Historically, 6-OHDA was the first toxin that quite selectively destroys catecholaminergic neurons due to uptake by the respective transporter. However, neurodegeneration induced by 6-OHDA is acute (within 24 hours) and thus does not mimic the slow neurodegeneration seen in PD (Table 1).
MPTP crosses the blood-brain-barrier and is converted by monoamine-oxidase B to MPP+ within astrocytes. MPP+ is taken up by the dopamine (DA) transporter, thereby it is enriched in DA neurons where it inhibits mito-chondrial complex I. Today, the MPTP treated monkey is a frequently used animal model for PD (for review see Gerlach and Riederer, 1996). Like with 6-OHDA, also MPTP does not model slow neurodegeneration.
Among the neurotoxins rotenone is of specific importance because this substance might help to discover one of the mechanisms responsible for neurodegeneration in PD. A well based hypothesis posits that a general mitochondrial complex I deficiency underlies the disease and that DA neurons (and the other neurons degenerating in PD) are espe cially vulnerable for complex I inhibition. Probably auto-oxidation of DA, which results in the formation of reactive oxygen species, contributes to the specific vulnerability of DA neurons. Indeed a general complex I deficiency (about 25%) in all tissues including blood platelets has been reported for PD and all toxins that destroy DA neurons inhibit complex I. But 6-OHDA and MPTP could not test this hypothesis because they are taken up by the DA transporter and accumulate selectively in the DA neurons. However rotenone which is lipophilic, enters every body cell and does not accumulate selectively in DA neurons.
It has been well known for a long time that rotenone is toxic for DA neurons however the in vivo specificity has not been investigated in depth. Betarbet et al. (2000) infused 2-3mg/kg i.v. rotenone during 28-36 days in rats using minipumps. They reported a quite selective substantia nigra degeneration. Additionally they found a-synuclein immuno-reactivity in the affected neurons.
In order to develop a technically less demanding rat model Alam and Schmidt (2002) investigated the effects of rotenone (1.5 and 2.5mg/kg), given systemically i.p. in oil on a daily basis. After about 20 days of treatment, signs of parkinsonism occur (catalepsy in the rat) and the concentration of nitric oxide (NO) as well as of peroxidation products rose in the brain, especially in the striatum (Bashkatova et al., 2004). After daily administration over 60 days rotenone destroyed DA neurons, DA concentrations in the striatum and prefrontal cortex were reduced, as well as tyrosine hydroxylase concentration in the striatum. Behaviourally, a full blown catalepsy was evident, together with hunchback posture and reduced locomotion (Alam and Schmidt, 2002). Concentrations of other transmitters assessed so far, such as serotonin and its metabolites are not, or much less, changed by rotenone (Alam and Schmidt, 2004a).
A strong criterion that a rotenone model of PD must fulfill to be accepted as predictive, is that the induced effects are antagonized by the clinically effective anti-parkinsonian drug L-DOPA. This has been tested and it was found that L-DOPA methylester (10mg/kg i.p. plus peripheral de-carboxylase inhibitor benserazide) potently reversed the parkinsonian signs in rotenone pretreated rats (Alam et al., 2004). When infused stereotaxically into the medial forebrain bundle of rats, rotenone destroys dopaminergic neurons and produces PD symptoms. Rotenone is about 2-3 times as potent as 6-OHDA in this procedure. The so induced parkinsonism is consistently counteracted by L-DOPA (Alam and Schmidt, 2004a).
These data clearly support the above mentioned hypothesis stating that a weak mitochondrial complex I deficiency may underlie PD which does not kill most cells of the body except the DA neurons and those which degenerate in PD. However there are still arguments not supporting this view: Sherer et al. (2003) conclude from their findings, that not the complex I inhibition and subsequent ATP loss is responsible for the neuronal damage, but that an additional unknown mechanism, causing oxidative stress, accounts for the toxicity. As this is also the case for MPTP, this additional mechanism should be unraveled. In conclusion, the rote-none data support the hypothesis that a general complex I deficiency my represent one of the factors underlying PD. This however does not substantiate the hypothesis unequivocally. Thus, does rotenone represent a valid model of PD? There is much evidence in favor of this view but some arguments are also against it. Hoglinger et al. (2003) replicated the experiments of Betarbet et al. (2000) and found neurodegeneration beyond the dopaminergic system which they consider to be not typical for idiopathic PD. Their conclusion is that the destruction caused by rotenone does not fully mimic early idiopathic PD which is confined to the DA system, but rather atypical PD with additionally non-dopaminergic lesions (Hirsch et al., 2003). Thus at least for PD with associated non-dopaminergic lesions, rotenone-induced parkinsonism represents a very promising animal model.
PD patients also suffer from disturbances in the peripheral autonomic nervous system. In line with this are the findings of Braak and Del Tredici (2005) showing that first signs of PD occur in the dorsal nucleus of vagus nerve. Most patients with PD, and all people suffering from PD-associated orthostatic hypotension, have a loss of cardiac sympathetic innervation, probably due to overproduction of a-synuclein. It remains to be established, but there are some indications that rotenone, due to its general complex I inhibition, can mimic these peripheral symptoms of PD too. The low testosterone concentrations which are typical for PD, are mimicked by rotenone in the rat (Alam and Schmidt, 2004b) as well as the DA-cell loss in the retina.
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