Animal Models

Several animal models exist for the neurodegenerative process in PD; unfortunately each model can mimic only some of the features of the disease but not the slow process of neurodegeneration in PD subjects. Still these models have been of great help in understanding the biochemical and molecular cascades as well as testing new drug treatments. The most well-known animal models are the MPTP mouse model, the 6-OHDA rat model, the methamphetamine mouse model and the recent UCH-L1-deficient (gad) mouse model.

MPTP mouse model

MPTP is a known neurotoxicant inducer of parkinsonism in human patients (28) that has subsequently been modelled extensively in mice as well as non-human primates (29-31). MPTP crosses the blood-brain barrier and is subsequently converted to the neurotoxic metabolite MPP+, a substrate of the dopamine transporter. This neurotoxin causes specific neuronal cell death of the dopaminergic neurons residing in the substantia nigra (SN). Many have investigated this animal model with neurochemical, protein and genetic methods such as in situ hybridization (8,32-34). But the first to use the microarray technology in the MPTP mouse model were Grunblatt et al. (35). Here, we could show the involvement of OS in a concert of gene alterations that lead to cell death, while antioxidant therapy mostly reversed these alterations (35) (Table 1). In this model, we found genes involved in inflammation, transcription, cell cycle and growth as well as ubiquitin-proteasome processes. More importantly, these changes found in our further studies of time-course effects of acute injection of MPTP, altered gene expression in a specific manner where antioxidative, cell cycle and growth proteins are initially up-regulated while later, transcription factors, anti-inflammatory Parkin, a homolog to ubiquitin-protein ligase show activation (36) (Table 1). In further studies from other groups, chronic treatment of MPTP

Table 1. Gene expression profile studies in mice and rat models of PD in different time spans

Altered gene classes

Transcription factors and DNA synthesis and repair protein

Stress-response proteins

Cell cycle regulators

Time course (following drug administration)

Oncogene/tumour suppressors

2-4 h t c-FOS, t JUN-D, t c-JUN, t NF-KB/c-rel, t Crem (47,48)

t Oxidative-stress-induced protein A170, t OSP94 osmotic stress protein (47,48)

6-8 h t c-FOS, t c-JUN, t Crem (47,48), t NF-kB p65, ; NF-kB plG5, ; iNOS (36)

t Oxidative-stress-induced protein Al7G (36)

12-16 h t DNA ligase I, t DNA ligase III, t Atm, t Crem (47,48)

24 h-20 days

; iNOS, ; MAP-2, ; 14-3-3Y (36,37), ; Crem (48), I DNA-binding protein inhibitor, ^ 1-KBa, ; JAK1, ; JUN-D (42)

; G2/M-specific cyclin B2 (36), t CDK5, ;Gl/S-specific cyclin 2, ; Gl/S-specific cyclin 3 (42), ; CDK5r(p35), t CDK5r2(p39) (37)

; Prolactin, ; CCr6 (48), ; HSP9Gß (42), t chemokine receptor l-like 2 (38)

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