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Animal models are a very important approach to study the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. For instance, the application of the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is able to produce striking similarities to Parkinson's disease (PD) diagnosed in humans. MPTP is thought to selectively damage dopaminergic neurons predominantly those originating in the substantia nigra pars compacta (SNc) which leads to impaired dopaminergic neurotransmission accompanied by a loss of dopaminergic nerve terminals in the striatum. MPTP-induced neurochemical, behavioral, and histopathological alterations replicate very closely the clinical symptoms of PD patients, which will be discussed in this paper and render the MPTP model currently the most favored PD model to study therapeutic intervention strategies in an easy and reliable way in preclinical studies. We and many other research groups propose that the knowledge about the neurotoxic mechanisms of MPTP such as mitochondrial dysfunction with breakdown of energy metabolism and free radical production will help us to understand the underlying mechanisms of PD, which are not fully understood yet. In particular, the novel aspects of inflammatory processes and the involvement of reactive nitrogen species in addition to reactive oxygen species seem to be important milestones for a better understanding of the neurodegenerative effects of MPTP. In this review we focus on the MPTP mouse model which is easy practicable and widely used in neuroscience research and draw comparisons to the human pathology in PD.

The impact of pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a) in the pathology of Parkinson's disease (PD) and in MPTP neurotoxicity remains unclear. Here, male TNF-a (-/-) deficient mice and C57bL/6 mice were treated with MPTP (4 · 15mg/kg, 24 h intervals) and in one series, thalidomide was administered to inhibit TNF-a synthesis. Realtime RT-PCR revealed that the striatal mRNA levels of TNF-a, of the astrocytic marker glial fibrillary acidic protein (GFAP) and of the marker for activated microglia, macrophage antigen complex-1 (MAC-1), were significantly enhanced after MPTP administration. Thalidomide (50 mg/kg, p.o.) partly protected against the MPTP-induced dopamine (DA) depletion, and TNF-a (-/-) mice showed a significant attenuation of striatal DA and DA metabolite loss as well as striatal tyrosine hydroxylase (TH) fiber density, but no difference in nigral TH and DA transporter immunoreactivity. TNF-a deficient mice suffered a lower mortality (10%) compared to the high mortality (75%) seen in wild-type mice after acute MPTP treatment (4 · 20mg/kg, 2 h interval). HPLC measurement of MPP + levels revealed no differences in TNF-a (-/-), wild-type and thalidomide treated mice. This study demonstrates that TNF-a is involved in MPTP toxicity and that inhibition of TNF-a response may be a promising target for extending beyond symptomatic treatment and developing antiparkinsonian drugs for the treatment of the inflammatory processes in PD.

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