Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia

• Type of Material: Article
• Authors: Brik Kochoian, Emory University; Cassie Bure, Emory University; Stella Papa, Emory University
• Language: English
• Date: 2023-11-30
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.3390/cells12232754
• Title of Journal or Parent Work: Cells
• Volume: 12
• Issue: 23
• Start Page: 2754
• Grant/Funding Information: This research was funded by NIH grants NS045962, NS110416, NS125502, NS126924, and NIH/ORIP OD011132 (S.M.P.) and NIH/NRSA NS124269 (B.A.K.).
• Keywords: L-DOPA-induced dyskinesia; NMDAR; striatal projection neuron; Parkinson’s disease; phosphodiesterase; PDE10A; glutamate
• Research Categories: Biology, Neuroscience; Health Sciences, Pharmacology; Health Sciences, General

Abstract

A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson’s disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.