments for PD (Fox and mice. However, it has been claimed that when Brotchie 2010). mice are infused with a chronic low dose of The mechanism of MPTP toxicity has been MPTP over a period of 30 d using osmotic min- extensively studied and characterized (Dauer ipumps, inclusions immunoreactive for both and Przedborski 2003; Rappold and Tieu ubiquitin and a-synuclein can be detected (For- 2010). Because MPTP is lipophilic, it can nai et al. 2005). Additionally, with this regimen, rapidly cross the blood–brain barrier. In astro- Lewy bodies and degeneration of noradrenergic cytes, MPTP is metabolized by monoamine neurons are detected in the locus coeruleus. oxidase-B, and subsequently converted to the However, the reproducibility of this regimen active toxic cation 1-methyl-4-phenylpyridi- needs to be confirmed by other investigators. nium (MPPþ; Fig. 1). MPPþ is released from Behaviorally, motor deficits induced by MPTP the nigral and striatal astrocytes through the have been extensively characterized in both organic cation transporter 3 into the extracellular monkeys and mice. These abnormal pheno- space (Cui et al. 2009; Rappold and Tieu 2010) types are reversible by L-dopa or a dopamine where it is taken up by the neighboring do- agonist, confirming a connection between these paminergic neurons and terminals through the symptoms and damage in the nigrostriatal sys- dopamine transporter. Once accumulated in tem (Ogawa et al. 1985; Fredriksson and Archer dopaminergic neurons, MPPþ induces neuro- 1994; Rozas et al. 1998; Fernagut et al. 2002). In toxicity primarily by inhibiting complex I of the general, parkinsonian symptoms are better mitochondrial electrontransport chain, resulting reproduced in monkeys than in mice, and a in ATP depletion and increased oxidative stress more profound loss of striatal dopamine is (Nicklas et al. 1985; Mizuno et al. 1987). required in mice to produce some such deficits. Various mammalian species, including In addition to the nigrostriatal pathway, MPTP www.perspectivesinmedicine.org sheep, dogs, guinea pigs, cats, mice, rats, and has also been reported to induce loss of dopa- monkeys, have been treated with MPTP to minergic neurons in the enteric nervous system model PD (Bezard et al. 1998; Przedborski and alter colon motility in mice (Anderson et al. et al. 2001). To date, the MPTP-monkey model 2007). However, the relevance of this observa- remains the gold standard for preclinical testing tion to the commonly observed gastrointestinal of therapeutic strategies for PD (for a detailed dysfunction in PD patients requires further review of the MPTP-monkey model, please refer studies. to Bezard [2011]). For many researchers, how- In summary, with the caveat of its acute ever, the mouse remains a popular choice owing toxic property as seen with other neurotoxic to a lack of resources and trained personnel PD models, MPTP will continue to play a major for the monkey model. Additionally, available role in PD research based on its ability to pro- genetic mouse models allow investigators to duce PD-like effects in humans and nonhuman assess the roles of certain genetic mutations in primates, its reproducible L-dopa-responsive response to MPTP neurotoxicity. Rats are less lesion on the nigrostriatal system, and its ease sensitive to MPTP toxicity than mice (Giovanni of administration with the typical intraperito- et al. 1994). neal (i.p.) injection.

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PARAQUAT neurons in the nigral and striatal regions, gluta- mate neurons in the hippocampus, and dopa- After the discovery of MPTP (Langston et al. minergic neurons in the ventral tegmental area 1983) and the subsequent characterization of are not affected (Thiruchelvam et al. 2000b; MPPþ as an active metabolite of MPTP (Nicklas McCormack et al. 2002). However, the damage et al. 1985), a search for environmental contam- induced by paraquat in dopaminergic cell inants with a similar molecular structure to bodies and terminals has not been consistently MPPþ was initiated. The widely use herbicide observed (Thiruchelvam et al. 2000b; Cicchetti paraquat (N,N’-dimethyl-4-4’-bipiridinium) et al. 2005). Furthermore, even in studies in was identified as such an agent (Fig. 1) (Snyder which a loss in nigral dopaminergic neurons is and D’Amato 1985). Since then, this divalent detected, paraquat does not have an effect on cation has been used to model PD in mice. striatal dopamine levels (Thiruchelvam et al. Despite a similar structure to MPPþ, para- 2000b; McCormack et al. 2002). This lack quat shows different transport properties and of dopamine reduction might be related to mechanism(s) of toxicity. First, despite both the compensatory up-regulation of tyrosine being cations, in contrast to MPPþ, paraquat hydroxylase activity in the striatum after para- appears to have the ability to penetrate the quat injection (Thiruchelvam et al. 2000b; blood–brain barrier. This property is proposed McCormack et al. 2002; Ossowska et al. 2005). to be mediated by the neutral amino acid trans- When combined with manganese ethylenebis- porter (Shimizu et al. 2001; McCormack and Di dithiocarbamate (Maneb), a more significant Monte 2003). However, the extent to which loss in dopaminergic neurons and a trend paraquat accumulates in the brain is age reduction (20%, not statistically significant) dependent, with the highest levels detected in of striatal dopamine are produced (Thiru- 2-wk-old or .12-mo-old rats—suggesting the chelvam et al. 2000a,b). Even with this revised blood–brain barrier does play a role (Corasaniti paraquat/Maneb protocol, however, it remains et al. 1991), as young and old animals have unclear how the motor deficits reported in higher blood–brain-barrier permeability, in this model can be attributed to such a modest general. Second, MPPþ is an excellent substrate loss of striatal dopamine. A similar argument for the dopamine transporter, but paraquat is can be made in a rat model in which paraquat not (Richardson et al. 2005). Hence, it is still is injected weekly for 24 wks but only 30% uncertain how paraquat enters dopaminergic reduction in dopamine is detected (Ossowska neurons to induce neurotoxicity. Third, toxicity et al. 2005). Given that paraquat is known to induced by paraquat is primarily mediated by cause pulmonary toxicity (Clark et al. 1966; www.perspectivesinmedicine.org redox cycling with cellular diaphorases such Smith and Heath 1976; Cicchetti et al. 2005; as NADPH oxidase and nitric oxide synthase Saint-Pierre et al. 2006), which could affect (Day et al. 1999), leading to the generation motor performance, it may be necessary to of superoxide. Fourth, inside mitochondria, assess whether L-dopa can alleviate motor defi- paraquat is not a complex I inhibitor per se cits induced by paraquat. As discussed, this (Richardson et al. 2005), although this is the strategy has been used in the MPTP and presumed site where it is reduced to form super- 6-OHDA animal models to confirm that the oxide (Cocheme and Murphy 2008). observed motor deficit is linked to the damage When injected into mice, paraquat was of the nigrostriatal pathway. reported to induce motor deficits and loss of The strength of the paraquat or paraquat/ nigral dopaminergic neurons in a dose- (Brooks Maneb model is its potential relevance to envi- et al. 1999; McCormack et al. 2002) and age- ronmental toxicants as a risk factor for develop- (McCormack et al. 2002; Thiruchelvam et al. ing PD. Both of these chemicals have been used 2003) dependent manner. The effects of para- in overlapping geographical areas. Epidemio- quat on nigral dopaminergic neurons appear logical studies have suggested an increased risk to be specific as g-amino butyric acid (GABA) for PD after paraquat exposure (Hertzman

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Toxic Animal Models of Parkinson’s Disease

et al. 1990; Liou et al. 1997; Kamel et al. 2007; inherently more vulnerable. Second, the rela- Ritz et al. 2009; Tanner et al. 2011). Addition- tionship between complex I inhibition and the ally, paraquat treatment increases a-synuclein pathogenic mechanism of cell death in PD is aggregates reminiscent of Lewy bodies in PD reinforced. Third, it suggests that a chronic (Manning-Bog et al. 2002; Fernagut et al. low-dose neurotoxic regimen may be required 2007; Mak et al. 2010). Paraquat is also reported to produce Lewy bodies. This rationale was sub- in one study to reduce noradrenergic neurons in sequently applied in the chronic model of the locus coeruleus (Fernagut et al. 2007). How- MPTP, in which continuous delivery of MPTP ever, the lack of significant effect of paraquat on for 30 d using osmotic minipumps produces striatal dopamine depletion in the commonly a-synuclein aggregates (Fornai et al. 2005), used regimens may limit the use of this model although the reproducibility of this observation to assess neuroprotective therapies for PD. has not been reported by other laboratories. Fourth, the rotenone model reinforces the theory that environmental agents may play a ROTENONE role in the pathogenesis of sporadic PD. Rotenone is a pesticide that is widely used to kill Despite its positive features, the rotenone insects and nuisance fish in lakes. This chemical infusion model has not been widely adopted. is found naturally in plants that belong to the The primary concern is related to the high var- family of Leguminosa. Because this is a natural iability in animal sensitivity and the inability of product, it has also been used in organic farm- other investigators to consistently reproduce the ing. Due to its high lipophilicity, rotenone can parkinsonian neuropathology and phenotype readily cross the blood–brain barrier and enter of this model (Hoglinger et al. 2003; Fleming all cells without being dependent on a specific et al. 2004b; Lapointe et al. 2004; Zhu et al. transporter. The mechanism of toxicity of rote- 2004). To address these concerns, a revised rote- none is primarily mediated by its potent com- none model has been developed (Cannon et al. plex I inhibition. 2009). With this protocol, daily i.p. injection Based on the observations that MPPþ is a using medium chain fatty acid as a specialized complex I inhibitor and that reduced function vehicle, rotenone is reported to produce a more of this mitochondrial subunit has been reported consistent lesion in the nigrostriatal pathway, in PD patients (Parker et al. 1989; Schapira et al. accompanied by the presence of a-synuclein 1989), there has been an interest in using rote- and ubiquitin-positive inclusions and motor none to model PD. In initial studies in which deficits that are reversed by apomorphine high doses of rotenone were used, widespread (Cannon et al. 2009). In a separate study, these www.perspectivesinmedicine.org lesions beyond the nigrostriatal system were investigators also report loss of neurons and the reported (Heikkila et al. 1985; Ferrante et al. appearance of a-synuclein aggregation in the 1997; Rojas et al. 2009). The rotenone model myenteric plexus, as well as a decrease in gastro- thus received little attention until Greenamyre intestinal motility (Drolet et al. 2009). Although and colleagues developed a chronic low-dose promising, as with other newly developed mod- regimen (Betarbet et al. 2000). When infused els, the results of this modified rotenone model continuously via a jugular vein cannula at- needs to be replicated by other laboratories. tached to a subcutaneous osmotic minipump, rotenone produces selective nigrostriatal neuro- OTHER NIGROSTRIATAL NEUROTOXIC degeneration and a-synuclein-positive cyto- MODELS plasmic inclusions. This study generated significant interest in the field because, first, The following models have also been used to despite widespread complex I inhibition in the deplete striatal dopamine and induce neurotoxi- brain, selective neurodegeneration occurs in city in the nigrostriatal pathway. However, unless the nigrostriatal pathway, strengthening the the nature of study requires their specific effects, notion that nigral dopaminergic neurons are these models are not commonly used currently.

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RESERPINE (PCA), methamphetamine, 3,4-methylenedi- oxymethamphetamine (MDMA), and fenflu- Reserpine represents the earliest recognized ramine are also highly neurotoxic. In the context pharmacological PD model. In their seminal of PD models, methamphetamine is more com- work, Carlsson et al. (1957, 1959) showed that monly used than other amphetamine deriva- when rodents were treated with reserpine to tives. For brevity, only methamphetamine will deplete dopamine and other catecholamines be discussed; however, there are many overlap- in the brain, they developed akinesia, which ping effects among amphetamine derivatives could be successfully reversed by L-dopa. These (Przedborski and Tieu 2006). early observations have led to our current The neurotoxicity of methamphetamine appreciation for the role of striatal dopamine has been extensively studied in nonhuman in motor function, to the discovery and current primates, rats, and mice (Krasnova and Cadet use of L-dopa as the cornerstone treatment of 2009). Methamphetamine is toxic to both PD, as well as to the revolutionized strategy of serotoninergic and dopaminergic terminals. generating PD animal models. Regarding the latter effect, methamphetamine The depletion of monoamines and motor primarily destroys dopaminergic nerve termi- deficits induced by reserpine have been repli- nals in the striatum, nucleus accumbens, and cated in rabbits, guinea pigs, cats, and monkeys frontal cortex, but not their cell bodies in the (Bezard et al. 1998). Reserpine is believed to substantia nigra and ventral tegmental area mediate its effects by temporarily interfering (Axt et al. 1994; Krasnova and Cadet 2009), with the storage of catecholamines in synaptic unless high-dose regimens are used (Trulson vesicles via magnesium- and ATP-dependent et al. 1985; Sonsalla et al. 1996). This feature mechanisms (Bezard et al. 1998). Because the of selective cell-part toxicity is strikingly dif- effects are transient, nonspecific to dopamine, ferent from those seen with paraquat, which and not neurotoxic to the nigrostriatal pathway, primarily affects the cell bodies, and with those reserpine is no longer a popular choice for a seen with MPTP and 6-OHDA, which are toxic PD model. to both cell bodies and terminals. This neuro- toxic property of methamphetamine reinforces a-METHYL-PARA-TYROSINE the notion that degeneration of the terminals and cell bodies can be governed by different As an inhibitor of tyrosine hydroxylase, an processes. enzyme involved in dopamine synthesis, Methamphetamine can enter dopaminergic a-methyl-p-tyrosine is another pharmacologi- neurons through both active uptake by the dop- www.perspectivesinmedicine.org cal agent used to deplete dopamine (Spectors amine transporter (Zaczek et al. 1991a,b; Fuma- et al. 1965; Corrodi and Hanson 1966). Similar galli et al. 1998) and simple diffusion across to reserpine, the effect of a-methyl-p-tyrosine the plasma membrane. Inside dopaminergic on dopamine depletion is transient and without neurons, methamphetamine induces dopamine neurodegeneration in the nigrostriatal struc- release from the synaptic vesicles into the cyto- ture. Thus this molecule shares the same limi- sol (Sulzer et al. 1995) where it is reversely tations as the reserpine model. Occasionally, transported by the dopamine transporter into a-methyl-p-tyrosine is used in combination the synaptic cleft (Sulzer et al. 1993). Through with reserpine to potentiate the effect of dopa- these actions, in combination with blocking mine depletion (Carlsson and Carlsson 1989). dopamine degradation by monoamine oxidase (Scorza et al. 1997), methamphetamine induces dramatic release of dopamine into extracellular AMPHETAMINES space. In vivo microdialysis experiments dem- Amphetamines are widely abused psychostimu- onstrate that this release peaks within 1 h after lants. Besides their addictive properties, amphet- systemic injection (Clausing and Bowyer 1999; amine derivatives such as p-chloroamphetamine Kita et al. 2000; Cui et al. 2009), leading to acute

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Toxic Animal Models of Parkinson’s Disease

behavioral changes such as increased locomotor 1985), in foodstuffs (Niwa et al. 1989), and activity (Ricaurte et al. 1994; Segal and Kuczen- in mammalian organs, including the brain ski 1994). (Nagatsu 1997; DeCuypere et al. 2008). In the The mechanism by which methamphet- brain, these molecules can be formed endoge- amine induces in vivo neurotoxicity remains nously either enzymatically or nonenzymati- controversial. There are two major schools of cally from dopamine and its metabolites thought on this topic. One proposed mecha- (Nagatsu 1997; Naoi et al. 2002). Hence, these nism is related to the dramatic increase in do- isoquinoline derivatives have been found in pamine levels in the cytosol, resulting in oxidative brain regions that are rich in dopamine (Mus- stress (Cubells et al. 1994; Fumagalli et al. 1999; shoff et al. 2005). Because some isoquinoline Guillot et al. 2008). Supporting this view are derivatives are permeable to the blood–brain studies that show depleting intracellular dopa- barrier (Niwa et al. 1988; Kikuchi et al. 1991; mine with reserpine and a-methyl-p-tyrosine Thumen et al. 2002), exogenous sources may reduces (Gibb and Kogan 1979; Schmidt et al. also account for accumulation of these mole- 1985), and those that replenish dopamine, cules in the brain. The fact that these naturally such as L-dopa, reproduce (Gibb and Kogan occurring compounds bear structural similarity 1979; Thomas et al. 2008) methamphetamine to MPTP/MPPþ makes them attractive candi- toxicity. On the other hand, hyperthermia dates for being involved in the pathogenesis of induced by methamphetamine has been sug- PD. Indeed, the mechanisms of toxicity induced gested to be the culprit of its neurotoxicity. by isoquinolines have been shown to be very There is a significant body of evidence demon- similar to those of MPPþ, including their af- strating that hyperthermia correlates with neu- finity for the dopamine transporter and com- rotoxicity (Ali et al. 1994; Albers and Sonsalla plex I inhibition (Nagatsu 1997). 1995; Yuan et al. 2010), and that neuroprotec- Despite these common features, however, tive effects of treatments such as reserpine and conflicting neurotoxic properties have been a-methyl-p-tyrosine are related to their hypo- reported between isoquinoline derivatives and thermic effects (Albers and Sonsalla 1995; between animal species when the same mol- Yuan et al. 2001, 2002). In a recent study in ecule is used. For example, subcutaneous injec- which mice are genetically modified to be defi- tion of 1,2,3,4-tetrahydroisoquinoline (Nagatsu cient in brain dopamine synthesis either glob- and Yoshida 1988; Yoshida et al. 1990) induces ally or unilaterally without altering the core parkinsonian phenotypes and a reduction temperature, methamphetamine neurotoxicity in dopamine level in monkeys, but not in is comparable with control counterparts that mice—even at a high cumulative dose of 2.1g/ www.perspectivesinmedicine.org have normal dopamine levels, suggesting dopa- kg (Perry et al. 1988). Additionally, the effects mine is not necessary for methamphetamine of 1,2,3,4-tetrahydroisoquinoline in monkeys neurotoxicity (Yuan et al. 2010). In light of are not reproduced by other isoquinoline these studies, core temperature should be as- derivatives that have similar properties to sessed when neurotoxicity or neuroprotection 1,2,3,4-tetrahydroisoquinoline (Yoshida et al. is conducted in the methamphetamine animal 1993). Furthermore, some tetrahydroisoquino- models. The lack of PD-like brain pathology line derivatives such as 1-methyl-1,2,3,4-tetra- and the potential confounding factor of body hydroisoquinoline even have neuroprotective temperature make methamphetamine a less effects (Antkiewicz-Michaluk et al. 2004; Abe than ideal model of PD. et al. 2005; Okuda et al. 2006). Because one isoquinoline derivative can be transformed to another one, for example, 1,2,3,4-tetrahydroiso- ISOQUINOLINE DERIVATIVES quinoline (neurotoxic) can be converted by Isoquinoline and its derivatives can be found in N-methyltransferase in vivo to 1-methyl-1,2,3,4- the environment (Rommelspacher and Susilo tetrahydroisoquinoline (neuroprotective), which 1985), in plants (Rommelspacher and Susilo is then further oxidized by monoamine oxidase

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to N-methyl-isoquinolinium ion (neurotoxic) et al. 2005) along with a stable reduction in (Nagatsu 1997), the overall neurotoxic proper- striatal dopamine to 60% of the contralateral ties of a particular isoquinoline isoform can side (Herrera et al. 2000). To induce a more be difficult to interpret or predict. Adding chronic and progressive cell loss, LPS is infused another layer of complexity to the isoquino- into the rat supranigra for 2 wk using osmotic line-induced toxicity is the claim that these minipumps (Gao et al. 2002). Microglia activa- molecules down-regulate the expression of tion can be detected within 3 d and reaches a tyrosine hydroxylase rather than inducing the sustained plateau from 2 to 8 wk after infusion loss of dopaminergic structure (Lorenc-Koci of LPS. Significant loss of dopamine neurons et al. 2004), thus questioning the validity of (39%) was detectable at 6 wk and progressed previous studies that used reduced immuno- to 69% loss at 10 wk after the initiation of LPS reactivity of this enzyme as a marker for dopa- infusion. To avoid the technical challenges of minergic neurodegeneration. Together, these stereotactic surgery, a single systemic i.p. injec- studies raise the question of the reliability of tion of LPS has been described in mice (Qin using isoquinolines to model PD. Although et al. 2007). Although microglial activation there was an interest in the isoquinoline models occurs as early as 3 h after this peripheral injec- in the 1980s–1990s, a search of the literature tion, it takes 7 mo to observe a modest (23%) reveals that the use of this model has declined and 10 mo to have significant (47%) nigral over the last decade. dopaminergic cell loss. Overall, the LPS model has not been widely used. Several reasons may contribute to this lack LIPOPOLYSACCHARIDE of popularity. First, stereotactic injection is Neuroinflammation has been proposed to be a technical deterrent for many laboratories. involved in PD (Przedborski 2007; Hirsch and Second, it takes too long to detect nigrostriatal Hunot 2009). Although all the neurotoxic damage with i.p. injection. Although this pro- molecules described above can elicit an inflam- gressive cell loss can be an attractive feature, it matory response, it is difficult to delineate is not feasible for most neuroprotective studies. whether neuroinflammation is the cause or Third, protein aggregation and extranigral consequence of injured dopaminergic neurons. pathology have not been reported. Fourth, The consensus appears to be that neuroinflam- despite it being a useful tool to establish that mation is not the primary cause of cell death in neuroinflammation can cause nigral cell loss, these models, but rather, it may be a secondary its relevance to PD remains uncertain as it is event that perpetuates the vicious cycle of controversial that neuroinflammation is the www.perspectivesinmedicine.org neurotoxicity. Tostudy the role of neuroinflam- primary cause of cell death in this disorder. mation in causing cell death, the lipopoly- saccharide (LPS) model is probably more appropriate. BASIC ASSESSMENTS OF THE NIGROSTRIATAL DOPAMINERGIC LPS is a gram-negative bacterial endotoxin STRUCTURE AND FUNCTION that activates microglia through the toll-like receptor-4 receptor, leading to the production Depending on the nature of the study and the of inflammatory cytokines and chemokines. selected PD model, the methods required for LPS has been administered under various the analysis of neuropathology and function routes to induce nigrostriatal damage. It can may vary. However, whether planning to study be delivered stereotactically into the substantia neurodegeneration or neuroprotection using nigra, medial forebrain bundle, or striatum to neurotoxic models, it is common to assess the produce acute damage (Herrera et al. 2000). integrity and function of the nigrostriatal path- When injected unilaterally to the rat nigra, way. Over the years, there have been some well- microglia activation and stable loss of nigral developed and accepted techniques that are dopamine neurons occurs within 24 h (Iravani commonly used for these purposes. This

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Toxic Animal Models of Parkinson’s Disease

section will highlight such basic methods dopaminergic neurons in an adult mouse nigra and equipment with an emphasis on murine is commonly reported to be 8000–14,000. models. Detailed step-by-step procedures are The number may vary slightly depending on beyond the scope of this article and readers the strain (Zaborszky and Vadasz 2001). The are encouraged to consult the recommended distribution of dopaminergic neurons in the references. nigra is not homogenous. As illustrated in Figure 2, when the nigra is sectioned coronally, there is a significant difference in the density of Quantification of Dopaminergic Neurons in dopaminergic neurons between the caudal and the Substantia Nigra Par Compacta rostral regions. It is necessary, therefore, to sam- In the mesencephalon, there are three groups of ple the population of dopaminergic neurons at dopaminergic neurons classified historically as different levels throughout the entire nigra. The A8, A9, and A10 (Dahlstrom and Fuxe 1964; past practice of comparing the number of do- Hokfelt et al. 1984; Smith and Kieval 2000; paminergic neurons from only one nigral sec- Zaborszky and Vadasz 2001). The A8 group tion between animals should be avoided. One resides in the retrorubral area, whereas the way to sample the entire nigra efficiently is to A9 and A10 groups belong to the substantia count dopaminergic neurons systematically at nigra and ventral tegmental area, respectively a regular section interval, as illustrated in Fig- (Fig. 2). The estimated average number of ure 2. Tocount these neurons, the gold standard

ABCD

EFGH

SNpc

I www.perspectivesinmedicine.org

Striatum

JKLMNOP

Figure 2. Topographical distribution of dopaminergic neurons in the nigral and striatal regions. The cell bodies of dopaminergic neurons that reside in the substantia nigra pars compacta (SNpc) project their terminals to the dorsal striatum where dopamine is released (I). To illustrate the heterogeneous distribution of dopaminergic neurons in the entire SNpc (outlined) spanning from the caudal (A) to rostral regions (H), coronal sections (30 mm) are presented at fourth section intervals. Similarly, the distribution of dopaminergic terminals is not homogenous in the striatum (J–P). The density is relatively low in the caudal (J) as compared to the rostral region (P). Images are captured at eight section intervals of the striatum. Dopaminergic neurons and terminals are immunostained with an antibody against tyrosine hydroxylase and visualized using 3,30-diaminobenzidine.

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K. Tieu

is to use an unbiased stereological cell counting Quantification of Dopamine Content with optical dissector system (West et al. 1991, in the Striatum 1993, 1996; Tieu et al. 2003). Major compo- In addition to structural analysis (cell body nents required for this method are computer- and terminal), it is also critical to assess the ized stereology software and a microscope function of the nigrostriatal pathway. Measur- with a motorized stage. ing the amount of dopamine produced in the striatum and assessing motor movement (see Quantification of Dopaminergic Terminals below) are some such functional studies. The in the Striatum best way to measure dopamine is to use reverse- phase high-performance liquid chromatogra- The projection of terminals to the striatum phy (HPLC) coupled with an electrochemical from the nigral dopaminergic neurons has detector. With this method, samples prepared been well established (Joel and Weiner 2000). from striatal tissues are injected into HPLC. Fig- Although the total density of striatal dopami- ure 3 provides an example of what to expect nergic terminals frequently correlates with the when a striatal sample is analyzed using number of their cell bodies in the nigra, it is HPLC. To maximize efficiency and consistency, not uncommon to observe differential damage as well as to minimize the number of required or protection between these two structures. animals, the brain can be processed in such a For example, as discussed, in the paraquat way that data for striatal dopamine content, model, the dopaminergic cell bodies are more striatal terminal density, and nigral cell counts vulnerable than their terminals. On the other can be obtained within the same animal. For hand, striatal terminals are more sensitive to this approach, freshly removed brains are coro- methamphetamine, MPTP, or 6-OHDA toxic- nally sectioned at 1–2 mm caudal to the optic ity. Quantifying striatal dopaminergic terminals chiasm. The caudal half containing the substan- is therefore also informative. tia nigra is used for stereological cell counts, Similar to the uneven distribution of do- whereas the rostral half is divided midsagittally paminergic neurons throughout the nigra, the with one hemisphere used for striatal density density of dopaminergic terminals is also not and the other hemisphere used for HPLC mea- homogenous in the striatum. As illustrated in surement of dopamine. Figure 2 and previous studies (Tassin et al. 1976; Scally et al. 1978; Widmann and Sperk Detection of Lewy Body-like Aggregation 1986), dopaminergic innervation increases from the caudal to rostral part. Accordingly, As discussed, Lewy bodies are a neuropatholog- www.perspectivesinmedicine.org when quantifying dopaminergic terminals, ical hallmark in PD. Although the neurotoxic representative regions of the striatum should property of this feature is not fully established, be assessed (Fig. 2). The density of striatal dopa- it does suggest the presence of misfolded pro- minergic terminals can be digitized and then tein and inefficiency in protein processing or quantified based on optical density or fiber degradation. Whether studying neurodegenera- density of tyrosine hydroxylase immunoreactiv- tive or neuroprotective processes in PD models, ity (Tieu et al. 2003; Fernagut et al. 2007). As it may be desirable to determine the presence or an alternative to immunohistochemistry, fresh absence of protein aggregations. Several meth- striatal tissues can be isolated for immunoblot- ods have been used. For example, thioflavin S ting using tyrosine hydroxylase or dopamine can be used to identify the presence of fibrillary transporter as markers to assess for the levels protein (Conway et al. 2000; Manning-Bog et al. of striatal dopaminergic terminals. Some 2002). However, it is more common to use an potential disadvantages of this later approach antibody to assess the pattern and level of in- are the limited quantity of striatal tissue and tracellular a-synuclein (Betarbet et al. 2000; the lack of resolution of the size and pattern of Vila et al. 2000; Fornai et al. 2005). Because the lesion. misfolded or fibrillary a-synuclein is relatively

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Toxic Animal Models of Parkinson’s Disease

16 DA

14

4 DHBA

2 DOPAC 5-HIAA HVA 5-HT 3-MT Response signal (nA) 0 6420 1412108 Retention time (min)

Figure 3. High-performance liquid chromatography (HPLC) chromatogram of catecholamines in striatal tissue. The striatum was freshly dissected and processed for HPLC measurement as described (Cui et al. 2009). Samples were eluted on a narrow-bore (inner diameter: 2 mm) reverse-phase C18 column (MD-150, ESA Inc) using a 12-channel CoulArray 5600A (ESA). A highly sensitive amperometric microbore cell (model 5041, ESA Inc.) was used to analyze the content of dopamine with a potential set at þ220 mV.The striatum is a major “input” structure of the basal ganglia. In addition to receiving extensive dopaminergic terminals from the substantia nigra, the striatum also contains serotonergic terminals from the dorsal raphe nuclei. Dopamine and serotonin, as well as their metabolites, therefore, are often detectable in the same striatal samples. Abbreviations: DA (do- pamine), DOPAC (3,4-dihydroxyphenylacetic acid, a metabolite of DA), HVA(homovanillic acid, a metabolite of DA), 3-MT (3-methoxytyramine, a metabolite of DA), 5-HT (serotonin), 5-HIAA (5-hydroxyindoleacetic acid, a metabolite of 5-HT), DHBA (3,4-dihydroxybenzylamine, internal control for the measurement of catecholamines).

resistant to proteolysis (Conway et al. 2000; more in-depth discussion of these methods, Giasson et al. 2001; Miake et al. 2002), one sim- including their strengths and weaknesses, read- ple way to detect the presence of a-synuclein ers are encouraged to consult other reviews aggregates is to treat brain sections with pro- (Sedelis et al. 2001; Brooks and Dunnett 2009; teinase K, followed by immunohistochemistry Taylor et al. 2010). Briefly, one simple and basic using an antibody against a-synuclein (Ferna- way to assess locomotor activity is to use auto- gut et al. 2007; Beach et al. 2008). mated open-field chambers. Typically, mice are placed in transparent chambers that are equipped with horizontal and vertical infrared Assessment of Motor Function photobeams. The movement of each animal is www.perspectivesinmedicine.org The functional relationship between the deple- tracked and quantified based on photobeam tion of striatal dopamine and the motor deficits breaks that are registered in a computer and in PD was discovered more than 50 years ago processed for parameters such as jumps, trav- (Carlsson et al. 1957; Carlsson 1959). Since eled distance, and vertical, ambulatory, or ster- this discovery, subsequent PD animal models eotypical movements in different bin sizes over have been generated with the objectives of different periods of time. Most PD models inducing a loss in nigrostriatal dopaminergic have reduced locomotor activity (Taylor et al. structure and dopamine content to accurately 2010). The rotation test has been used for reproduce PD pathology and L-dopa responsive decades to assess the motor asymmetry in the motor deficits as seen in PD. Many behavioral unilateral 6-OHDA lesion rat, and more tests are therefore designed to assess motor phe- recently in mice (Nishimura et al. 2003; Iancu notypes linked to the nigrostriatal function. et al. 2005). As discussed previously, subsequent Behavioral tests routinely used to quantify to the 6-OHDA injection, the magnitude of the locomotor activities in animal models of PD nigrostriatal lesion correlates with the circling include locomotor activity, rotation, rotarod, motor behavior (Ungerstedt 1968; Ungerstedt stride length of the paws, and pole test. For a and Arbuthnott 1970; Hefti et al. 1980;

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Przedborski et al. 1995). The direction of rota- for PD also greatly benefited from these models. tion is ipsilateral to the lesion if dopamine However, despite these accomplishments, current released from the intact terminals is induced models still have significant shortcomings. Some by compounds such as amphetamine; how- such limitations are highlighted in the models ever, an agonist such as apomorphine stimu- discussed in this article. lates the sensitized dopaminergic receptors on Confronted with the pros and cons of the lesioned side and will lead to contralateral numerous PD models, a new investigator may rotation. This rotation can be quantified using find it challenging to make a selection. Because a rotameter test bowl (Brooks and Dunnett there is no perfect model, the decision should be 2009). To measure abnormal movement that carefully balanced by considerations such as the is analogous to the shuffling gait in PD patients, following: (1) What is the nature and the goal of the “footprint” test can be used to measure the the study? If the loss of the nigrostriatal pathway stride length of the paws. With this test, the fore is required to address the question, then a neu- and hind limbs of the animal are inked with dif- rotoxic model is necessary. However, if a tar- ferent colors and the stride length is quantified get known to cause PD is the primary interest, after awalk down the narrow corridor (Fernagut then perhaps a genetic model is relevant with et al. 2002; Brooks and Dunnett 2009). Tomeas- the caveats that these animals do not display ure body coordination and balance, either the appreciable neurodegeneration, and require rotarod or pole test can be used. In the rotarod time to develop motor deficits. (2) How tech- test (Dunham and Miya 1957; Rozas et al. nically involved is the model? i.p. injection cer- 1998; Brooks and Dunnett 2009), the most tainly is more convenient and consistent than commonly used behavioral test, a mouse is stereotactic delivery into the brain or the placed on a rod that can rotate at a fixed or an implantation of osmotic minipumps. (3) How accelerating speed. The length of time an animal reproducible is the model? Once an investiga- can maintain balance and stay on the rotating tor has navigated through such questions and rod is recorded. In the pole test (Ogawa et al. arrived at a decision, the technical aspects will 1985; Fleming et al. 2004a), the animal is placed follow that particular model. By providing an facing upward on top of a vertical wooden or overview of the methods commonly used to wire-mesh pole. The time that it takes the ani- assess the nigrostriatal structure and function, mal to orient downward and the total time this article may also provide a foundation to that it takes to descend down to the base of the guide a new investigator through the next step pole are recorded. of entering the PD research arena. www.perspectivesinmedicine.org CONCLUDING REMARKS ACKNOWLEDGMENTS Since the initial discovery by Carlsson and This work was supported in part by the U.S. colleagues in the 1950s that L-dopa restored mo- National Institutes of Health Grants No. tor deficits induced by reserpine (Carlsson et al. ES014899 and No. ES17470. I would like to 1957; Carlsson 1959), many animal models of thank Phillip M. Rappold and Adrianne Chesser PD have been developed with the primary objec- for proofreading this manuscript. I am also tive of improving PD-like pathology and pheno- thankful for the illustrations prepared by Meg- types in existing ones for bettering the utility of han Shoemaker. these models for developing treatments. Together, these models have contributed to the develop- REFERENCES ment of some current PD treatments such as Reference is also in this collection. L-dopa, dopamine agonists, and monoamine oxidase-B inhibitors. Our current understand- Abe K, Saitoh T, Horiguchi Y, Utsunomiya I, Taguchi K. 2005. Synthesis and neurotoxicity of tetrahydroisoquino- ing of the basal ganglia circuitry, pathogenic line derivatives for studying Parkinson’s disease. Biol mechanisms, and potential therapeutic targets Pharm Bull 28: 1355–1362.

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A Guide to Neurotoxic Animal Models of Parkinson's Disease

Kim Tieu

Cold Spring Harb Perspect Med 2011; doi: 10.1101/cshperspect.a009316

Subject Collection Parkinson's Disease

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