Exploring the Inhibition of Phosphodiesterase 4 (PDE4) Enzyme as a New Approach to Treat L-DOPA Induced Dyskinesias in Parkinson's Disease

• Grant number: 23/09644-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2023
• End date: October 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Fernando Eduardo Padovan Neto
• Grantee: Estela Hiilesmaa
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The main treatment for Parkinson's disease is the drug L-3,4-dihydroxyphenylalanine (L-DOPA), which increases the availability of dopamine in the basal ganglia and regulates motor activity. However, the chronic use of L-DOPA can lead to the development of L-DOPA-induced dyskinesias (LIDs). Few treatment options are currently available for managing LIDs. A promising strategy involves the administration of phosphodiesterase 4 (PDE4) inhibitors, which hydrolyze and control the availability of the second messenger, cyclic adenosine 3',5'-monophosphate (cAMP). The PDE4 enzyme interferes with cellular signaling in the basal ganglia and interacts with dopaminergic signaling. This project aims to investigate the therapeutic potential of PDE4 inhibition in treating LIDs. To this end, parkinsonian symptoms will be induced in rats via the central injection of the neurotoxin 6-hydroxydopamine. The animals will then be subjected to chronic L-DOPA treatment to induce dyskinesias. Once dyskinesias are established, L-DOPA will be co-administered with the PDE4 inhibitor, roflumilast. The abnormal involuntary movements elicited by both drugs will be evaluated and compared using a dyskinesia scale adapted for rodents. If the antidyskinetic effect of roflumilast is confirmed, the animals will be treated with the adenylate cyclase inhibitor, SQ22536, to assess the contribution of cAMP to roflumilast's effects. It is anticipated that the pharmacological inhibition of the PDE4 enzyme will attenuate LIDs, possibly by increasing cAMP levels and thus, regulating motor activity in the basal ganglia circuits.