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Treatment of rats with rotenone has been proposed in the year 2000 to provide an animal model of idiopathic Parkinson’s disease. We review here the experience that has been gained meanwhile with this model. The published data suggest that the model does not ideally reproduce the pathophysiology of Parkinson’s disease, that Rotenone treatment does not cause a purely neurodegenerative concondition, that the Rotenone model does not ideally recapitulate the motor symptoms of Parkinson’s disease, that degeneration of the dopaminergic neurons is highly variable, that striatal neurons appear to degenerate more consistently than neurons in the substantia nigra, and that cytoplasmic accumulation of the tau protein is more abundant than alpha-synuclein aggregation in severely lesioned animals. In summary, these data suggest that Rotenone-treated rats model atypical Parkinsonism rather than idiopathic Parkinson’s disease.

A general complex I deficit has been hypothesized to contribute to neurodegeneration in Parkinson’s disease (PD) and all toxins used to destroy dopaminergic neurons are complex I inhibitors. With MPTP or 6-OHdopamine, this hypothesis can not be tested since these toxins selectively accumulate in the dopaminergic neurons. However with rotenone, which penetrates all cells, the hypothesis can be tested. Thus, the proof of the hypothesis is whether or not rotenone-induced neurodegeneration mimics the degenerative processes underlying PD. Low doses of rotenone (1.5 or 2.5 mg/kg in oil i.p.) were administered to Sprague Dawley rats on a daily basis. After about 20 days of treatment, signs of parkinsonism occurred and the concentrations of NO and peroxidase products rose in the brain, especially in the striatum. After 60 days of treatment, rotenone had destroyed dopaminergic neurons. Behaviourally, catalepsy was evident, a hunchback posture and reduced locomotion. Other transmitter systems were not, or much less affected. L-DOPA-methylester (10 mg/kg plus decarboxylase inhibition) potently reversed the parkinsonism in rats. Also when infused directly into the dopaminergic neurons, rotenone produced parkinsonism which was antagonized by L-DOPA. Some peripheral symptoms of PD are mimiced by rotenone too, for example a low testosterone concentration in the serum and a loss of dopaminergic amacrine cells in the retina. These results support the hypothesis of an involvement of complex I in PD and render the rotenone model as a suitable experimental model. The slow onset of degeneration make it suitable also to study neuroprotective strategies. Evidence that rotenone-induced neurodegeneration spreads beyond the dopaminergic system is not contradictory given that, according to the new staging studies, also degeneration in PD is not confined to dopamine neurons.

Rats lesioned shortly after birth with 6-hydroxydopamine are posed as a near-ideal model of severe Parkinson’s disease, because of the non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, near-total dopamine (DA)-denervation of striatum, reproducibility of effect, and relative absence of overt behavioral effects – there is no aphasia, no adipsia, and no change in motor activity. In vivo microdialysis findings reinforce the utility of the animal model, clearly demonstrating L-DOPA beneficial actions without an increase in hydroxyl radical production.

Objectives . To elucidate the role of α-synuclein in the pathogenesis of Parkinson’s disease (PD), both human α-synuclein transgenic mice and targeted overexpression of human α-synuclein in rat substantia nigra (SN) by viral vector-based methods have been studied, however little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in the brains of patients with PD are recapitulated in these models. Methods and results . We used the recombinant adeno-associated viral (rAAV) vector system for human α-synuclein gene transfer to rat SN and observed approximately 50% loss of dopaminergic neurons in SN at 13 weeks after infection. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of PD, such as phosphorylation of α-synuclein at Ser129 and activation of caspase-9. Both findings were also evident in cortical tissues overexpressing α-synuclein via rAAV. Conclusions . Our results indicate that overexpression of α-synuclein via rAAV apparently recapitulates several important features of brains with PD and dementia with Lewy bodies (DLB), and thus α-synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of PD and DLB. This model is also useful for the gene therapy research.

The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds’ balance can be observable in many disorders. It can be occur in neurodegenerative disorders, such as Parkinson’s disease, Huntington’s and Alzheimer’s disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of QUIN concentration or decrease of KYNA concentration could enhance the symptoms of several diseases. According to numerous studies, lowered KYNA level was found in patients with Parkinson’s disease. It can be also noticeable that KYNA-treatment prevents against the QUIN-induced lesion of rat striatum in animal experiments. Administrating of KYNA can be appear a promising therapeutic approach, but its use is limited because of its poorly transport across the blood-brain barrier. The solution may be the development of KYNA analogues (e.g. glucoseamine-kynurenic acid) which can pass across this barrier and disengaging in the brain, then KYNA can exert its neuroprotective effects binding at the excitatory glutamate receptors, in particular the NMDA receptors. Furthermore, it seems hopeful to use kynurenine derivatives (e.g. 4-chloro-kynurenine) or enzyme inhibitors (e.g. Ro-61-8048) to ensure an increased kynurenic acid concentration in the central nervous system.

Several new advances facilitate current understanding of the progression of Parkinson’s disease. The application of statistical modeling techniques has helped to estimate rates of clinical decline in the context of symptomatic interventions. These approaches may allow a new means for testing neuroprotection effects even when patients are on dopaminergic treatment. Further, the development of new rating scales, specifically the Movement Disorder Society-initiated revision of the Unified Parkinson’s Disease Rating Scale has capitalized on a greater clinical appreciation of non-motor elements of Parkinson’s disease. Finally, adaptations of new technologies that are computer-based and enable data transmission from at-home environments allow researchers to capture disease impairment and disability with potentially greater precision and much more frequently than permissible in a hospital clinic or practice setting.

Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo-/akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinson’s disease (PD). Progressive loss of nigral neurons with Lewy bodies is considered an essential neuropathological feature. Recent studies, however, indicate that nigral degeneration is only a part of this synucleinopathy, and clinical symptoms go far beyond motor parkinsonism. Olfactory disturbances, autonomic dysfunction, pain, sleep fragmentation, depression, and dementia with or without psychosis are frequently seen. The variability in the expression of these signs and symptoms suggests multiple causes and/or pathogeneses within the present diagnostic disease entity. In this article, a recently proposed staging of PD-related brain pathology will be correlated with the various clinical expressions. It will be argued that the specific topographical sequence of the pathology, depending on the extent and progression of the degenerative process at defined sites, may explain the individually variable expression of this disease.

The association of Parkinson’s disease (PD) with an impaired sense of smell was first reported about thirty years ago. Since then, it has become quite firmly established that olfactory dysfunction is one of the first and most prevalent clinical manifestations of this disorder. Recent data from an ongoing prospective study indicate that otherwise unexplained hyposmia in first degree relatives of patients with sporadic PD is associated with an increased risk of developing clinical PD of at least 13%. In particular, a combination of impaired olfactory function and reduced striatal [^123I]β-CIT binding on a baseline SPECT scan appears to be a strong predictor of a subsequent diagnosis of PD. Pathological studies support these observations by demonstrating that the anterior olfactory structures may be one of the induction sites of PD pathology. Considering that there is a doubling rather than a loss of dopaminergic neurons in the olfactory bulb in PD patients, the pathophysiology of olfactory dysfunction in PD is far from being elucidated. Studying prodromal manifestations of PD, such as olfactory dysfunction, and their underlying pathophysiology may greatly contribute to the development of treatment strategies that focus on preclinical detection and slowing down disease progression.

Gait is affected in all stages of Parkinson’s disease (PD) and is one of the hallmarks for disease progression. The fear of getting into the wheel chair is one of the first thoughts many patients ask about when the diagnosis of PD is given. At the early stages of the disease gait disturbances are present and can be measured but in most patients it does not cause significant functional disturbances. In contrast, as the disease progress, gait disturbances and postural control abnormalities are becoming major causes for lost of mobility and falls. These unfortunate consequences should be forecasted at the early stages of the disease and a preventive approach should be taken. Treatment of gait disturbances at the early stages of the disease is mainly to encourage patients to exercise and walk daily and by drugs in those with disabling symptoms. At the advanced stages, treatment should be aggressive in order to keep the patient walking safely. Drugs, physiotherapy and functional neurosurgery should be used wisely for best outcomes and least side effects. When time comes and the risk of falls is very significant, walking aids should be suggested and if no other option is left, wheel chair is a very reasonable option to maintain mobility out of home, preserving quality of life and avoiding falls with all it severe consequences.

Vision in PD. In PD an impairment of dopaminergic neurons of the preganglionic retina and a defect of the retinal nerve fibers (axons of the retinal ganglion cells) has been demonstrated and a correlation of loss of spatial contrast sensitivity, with the progression of motor impairment in PD has been described. These low level visual deficits contribute but do not directly explain behavioural visual deficits in PD involving spatial cognition, internal representation, space navigation and visual categorization. Language deficits in non-demented PD patients can include impairments in comprehension, verbal fluency, and naming. Comprehension deficits become evident when patients are required to process sentences with noncanonical, irregular grammatical structures. Semantic memory deficits may result in the impairments in category fluency and confrontational naming. Selective language deficits may be due to impaired dynamics of the “phonological loop” connecting the pre-frontal cortex and the basal ganglia. A more encompassing linguistic and functional model of PD specific language impairments would be useful for evaluating language deficits in the context of motor dysfunction.