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Neuroinflammatory reactions in in vitro models of Parkinson's Disease and L-DOPA-induced dyskinesia: tetracyclines and cannabinoids as possible therapeutic agents

Abstract

There is evidence in the literature that the inflammatory process may contribute to and / or exacerbate the clinical manifestations of Parkinson's disease and dyskinesias (abnormal involuntary movements) associated with Parkinson's disease and disease therapy. There is a great socio-economic impact of these disorders on the lives of patients and their families. Thus, it is necessary to have a better understanding of the neuropathological and biochemical mechanisms common to the disease and dyskinesia induced by treatment with L-DOPA and its probable comorbidities such as the inflammatory process. This is an essential step towards the discovery of new therapeutic approaches. Several studies in our laboratory point to dysfunctions in endocannabinoid neurotransmission (in addition to dopaminergic, glutamatergic and serotonergic) in animal models of Parkinson's disease and dyskinesias. In addition, the treatment of phytocannabinoids, such as cannabidiol (CBD) and tetracyclines, such as doxycycline (DOX) points to neuroprotection, reducing the manifestation of dyskinesia, associated with a potent anti-inflammatory activity. Our findings indicate that neuroinflammation is a clear process in the pathophysiology of Parkinson's disease, with an evident role in the manifestation and / or maintenance of dyskinesias. However, the role of this process in the development of dyskinesias induced by L-DOPA (dopamine precursor) is still poorly understood. Our hypothesis in this study is that there is a neuroinflammatory process in the denervated striatum of Parkinsonian animals, which would be exacerbated by chronic treatment with L-DOPA or dopaminergic agonist, which could favor / cause the onset / induction of dyskinesias. In this way, the glial cells would be responsible or important assistants of the neuroinflammatory process, through the release of flags such as cytokines / chemokines, and active morphology. There would be a change in glial activity and in the signaling cascade to induce components of the inflammatory process that would modulate the profile of molecular changes in the injured tissue. Our specific objectives are, in models of neuronal and glial culture: (i) - Reproduce the model of PD and dyskinesia in culture, mimicking the inflammatory environment to observe the response of glial and neuronal cells to this stimulus. (ii) - Assess whether there is and how the neuronal and glial neuroinflammatory process decreases in culture after administration of DOX and other tetracyclines. (iii) - With the advantage of being part of a pioneering group in the study of the cannabinoid system, assessing whether and how the neuronal and glial neuroinflammatory process decreases in culture after administration of CBD and other cannabinoid agents. (AU)

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