The action of cannabinoid drugs in glial-derived neuroinflammation process: a link to L-dopa-induced dyskinesia

Abstract

Dopamine precursor L-DOPA remains the most efficient treatment for Parkinson's disease motor symptoms, at least in the early and middle stages of the disorder. However, chronic treatment with L-DOPA induces several non-motor and motor complications, including L-DOPA-induced dyskinesia (LID). Our hypothesis is that inflammatory mechanisms are also responsible for the LID, since a proinflammatory environment in the striatum can be induced by excessive levels of glutamate and dopamine (DA) released in the striatal extracellular fluid after administration of L-DOPA. Despite the large number of studies that propose new approaches for the treatment of LID, the effectiveness of new pharmacological treatments is still limited. Previous studies have shown drugs related to the endocannabinoid system may attenuate the dyskinesia that develops after chronic dopaminergic replacement therapy. Recent data from the group indicates that treatment with cannabidiol, the main non-psychomimetic compound of Cannabis sativa, together with the TRPV-1 receptor antagonist, is able to reduce LID by reducing inflammatory compounds, such as the cyclooxygenase-2 enzyme and the immediate response gene NF-™B. However, the involvement of glial cells in the LID and, mainly, the effect of cannabinoid drugs on them is still unknown. Based on that, our collaboration with the French team aims to analyze, in vitro, whether treatment with L-DOPA and DA or glutamate generates an inflammatory process in astrocytes and microglia, comparing them to a classic inflammatory agent, LPS. We also intend to investigate whether F101 or HU910 (drugs that act on the cannabinoid system) are capable of altering the production of cytokines and glutamate in astrocytes and microglia, using sulfasalazine (microglial glutamate release inhibitor) as control. To do this, we will use an in vitro model of newly developed glial cells through collaboration with the French team to use as a model of neuroinflammatory reactions relevant to LID. (AU)