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Effects of sodium nitroprusside on the corticostriatal pathway during the occurrence of L-DOPA-induced dyskinesias

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Author(s):
Danilo Leandro Ribeiro
Total Authors: 1
Document type: Master's Dissertation
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Fernando Eduardo Padovan Neto; Marcela Bermudez Echeverry; Elaine Aparecida Del Bel Belluz Guimaraes
Advisor: Fernando Eduardo Padovan Neto
Abstract

Parkinson\'s disease is characterized by the gradual loss of dopaminergic neurons from the substantia nigra pars compacta. Treatment is aimed at dopaminergic replacement in the striatum with the use of L-DOPA. However, the chronic use of L-DOPA can lead to motor complications such as L-DOPA-induced dyskinesias (LIDs). The striatum is mainly composed of medium spiny neurons (MSNs) that are divided according to their projection target. The direct pathway (dMSNs) projects to the motor portions of the inner pale globe (GPi) and cross-linked reticulated substantia nigra (SNr), while the indirect pathway (iMSNs) projects indirectly to the exit nuclei through connections with the globe pale external (GPe) and subthalamic nucleus (STN). It is suggested that LIDs arise due to the imbalance in the activity of these pathways, with hyperactivation of the direct path occurring. Nitric oxide (NO) is associated with the modulation of striatal projection pathways through nNOS-NO-sGC-cGMP signaling. Our working hypothesis is that the use of inhibitors and NO donors are able to reduce the exaggerated activity of the corticostriatal pathway and in this way balance the activity of the striatal output pathways, attenuating LIDs. Behavioral analyzes of LIDs in parkinsonian rats using the compounds ODQ and 7-NI (which inhibit the enzymes soluble guanylate cyclase (sGC) and neuronal nitric oxide synthase (nNOS), respectively) had no effect on dyskinesias even at different doses of L -DOPA, in contrast to studies that show that these inhibitors have anti- dyskinetic effects. The NO signaling pathway is complex and both the increase and decrease in cGMP levels can have anti-dyskinetic effects. Thus, we used the NO donor sodium nitroprusside (SNP) to observe the effects of this drug on LIDs. Treatment with SPN (2 mg / kg) increased the incidence of dyskinesias when compared to control animals. To assess the action of SNP on the activity of the cortico-striatal pathway, we performed electrophysiological records in vivo in anesthetized animals. The analyzes showed a facilitation in the activity of the cortico-striatal pathway in the animals treated with NPS and L-DOPA when compared to the controls. Thus, our results suggest that the increased signaling of the NO pathway can generate hyperactivity in MSNs and, consequently, the increase in LIDs. (AU)

FAPESP's process: 19/04188-0 - Role of neuronal nitric oxide synthase in striatal medium spiny neuron activity during the occurrence of L-DOPA-induced dyskinesia
Grantee:Danilo Leandro Ribeiro
Support type: Scholarships in Brazil - Master