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Investigation of the roles of ghrelin in experimental models of early stages of Parkinson’s disease : towards a clarification of ghrelin’s diagnostic and therapeutic potentials

Abstract : Parkinson’s disease (PD) is the second most frequent neurodegenerative disease in the world. It is characterized by motor symptoms such as bradykinesia, rigidity and resting tremor. Its definite diagnosis relies on the identification of specific neuropathological hallmarks at autopsy including severe neuronal death within the substantia nigra (SN) and the presence of Lewy bodies in the surviving neurons. PD progresses slowly and the first motor symptoms appear when more than 50% of the SN has degenerated. Therefore, the clinical diagnosis is established late in the course of the disease, thus restricting the therapeutic window for clinicians. In addition, the currently available therapeutic options can only temporarily alleviate PD motor symptoms. The challenges of current PD research are: 1) to anticipate the diagnosis and be able to identify the disease as early as possible, when the SN is still intact enough to implement a disease-modifying/neuroprotection strategy to prevent the appearance of motor symptoms, and 2) to improve current medications and/or develop new therapeutic strategies able to stop the disease before the motor phenotype is installed. The decade preceding PD clinical diagnosis is of particular interest since patients often complain about non-motor symptoms such as anosmia, depression or constipation. Moreover, recent evidences suggest that PD-characteristic lesions could first appear in the peripheral nervous system and slowly progress towards the brain. Thus PD earlier stages and their characteristics deserve better investigations using appropriate experimental models. In this regard, recent studies realized in animal and cellular models of advanced parkinsonism have suggested that ghrelin, an orexigenic peptide mainly produced in the stomach, could play a neuroprotective role in PD. Indeed, exposure to ghrelin has shown a protective effect against the neuronal death in animal and cellular models of parkinsonism. In addition, in a rodent model of parkinsonism, ghrelin was shown to alleviate the L-DOPA-induced worsening of gastro-intestinal symptoms, L-DOPA being the current main therapeutic option in PD. Moreover, ghrelin plasma concentrations have shown alterations in early stages of the disease in small cohorts of PD patients. We therefore hypothesized that ghrelin might play an important role in PD early stages and could serve as a biomarker and a neuroprotective agent in PD. In this context, the aim of my PhD was to investigate the roles of ghrelin in PD early stages using both in vitro and in vivo approaches.We first studied the effects of ghrelin in primary mesencephalic cells exposed to the pesticide rotenone, a potent inhibitor of mitochondrial complex I known for its association with PD. Contrary to the data of the literature, we show a dose and time-dependant deleterious effect of ghrelin on mesencephalic cells exposed to rotenone. This does not confirm the neuroprotective potential of ghrelin in our experimental conditions. In parallel, we investigated the potential of ghrelin as a biomarker in a rodent model of parkinsonism mimicking early stages of the disease after chronic oral exposure to low doses of rotenone. We first validated this model in our animal facility and confirmed that mice exposed to such a regimen develop progressive non-motor alterations but no dopaminergic neuronal death in the SN after 1.5 months. Our initial results do not show a modification of plasma ghrelin levels in rotenone-exposed mice at early stages of the pathological condition. However, confounding factors such as anxiety might have altered ghrelin levels. This should therefore be further ascertained in animals stratified for their anxiety levels and/or in longer exposures. In conclusion, these results challenge the suggested role of ghrelin as a disease-modifying agent in PD and set the bases for future investigations of ghrelin in the context of PD.
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Aliçia Stiévenard. Investigation of the roles of ghrelin in experimental models of early stages of Parkinson’s disease : towards a clarification of ghrelin’s diagnostic and therapeutic potentials. Human health and pathology. Université du Droit et de la Santé - Lille II, 2016. English. ⟨NNT : 2016LIL2S041⟩. ⟨tel-02448918⟩

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