The action of cannabinoid drugs in L-dopa-induced dyskinesia: analysis of neuroinflammation and glutamate release in glial cells

Abstract

The loss of dopaminergic (DA) neurons in Parkinson's disease (PD) is accompanied by persistent neuroinflammatory reactions mediated by astrocytes and microglial cells. This process, which is not yet fully characterized, probably perpetuates and amplifies the progression of this disorder. The DA precursor, L-DOPA, remains the most efficient treatment for PD 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 LID, since a pro-inflammatory environment in the striatum can be induced by excessive levels of glutamate and 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 that drugs related to the endocannabinoid system may attenuate the dyskinesia that develops after chronic dopaminergic replacement therapy. Recent data from our group indicate that treatment with cannabidiol, the main non-psychomimetic compound of Cannabis sativa, together with the TRPV-1 receptor antagonist capsazepine is able to reduce LID by reducing inflammatory factors such as the cyclooxygenase-2 enzyme and the protooncogene NF-™B. However, the involvement of glial cells in the LID, its action on glutamatergic imbalance existent in this pathology and, mainly, the effect of cannabinoid drugs on them is still incipient. Based on this, the proposed project has three main objectives: (i) to investigate whether mimetic compounds F101 (synthetic analogue of cannabidiol) and HU-910 (synthetic analogue of CB2 agonists) are able to reduce LID. As LID may be a consequence of an abnormal glutamate increase in the striatum, which may lead to neuroinflammation, we will also use the microglial glutamate transporter inhibitor sulfasalazine ; (Ii) to analyze, in vitro, whether treatment with L-DOPA/DA or glutamate generates an inflammatory process in astrocytes and microglia, comparing them to a classic inflammatory agent, LPS; (Iii) investigate whether F101 or HU910 are capable of altering the production of cytokines and glutamate in astrocytes and microglia using sulfasalazine as control. To do this, we will use a previously developed L-DOPA induced dyskinesia model, well characterized by the Brazilian team and a recently developed in vitro glial cell system, through collaboration with a French team to use as a model of neuroinflammatory reactions relevant to dyskinesia. (AU)