Role of neuronal nitric oxide synthase and phosphodiesterase 10A in striatal medium spiny neuron activity during L-Dopa-induced dyskinesia

• Grant number: 17/00003-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: December 01, 2017
• End date: November 30, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fernando Eduardo Padovan Neto
• Grantee: Fernando Eduardo Padovan Neto
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Anthony Ronald West ; Elaine Aparecida Del Bel Belluz Guimarães ; Kuei Y. Tseng
• Associated research grant(s): 24/09095-9 - Society for Neuroscience Annual Meeting 2024, AR.EXT; 20/00653-8 - Phosphodiesterase 10A signaling in L-DOPA-induced dyskinesias, AP.R SPRINT
• Associated scholarship(s): 22/10432-4 - Characterization of the evolution of cognitive and morphological alterations in the 3xTg-AD mouse model of Alzheimer's disease., BP.IC; 22/01536-0 - Role of neuronal nitric oxide synthase and phosphodiesterase 10A in striatal medium spiny neuron activity during L-DOPA-induced dyskinesia., BP.TT; 21/08742-2 - Role of neuronal nitric oxide synthase and phosphodiesterase 10A in striatal medium spiny neuron activity during L-DOPA-induced dyskinesia., BP.TT; + associated scholarships 19/26152-8 - Characterization of the effects of phosphodiestrerase 10A inhibition on c-fos expression in the striatum of dyskinetic rats, BP.IC; 19/24392-1 - Role of neuronal nitric oxide synthase and phosphodiesterase 10A in striatal medium spiny neuron activity during L-DOPA-induced dyskinesia, BP.TT; 19/03754-2 - Role of neuronal nitric oxide synthase and phosphodiesterase 10A in striatal medium spiny neuron activity during L-DOPA-induced dyskinesia, BP.TT; 19/04188-0 - Role of neuronal nitric oxide synthase in striatal medium spiny neuron activity during the occurrence of L-DOPA-induced dyskinesia, BP.MS; 18/24428-3 - Analysis of spontaneous and cortically evoked activity of striatal medium spiny neurons during the occurrence of L-DOPA-induced dyskinesias, BP.IC; 18/12956-5 - Role of phosphodiesterase 10A in striatal medium spiny neuron activity during L-DOPA-induced dyskinesia, BP.MS; 18/01215-4 - Role of neuronal nitric oxide synthase and phosphodiesterase 10A in striatal medium spiny neuron activity during l-DOPA-induced dyskinesia, BP.JP - associated scholarships

Abstract

Parkinson's Disease (PD) is a progressive neurodegenerative disorder that affects 1% of people over the age of 60. The primary motor symptoms of PD include resting tremor, slowness of movements, rigidity and postural instability. These symptoms result from the degeneration of the dopaminergic cells in the Substantia Nigra pars compacta (SNc). L-DOPA remains the gold standard treatment for PD. However, with repeated administration, L-DOPA can cause abnormal involuntary movements (e.g. L-DOPA-induced dyskinesia; LID) in 75-80% of PD patients. There is a clear need for novel preclinical and clinical research to identify an effective antidyskinetic intervention that provides PD patients with a better quality of life during the on-state of L-DOPA treatment. The cellular, synaptic, and circuit mechanisms responsible for LID are unknown, but several key findings suggest that abnormal activity in the input nucleus of the basal ganglia, the striatum, is responsible. The striatum receives massive cortical excitatory inputs and is densely innervated by dopaminergic projections. The glutamatergic and dopaminergic information is integrated within the striatal Medium Spiny Neurons (MSNs) and transmitted to the output nuclei of the basal ganglia, the internal portion of the globus pallidus and the Substantia Nigra pars reticulata (SNr). MSNs can project directly (dMSNs) or indirectly (iMSNs) to the output nuclei of basal ganglia. dMSNs express preferentially D1 dopaminergic receptors as well as the neuropeptides dynorphin and substance P. The iMSNs express mainly D2 dopaminergic receptors and the neuropeptide enkephalin. Models of PD propose that chronic L-DOPA exposure generates a hyperdopaminergia state that contributes to imbalance in the activity of striatal MSNs, generating hyperactivity of dMSNs and hypoactivity of iMSNs. This imbalance between MSN activity during the on-state of L-DOPA treatment would be responsible for the appearance of LID. Unfortunately, direct electrophysiological evidence is lacking. Using in vivo electrophysiological recordings of spontaneous and cortically evoked activity in the 6-hydroxydopamine (OHDA)-lesioned rat model of PD, our Aim 1 seeks to characterize the physiology of dMSNs and iMSNs during the on-state of L-DOPA treatment in dyskinetic rats. Dissecting these two groups of neurons will be the first step in developing improved PD therapeutics. Once this part of the study is completed, our Aim 2 is to test how selective targeting of neuronal nitric oxide synthase (nNOS) and phosphodiesterase 10A (PDE10A) signaling impacts on spontaneous and cortically-evoked activity of MSNs in the dyskinetic striatum. Preliminary behavioral data has demonstrated that pharmacological blockage of those two enzymes can reduce the incidence of LIDs when given to dyskinetic rats. By the end of the project, we expect to demonstrate clear preclinical evidence for the long-term antidyskinetic properties achieved with nNOS and PDE10A inhibition. The clinical implications of this discovery are expected to advance the treatment options for patients with PD. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GUIMARAES, RAYANNE POLETTI; RIBEIRO, DANILO LEANDRO; DOS SANTOS, KEILA BARIOTTO; GODOY, LIVEA DORNELA; CORREA, MIRELLA ROSINE; PADOVAN-NETO, FERNANDO EDUARDO. The 6-hydroxydopamine Rat Model of Parkinson's Disease. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, n. 176, OCT 2021. (17/00003-0)

BARIOTTO-DOS-SANTOS, KEILA; RIBEIRO, DANILO LEANDRO; GUIMARAES, RAYANNE POLETTI; PADOVAN-NETO, FERNANDO EDUARDO. Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, n. 176, OCT 2021. (17/00003-0)

GODOY, LIVEA DORNELA; FALCOSKI, RAQUEL; INCROCCI, ROBERTA MONTEIRO; VERSUTI, FABIANA MARIS; PADOVAN-NETO, FERNANDO E.. The Psychological Impact of the COVID-19 Pandemic in Remote Learning in Higher Education. EDUCATION SCIENCES, v. 11, n. 9, SEP 2021. (17/00003-0)

CERVEIRA, A. J. D. O.; RAMALHO, B. A. C.; DE SOUZA, C. C. B.; SPADARO, A. P.; RAMOS, B. A.; WICHERT-ANA, L.; PADOVAN-NETO, F. E.; DE LACERDA, K. J. C. C.. Automating behavioral analysis in neuroscience: Development of an open-source python software for more consistent and reliable results. JOURNAL OF NEUROSCIENCE METHODS, v. 398, p. 11-pg., 2023-09-12. (17/00003-0)