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Review
. 2011 Sep;1(1):a009316.
doi: 10.1101/cshperspect.a009316.

A guide to neurotoxic animal models of Parkinson's disease

Kim Tieu  1
Affiliations
Review

A guide to neurotoxic animal models of Parkinson's disease

Kim Tieu. Cold Spring Harb Perspect Med. 2011 Sep.

Abstract

Parkinson's disease (PD) is a neurological movement disorder primarily resulting from damage to the nigrostriatal dopaminergic pathway. To elucidate the pathogenesis, mechanisms 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.

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Figures

Figure 1.
Figure 1.
Structures of neurotoxic molecules used to induce nigrostriatal damage in some common animal models of PD.
Figure 2.
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 µm) 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 3,3′-diaminobenzidine.
Figure 3.
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 +220 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 (dopamine), 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).
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