Role of neuronal nitric oxide synthase in striatal medium spiny neuron activity during the occurrence of L-DOPA-induced dyskinesia

• Grant number: 19/04188-0
• Support type: Scholarships in Brazil - Master
• Effective date (Start): April 01, 2019
• Effective date (End): April 30, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal researcher: Fernando Eduardo Padovan Neto
• Grantee: Danilo Leandro Ribeiro
• Home Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 17/00003-0 - Role of neuronal nitric oxide synthase and phosphodiesterase 10A in striatal medium spiny neuron activity during L-Dopa-induced dyskinesia, AP.JP

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 is to target neuronal nitric oxide synthase (nNOS) signaling and understand how nitric oxide impacts on spontaneous and cortically-evoked activity of MSNs in the dyskinetic striatum. Preliminary behavioral data has demonstrated that pharmacological blockage of nNOS 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 inhibition. The clinical implications of this discovery are expected to advance the treatment options for patients with PD. (AU)