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Ideally, animal models of neurodegenerative diseases should reproduce the clinical manifestation of the disease and a selective neuronal loss. In this review we will take as an example Parkinson’s disease because its pathophysiology is well known and the neuronal loss well characterized. Indeed, Parkinson’s disease is characterized by a loss of some but not all dopaminergic neurons, a loss of some non dopaminergic neurons and alphasynuclein positive inclusions resembling Lewy bodies. There are at least two ways to develop animal models of PD based on the etiology of the disease and consist in 1) reproducing in animals the mutations seen in inherited forms of PD; 2) intoxicating animals with putative environmental toxins causing PD. In this review we discuss the advantages and the drawbacks in term of neuroproction of the currently used models.

A retrospective study of a 50-year autopsy series of 900 patients with the clinical diagnosis of parkinsonism (31.2% with dementia) revealed pure Lewy body disease (LBD) in 84.9%, but only 44.7% with idiopathic Parkinson disease (PD); 16% were associated with cerebrovascular lesions, 14.8% with Alzheimer pathology; 8.9% were classified dementia with Lewy bodies (DLB), 9.4% showed other degenerative disorders, and 5.6% other/ secondary parkinsonian syndromes. The frequency of LBD during different periods was fairly stable, with increase of DLB and PD plus Alzheimer changes, but decrease of associated cerebrovascular lesions during the last decades. Using variable clinical diagnostic criteria not only by specified neurologists, the misdiagnosis rate ranged from 11.5 to 23% and was similar to that in most previous clinico-pathological studies. The majority of cases with false clinical diagnosis of PD had a final pathological diagnosis of DLB with or without Alzheimer lesions. A postmortem series of 330 elderly patients clinically diagnosed as parkinsonism with (37.6%) and without dementia showed that IPD, Braak stages 3–5 were rarely associated with cognitive impairment, which was frequently seen in IPD with associated Alzheimer pathology (35.5%), DLB (33.9%), and in Alzheimer disease (AD) or mixed dementia (17%), whereas it almost never was associated with minor cerebrovascular lesions.

In Parkinson’s disease clinical and experimental evidence suggest that neuroinflammatory changes in cytokines caused by microglial activation contribute to neuronal death. Experimentally, neuroinflammation of dopaminergic neurons can be evoked by lipopolysaccharide (LPS) exposure. In mesencephalic primary cultures LPS (100μg/ml) resulted in 30–50% loss of dendritic processes, changes in the perikarya, cellular atrophy and neuronal cell loss of TH-immunoreactive (TH^+) cells. iNOS activity was increased dose dependently as well as prostaglandin E_2 concentrations. Ginsenosides, as the active compounds responsible for ginseng action, are reported to have antioxidant and anti-inflammatory effects. Here ginsenoside Rd was used to counteract LPS neurodegeneration. Partial reduction of LPS neurotoxic action was seen in dopaminergic neurons. Cell death by LPS as well as neuroprotective action by ginsenoside Rd was not selective for dopaminergic neurons. Neuronal losses as well as cytoprotective effects were similar when counting NeuN identified neurons. The anti-inflammatory effect of ginsenoside Rd could equally be demonstrated by a reduction of NO-formation and PGE_2 synthesis. Thus, protective mechanisms of ginsenoside Rd may involve interference with iNOS and COX-2 expression.

Biochemical studies on postmortem brains of patients with Parkinson’s disease (PD) have greatly contributed to our understanding of the molecular pathogenesis of this disease. The discovery by 1960 of a dopamine deficiency in the nigro-striatal dopamine region of the PD brain was a landmark in research on PD. At that time we collaborated with Hirotaro Narabayashi and his colleagues in Japan and with Peter Riederer in Germany on the biochemistry of PD by using postmortem brain samples in their brain banks. We found that the activity, mRNA level, and protein content of tyrosine hydroxylase (TH), as well as the levels of the tetrahydrobiopterin (BH4) cofactor of TH and the activity of the BH4-synthesizing enzyme, GTP cyclohydrolase I (GCH1), were markedly decreased in the substantia nigra and striatum in the PD brain. In contrast, the molecular activity (enzyme activity/enzyme protein) of TH was increased, suggesting a compensatory increase in the enzyme activity. The mRNA levels of all four isoforms of human TH (hTHl-hTH4), produced by alternative mRNA splicing, were also markedly decreased. This finding is in contrast to a completely parallel decrease in the activity and protein content of dopamine β-hydroxylase (DBH) without changes in its molecular activity in cerebrospinal fluid (CSF) in PD. We also found that the activities and/or the levels of the mRNA and protein of aromatic L-amino acid decarboxylase (AADC, DOPA decarboxylase), DBH, phenylethanolamine N-methyltransferase (PNMT), which synthesize dopamine, noradrenaline, and adrenaline, respectively, were also decreased in PD brains, indicating that all catecholamine systems were widely impaired in PD brains.

In Parkinson’s and other neurodegenerative diseases, a therapeutic strategy has been proposed to halt progressive cell death. Propargylamine derivatives, rasagiline and (—)deprenyl (selegiline), have been confirmed to protect neurons against cell death induced by various insults in cellular and animal models of neurodegenerative disorders. In this paper, the mechanism and the markers of the neuroprotection are reviewed. Propargylamines prevent the mitochondrial permeabilization, membrane potential decline, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase. At the same time, rasagiline induces anti-apoptotic pro-survival proteins, Bcl-2 and glial cell-line derived neurotrophic factor, which is mediated by activated ERK-NF-κB signal pathway. DNA array studies indicate that rasagiline increases the expression of the genes coding mitochondrial energy synthesis, inhibitors of apoptosis, transcription factors, kinases and ubiquitin-proteasome system, sequentially in a time-dependent way. Products of cell survival-related gene induced by propargylamines may be applied as markers of neuroprotection in clinical samples.

Strategies of cell therapy for the treatment of Parkinson’s disease (PD) are focused on replacing damaged neurons with cells to restore or improve function that is impaired due to cell population damage. In our studies, we used mesenchymal stromal cells (MSCs) from mouse bone marrow. Following our novel neuronal differentiation method, we found that the basic cellular phenotype changed to cells with neural morphology that express specific markers including those characteristic for dopaminergic neurons, such as tyrosine hydroxylase (TH). Intrastriatal transplantation of the differentiated MSCs in 6-hydroxydopamine-lesioned mice led to marked reduction in the amphetamine-induced rotations. Immunohistological analysis of the mice brains four months post transplantation, demonstrated that most of the transplanted cells survived in the striatum and expressed TH. Some of the TH positive cells migrated toward the substantia nigra. In conclusion, transplantation of bone marrow derived stem cells differentiated to dopaminergic-like cells, successfully improved behavior in an animal model of PD suggesting an accessible source of cells that may be used for autotransplantation in patient with PD.

Five men with advanced idiopathic Parkinson’s disease (PD) were examined to assess the effect of low dose methylphenidate (MPD) on gait. The patients were tested during “off” state before and two hours after the intake of 10mg MPD while walking an “8 trajectory”. The total walking time, total freezing time, number of freezing episodes and the nonfreezing walking time were assessed. The obtained data were compared by the Wilcoxon Signed Rank test with a type I error rate of 0.05. The results showed a statistically significant improvement in all gait parameters after MPD intake. Moreover, a good correlation in the grade of improvement for each individual gait characteristic was found. The study demonstrates that low dose of MPD may improve gait, and especially freezing, in patients with severe PD, without the need for exogenous L-dopa. The mechanism of MPD action in patients with advanced PD is further discussed.

The neurotoxin l-trichloromethyl-l,2,3,4-tetrahydro-β-carboline (TaClo) has been reported, both in vitro and in vivo models, to produce neurodegeneration and parkinsonian symptoms after prolonged exposure in rats. The aim of the present study was to investigate the effects of TaClo on the cognitive performance of rats. We used the COGITAT hole board system where rats can find hidden pellets by exploring the board. TaClo-treated rats found as many pellets as control rats treated with saline. Furthermore, their search was as efficient as that of control animals since there were no differences between the groups regarding explorative activity, visits to nonbaited holes and time needed to find the pellets. These results suggest that there is no deficit in spatial memory following the chronic administration of TaClo to rats.

Transcranial magnetic stimulation is a tool in the neurosciences to study motor functions and nervous disorders, amongst others. Single pulses of TMS applied over the primary motor cortex lead to a so-called cortical silent period in the recording from the corresponding muscle, i.e. a period of ∼ 100 ms with no muscle activity. We here show that in Parkinson’s disease (PD), this cortical silent period in some cases is interrupted by short bursts of EMG activity. We describe in detail these interruptions in two patients with PD. These interruptions may number up to 3 per cortical silent period and show a consistent frequency across trials and hemispheres within a given patient; the two patients described here do differ, however, in the time-delay of the interruptions and hence the induced frequency. For one patient, the frequency of the interruptions proved to be around 13 Hz, the other patient showed a frequency of around 17 Hz. The results corroborate earlier findings of cortical oscillations elicited by pulses of TMS and may be related to abnormal oscillatory activity found in the cortical-subcortical motor system in PD.

In order to reach a deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, we showed that CYP450 (2E1) inhibitors, such as diallyl sulfide (DAS) or phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. Furthermore we showed that CYP 2E1 is present in the brain and in the basal ganglia of mice (Vaglini et al., 2004). However, because DAS and PIC are not selective CYP 2E1 inhibitors and in order to provide direct evidence for CYP 2E1 involvement in the enhancement of MPTP toxicity, CYP 2E1 knockout mice (GONZ) and wild type animals (SVI) of the same genetic background were treated with MPTP or the combined DDC + MPTP treatment. In CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTP toxicity, although enhancement of MPTP toxicity was regularly present in the SVI control animals. The immunohistochemical study confirms our results and suggests that CYP 2E1 may have a detoxifying role.