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

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.

Keywords: L-DOPA-induced dyskinesia; NMDAR; PDE10A; Parkinson’s disease; glutamate; phosphodiesterase; striatal projection neuron.

Figure 1

Microcircuitry of striatal projection neurons. The scheme is an oversimplification of the microcircuitry. DA stimulation modulates the activity of the d- and iSPNs. DAR signaling is mediated by activation of cyclic nucleotide synthesis through two pathways (AC-cAMP and NO-GC-cGMP). PDEs are catabolic enzymes for cAMP and cGMP (PDE10, PDE1, PDE2, PDE4, PDE7, and PDE9 are abundant in the striatum). SPNs receive excitatory signals mediated by glutamate ionotropic (NMDAR and AMPAR) and metabotropic receptors (groups I–III), the latter also acting presynaptically to modulate glutamate release. Arrows represent activation, and perpendicular lines represent inactivation. Abbreviations: SPN = striatal projection neuron; PDE = phosphodiesterase; NOS = nitric oxide synthase; NO = nitric oxide; GC = guanylate cyclase; cGMP = cyclic guanosine monophosphate; PKG = protein kinase G; AC = adenylate cyclase; cAMP = cyclic adenosine monophosphate; PKA = protein kinase A; DARPP-32 = dopamine- and cAMP-regulated neuronal phosphoprotein; CREB = cAMP response element binding protein.