Experimental models of Parkinson's disease: from the static to the dynamic.
ABSTRACT The experimental models of Parkinson's disease (PD) available today can be divided into two categories according to the mode of action of the compound used: transient pharmacological impairment of dopaminergic transmission along the nigrostriatal pathway or selective destruction by a neurotoxic agent of the dopaminergic neurons of the substantia nigra pars compacta. The present article looks at the relative merits of each model, the clinical symptoms and neuronal impairment it induces, and the contribution it could make to the development of a truly dynamic model. It is becoming more and more clear that there is an urgent need for a chronic model integrating all the clinical features of PD including resting tremor, and reproducing the gradual but continuous nigral degeneration observed in the human pathology. Discrepancies have been reported several times between results obtained in classic animal models and those described in PD, and it would seem probable that such contradictions can be ascribed to the fact that animal models do not, as yet, reproduce the continuous evolution of the human disease. Dynamic experimental models which come closer to the progressive neurodegeneration and gradual intensification of motor disability so characteristic of human PD will enable us to investigate crucial aspects of the disease, such as compensatory mechanisms and dyskinesia.
Full-textDOI: · Available from: Erwan Bezard, Jun 02, 2014
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Article: Experimental models of Parkinson's disease: from the static to the dynamic.
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ABSTRACT: Parkinson’s disease (PD) is characterised by a progressive loss of dopaminergic neurones from the SNpc, leading to numerous downstream changes in the basal ganglia circuitry. Overactivity of the glutamatergic subthalamonigral pathway may underlie this continual degeneration of the nigrostriatal system. With this in mind, this thesis examined whether selective activation of group III metabotropic glutamate receptor subtypes may offer a novel strategy to halt persistent degeneration in PD. Initial distribution studies revealed mGlu4 and 7 group III mGlu receptor subtypes, demonstrated particularly intense immunoreactivity in the SNpc, suggesting these receptors may be ideally positioned to provide neuroprotective effects. Therefore, the first objective was to confirm this neuroprotective possibility using a broad spectrum agonist, L-AP4. Sub-chronic supranigral L-AP4 treatment mediated functional neuroprotection against a unilateral 6-OHDA lesion of the SN, confirmed by behavioural assessment and post-mortem analyses. Secondly, the pharmacological identity of the group III mGlu receptor mediating this protective effect was examined. To investigate mGlu4 receptors, the novel mGlu4 selective PAM VU0155041, was also shown to provide functional neuroprotection in the 6-OHDA rat model to an almost comparable level reached with L-AP4. Whilst these neuroprotective effects are likely mediated by an inhibition of glutamate to protect from glutamate-mediated excitotoxicity, VU015504 also led to a significant reduction in levels of GFAP and IBA-1 suggesting an additional anti-inflammatory action. Further studies revealed little evidence for co-localisation of mGlu4 receptors with GFAP in the SN suggesting this anti-inflammatory component likely reflects an indirect effect via stimulation of neuronal mGlu4 receptors. Finally, to investigate mGlu7 receptors, the selective allosteric agonist AMN082, was also shown to protect the nigrostriatal tract and demonstrate a degree of preservation of motor function. In contrast, mGlu8 receptor activation using the selective agonist DCPG, failed to protect the nigrostriatal tract or preserve motor behaviour. Collectively, these findings demonstrate that, of the group III mGlu receptors investigated, mGlu4 offers the most potential as a promising target for establishing disease modification in PD.
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ABSTRACT: The distributions of dopamine D1 and D2/3 binding sites in living brain have not been compared directly using positron emission tomography (PET). To map these binding sites, we first optimized methods for the assay of dopamine receptors in brain of Göttingen miniature pigs. The binding potentials (pB) of [11C]NNC 112 for dopamine D1 receptors and [11C]raclopride for dopamine D2/3 receptors were calculated in pig striatum volumes of interest using metabolite corrected arterial inputs or using cerebellum as a non-binding reference region. Depending upon the method for quantitation, the pB for [11C]NNC 112 was 1.2–5.1 in pig striatum, whereas the pB for [11C]raclopride was 1.0–1.8. We used the reference tissue method of Logan to calculate pB maps for the two tracers. The maps were co-registered to the common stereotaxic space for the pig brain and normalized to a global mean for pB in striatum; t-maps showed that dopamine D1 binding was relatively more abundant in the ventral–anterior striatum of the pig, while dopamine D2/3 binding was greater in the dorsal striatum. Similar comparisons were made for the pBs of [11C]Sch 23390 for dopamine D1 receptors and for [11C]raclopride in the brain of six rhesus monkeys. The magnitudes of pB for both binding sites in monkey brain were close to those in the pig. Consistent with the pig results, there were distinct gradients in the distributions of the two binding sites in monkey brain: D1 binding predominated in the ventral striatum, whereas D2/3 binding was relatively greater in the dorsal-posterior striatum. Gradients of dopamine receptor concentration within the striatum may be a general phenomenon of mammalian brain.NeuroImage 05/2004; DOI:10.1016/S1053-8119(04)00148-X · 6.13 Impact Factor
Article: Funzioni motorie[Show abstract] [Hide abstract]
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