Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/23/2754 |
| _version_ | 1797400292985143296 |
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| author | Brik A. Kochoian Cassandra Bure Stella M. Papa |
| author_facet | Brik A. Kochoian Cassandra Bure Stella M. Papa |
| author_sort | Brik A. Kochoian |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T01:53:28Z |
| format | Article |
| id | doaj.art-09c5807a947d424a9473e2903981df73 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T01:53:28Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-09c5807a947d424a9473e2903981df732023-12-08T15:13:15ZengMDPI AGCells2073-44092023-11-011223275410.3390/cells12232754Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced DyskinesiaBrik A. Kochoian0Cassandra Bure1Stella M. Papa2Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USAEmory National Primate Research Center, Emory University, Atlanta, GA 30329, USAEmory National Primate Research Center, Emory University, Atlanta, GA 30329, USAA 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.https://www.mdpi.com/2073-4409/12/23/2754L-DOPA-induced dyskinesiaParkinson’s diseaseglutamatephosphodiesterasestriatal projection neuronNMDAR |
| spellingShingle | Brik A. Kochoian Cassandra Bure Stella M. Papa Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia Cells L-DOPA-induced dyskinesia Parkinson’s disease glutamate phosphodiesterase striatal projection neuron NMDAR |
| title | Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia |
| title_full | Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia |
| title_fullStr | Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia |
| title_full_unstemmed | Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia |
| title_short | Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia |
| title_sort | targeting striatal glutamate and phosphodiesterases to control l dopa induced dyskinesia |
| topic | L-DOPA-induced dyskinesia Parkinson’s disease glutamate phosphodiesterase striatal projection neuron NMDAR |
| url | https://www.mdpi.com/2073-4409/12/23/2754 |
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