A Guide to Neurotoxic Animal Models of Parkinson's Disease

Tieu, Kim

doi:10.1101/cshperspect.a009316

Cited by 400 publications

(330 citation statements)

References 162 publications

Supporting

Mentioning

306

Contrasting

Unclassified

Order By: Relevance

“…It has been noted that different toxicants seem to affect the nigrostriatal structure differentially (9). In the MPTP model, for example, both striatal terminals and nigral cell bodies are affected.…”

Section: Discussionmentioning

confidence: 99%

“…1C). This lack of DA reduction in wild-type mice despite a loss of DA neurons is proposed to be related to the compensatory up-regulation of TH activity in the striatum after PQ 2+ injection (9). On the basis of our previously proposed function of Oct3 in mediating the neurotoxicity of methamphetamine (12), it is possible that the striatal neurotoxicity observed in the Oct3 −/− mice was due to a reduced PQ buffering capacity in non-DA cells, and, hence, more PQ was available for DAT-mediated transport into DA terminals.…”

Section: Pq 2+ Induces Striatal Neurotoxicity and Da Overflow In Micementioning

confidence: 99%

“…When PQ 2+ is injected into mice, it induces a loss of nigral DA neurons, but the striatum is spared (7,8), most likely due to compensatory striatal sprouting in the remaining neurons (9). In addition, PQ 2+ induces α-synuclein up-regulation and aggregation (10), a neuropathological feature detected in PD patients.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3

Rappold

Cui

Chesser

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

171

156

View full text Add to dashboard Cite

The herbicide paraquat (PQ) has increasingly been reported in epidemiological studies to enhance the risk of developing Parkinson's disease (PD). Furthermore, case-control studies report that individuals with genetic variants in the dopamine transporter (DAT, SLC6A) have a higher PD risk when exposed to PQ. However, it remains a topic of debate whether PQ can enter dopamine (DA) neurons through DAT. We report here a mechanism by which PQ is transported by DAT: In its native divalent cation state, PQ 2+ is not a substrate for DAT; however, when converted to the monovalent cation PQ + by either a reducing agent or NADPH oxidase on microglia, it becomes a substrate for DAT and is accumulated in DA neurons, where it induces oxidative stress and cytotoxicity. Impaired DAT function in cultured cells and mutant mice significantly attenuated neurotoxicity induced by PQ + . In addition to DAT, PQ + is also a substrate for the organic cation transporter 3 (Oct3, Slc22a3), which is abundantly expressed in non-DA cells in the nigrostriatal regions. In mice with Oct3 deficiency, enhanced striatal damage was detected after PQ treatment. This increased sensitivity likely results from reduced buffering capacity by non-DA cells, leading to more PQ + being available for uptake by DA neurons. This study provides a mechanism by which DAT and Oct3 modulate nigrostriatal damage induced by PQ 2+ /PQ + redox cycling.neurodegeneration | extraneuronal monoamine transporter | astrocytes | in vivo microdialysis P arkinson's disease (PD) is characterized primarily by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (1). Although in past decades discoveries of genetic mutations linked to PD have significantly impacted our current understanding of the pathogenesis of this devastating disorder, it is likely that the environment plays a critical role in the etiology of sporadic PD. Human epidemiological studies indicate that exposure to herbicides, pesticides, and heavy metals increase the risk of PD. One such environmental toxicant is paraquat (PQ 2+ , N,N′-dimethyl-4-4′-bipiridinium) (2, 3). This molecule exists natively as a divalent cation, but can undergo redox cycling with cellular diaphorases such as NADPH oxidase and nitric oxide synthase (4) (NOS) to yield the monovalent cation PQ + . From this redox cycle, superoxide is generated, leading to oxidative stress-related cytotoxicity. (For clarity and brevity, the abbreviations PQ 2+ and PQ + will be used to signify the respective cations, whereas PQ represents a general term when the valency is ambiguous.) On the basis of its structural similarity to 1-methyl-4-phenylpyridinium (MPP + ), an active metabolite of the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (5), PQ 2+ has been predicted to be a potential environmental parkinsonian toxicant (6), and with subsequent recent epidemiological studies (2, 3), there has been increasing interest in this herbicide as a potential pathogenic agent in PD.When PQ 2+ is injected into mice, it induces a ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Pq 2+ Induces Striatal Neurotoxicity and Da Overflow In Micementioning

confidence: 99%

See 1 more Smart Citation

Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3

Rappold

Cui

Chesser

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

171

156

View full text Add to dashboard Cite

show abstract

“…MPTP, a neurotoxin, is routinely used to induce PD-like neurodegeneration in experimental animal models [13] . In the brain, MPTP is converted to the active metabolite MPP + by monoamine oxidase B within non-dopaminergic cells, after which MPP + enters dopaminergic neurons via the dopamine transporter [14] .…”

Section: Discussionmentioning

confidence: 99%

6-Shogaol, an active compound of ginger, protects dopaminergic neurons in Parkinson's disease models via anti-neuroinflammation

Park

Kim

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: 6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown various neurobiological and anti-inflammatory effects. The aim of this study was to examine the effects of 6-shogaol on neuroinflammatory-induced damage of dopaminergic (DA) neurons in Parkinson's disease (PD) models. Methods: Cultured rat mesencephalic cells were treated with 6-shogaol (0.001 and 0.01 μmol/L) for 1 h, then with MPP + (10 µmol/L) for another 23 h. The levels of TNF-α and NO in medium were analyzed spectrophotometrically. C57/BL mice were administered 6-shogaol (10 mg·kg -1 ·d -1 , po) for 3 d, and then MPTP (30 mg/kg, ip) for 5 d. Seven days after the last MPTP injection, behavioral testings were performed. The levels of tyrosine hydroxylase (TH) and macrophage antigen (MAC)-1 were determined with immunohistochemistry. The expression of iNOS and COX-2 was measured using RT PCR. Results: In MPP + -treated rat mesencephalic cultures, 6-shogaol significantly increased the number of TH-IR neurons and suppressed TNF-α and NO levels. In C57/BL mice, treatment with 6-shogaol reversed MPTP-induced changes in motor coordination and bradykinesia. Furthermore, 6-shogaol reversed MPTP-induced reductions in TH-positive cell number in the substantia nigra pars compacta (SNpc) and TH-IR fiber intensity in stratum (ST). Moreover, 6-shogaol significantly inhibited the MPTP-induced microglial activation and increases in the levels of TNF-α, NO, iNOS, and COX-2 in both SNpc and ST. Conclusion: 6-Shogaol exerts neuroprotective effects on DA neurons in in vitro and in vivo PD models.

show abstract

“…Nevertheless, reserpine and haloperidol models had serious limitations in mimicking PD pathogenesis since drug-treated animals exhibited transient striatal dopamine depletion not associated with the typical neurodegeneration in substantia nigra. 54 However, the pivotal role played by these models in assessing the therapeutic efficacy of drugs still in current clinical use cannot be undermined.…”

Section: Animal Models Of Parkinson's Diseasementioning

confidence: 99%