Most of the models of PD based on the use of neurotoxins try to mimic the effect of environmental toxins or reproduce the biochemical changes seen in the brain of patients post mortem. Yet, these two approaches are not mutually exclusive. In line with this, the vast majority of models are based on the finding that the activity of complex-1 in the mitochondria is decreased in PD. The toxin most commonly used to induce a complex-1 deficiency is MPTP, which induces a parkin-sonian syndrome in both humans and animals. Recently, we re-evaluated this model in C57Bl6 mice from both a behavioral and a biochemical standpoint (Rousselet et al., 2003). Using a chronic injection protocol and various cumulative doses of MPTP (60 mg, 420 mg, 540 mg), we showed that MPTP induced a dose-dependent loss of dopaminergic neurons in the substantia nigra. Furthermore, at the highest dosage, MPTP also partially destroyed dopaminergic neurons in the ventral tegmental area, thus reproducing the differential vulnerability of dopaminergic neurons in PD. Dopamine measurements made in the striatum and in the frontal cortex of these animals evidenced a major loss of dopamine in the striatum and a more moderate but significant loss in the prefrontal cortex of about 50%. In terms of behavior, the animals surprisingly displayed a hyperactivity that was dependent on the dose of MPTP injected (the higher the MPTP dose, the higher the locomotor activity). These results are at first sight puzzling since they suggest that the increased locomotor activity was associated with the dopaminergic denervation, in contrast to what is seen in patients with PD. Yet, reports in rat have indicated that dopamine deficiency in the frontal cortex is associated with increased locomotor activity. Furthermore, despite the chronic intoxication, no a-synuclein- or ubiquitin-positive inclusions were seen in these animals. However, Fornai and co-workers recently reported that a continuous infusion of mice with MPTP using an osmotic pump not only induced a degeneration of dopaminergic neurons but also the formation of a-synuclein- and ubiquitin-positive inclusions (Fornai et al., 2005). Given the behavioral limitations of MPTP-intoxicated mouse model, species more closely related to humans have been used to mimic the symptoms of PD. We recently developed a model of PD in green monkeys with progressive MPTP intoxication at very low doses. After a few MPTP injections, the monkeys were assessed as normal on a monkey parkin-sonian rating scale but already displayed subtle behavioral changes in a reach and grasp test (Pessiglione et al., 2003). Indeed, whereas control animals had a fully appropriate trajectory when asked to take some food with or without an obstacle in front of their hand, MPTP-intoxicated monkeys had aberrant initial trajectories which were corrected by visual guidance. This suggests that at the early phase of the disease, some compensatory mechanisms may occur. Then, with further MPTP injections, the animals became symptomatic recovered and after more injections became parkinsonian with a stable disease. Neurochemical analysis performed post-mortem evidenced a minimal degeneration of dopaminergic terminals in the dorsal striatum of the presymptomatic animals and an almost total wipe out of dopaminergic innervation in the severely parkinsonian animals. Furthermore, in another group of monkeys chronically intoxicated with MPTP we found that two years after the last MPTP intoxication a major glial reaction was still detectable in the substantia nigra (Barcia et al., 2004). This glial reaction consisted in an astrogliosis, considered as a scar after the degeneration of dopaminergic neurons. Furthermore, a microgliosis identified by HLA-DR immunoreactivity was also seen. Because this microgliosis is generally considered as an index of an ongoing pathological process these data suggest that neuronal alteration may progress in this model. Taken together, these data indicate that MPTP-intoxicated monkeys constitute an interesting model of PD reproducing neuronal loss, behavioral changes and perhaps the progression of the lesion. However, no Lewy body-like inclusions have yet been observed in this model. It would therefore be tempting to use in monkeys the intoxication protocol developed by Fornai and co-workers in rodents that induced the accumulation of proteins in Lewy body-like structures.
Other complex-1 inhibitors have been used to develop animal models of PD. In particular, Betarbet and co-workers used rotenone in rats to develop such a model (Betarbet et al., 2000). They showed a loss of dopaminergic neurons in the substantia nigra and the presence of a-synuclein-positive inclusions in the remaining neurons of the treated animals. More recently, using an identical protocol, we showed that non-dopaminergic neurons, mostly in the basal ganglia, were also affected by rotenone (Hoglinger et al.,
2003). The fact that rotenone is a well-known insecticide for plants led to the notion that environmental toxins may be involved in the development of the parkinsonian syndrome. In line with this, an atypical form of PD has been described in the French Caribbean. This syndrome may be due to the consumption of a beverage of an infusion from certain tropical plants or the use of such plants for medicinal purposes. These plants contain acetogenins among which annonacin is a very potent complex-1 inhibitor. On this basis, using a similar protocol to that used for rotenone, we tested the possible deleterious effect of annonacin in rats (Champy et al.,
2004). We observed a loss of dopaminergic and non-dopaminergic neurons and behavioral changes reminiscent of the symptoms seen in this atypical form of PD, resembling progressive supranuclear palsy. These data indicate that environmental toxins might be responsible for some atypical forms of PD and that these toxins might therefore be used to develop animal models of the disease.
Other compounds have been used to mimic environmental toxins or biochemical changes seen in the brain of patients with
PD. In particular, altered protein processing and protein accumulation have attracted considerable interest in recent years. For example, a proteasome dysfunction having been reported specifically in the substantia nigra of patients with Parkinson's disease, McNaught and co-workers induced an inhibition of the proteasome in rats and demonstrated a hypokinetic behavior in these animals associated with a loss of dopaminergic neurons (McNaught et al., 2004). This model may be of interest but has not yet been used to test neuroprotective strategies.
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