Effects of a Novel Psychomotor Stabilizer, IRL790, on Biochemical Measures of Synaptic Markers and Neurotransmission

Bečanović, Kristina; Donno, Maria Vittoria de; Sousa, Vasco C.; Tedroff, Joakim; Svenningsson, Per

doi:10.1124/jpet.119.264754

Cited by 3 publications

(1 citation statement)

References 37 publications

(56 reference statements)

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“…The D3R antagonist IRL790 (Mesdopetam) is currently undergoing clinical trials for LID management in PD patients. Early phases suggest that IRL790 is well-tolerated and effective in reducing LID [ 86 , 87 ] and phase IIB trials (NCT04435431) are currently underway. As more information is gathered regarding the structural relationship between D3R and its binding/signaling partners, the number of highly specific D3R compounds is only expected to rise [ 12 , 88 ].…”

Section: Discussionmentioning

confidence: 99%

Dopamine D3 Receptor Plasticity in Parkinson’s Disease and L-DOPA-Induced Dyskinesia

Lanza

Bishop

2021

Biomedicines

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Parkinson’s Disease (PD) is characterized by primary and secondary plasticity that occurs in response to progressive degeneration and long-term L-DOPA treatment. Some of this plasticity contributes to the detrimental side effects associated with chronic L-DOPA treatment, namely L-DOPA-induced dyskinesia (LID). The dopamine D3 receptor (D3R) has emerged as a promising target in LID management as it is upregulated in LID. This upregulation occurs primarily in the D1-receptor-bearing (D1R) cells of the striatum, which have been repeatedly implicated in LID manifestation. D3R undergoes dynamic changes both in PD and in LID, making it difficult to delineate D3R’s specific contributions, but recent genetic and pharmacologic tools have helped to clarify its role in LID. The following review will discuss these changes, recent advances to better clarify D3R in both PD and LID and potential steps for translating these findings.

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Section: Discussionmentioning

confidence: 99%

Dopamine D3 Receptor Plasticity in Parkinson’s Disease and L-DOPA-Induced Dyskinesia

Lanza

Bishop

2021

Biomedicines

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Phosphoproteomics implicates glutamatergic and dopaminergic signalling in the antidepressant-like properties of the iron chelator deferiprone

Uzungil,

Luza,

Opazo

et al. 2024

Neuropharmacology

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Phosphoproteomics implicates glutamatergic and dopaminergic signalling in the antidepressant-like properties of the iron chelator deferiprone

Uzungil,

Luza,

Opazo

et al. 2023

Preprint

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Current antidepressants have limitations due to insufficient efficacy and delay before improvement in symptoms. Polymorphisms of the serotonin transporter (5-HTT) gene have been linked to depression (when combined with stressful life events) and to altered response to selective serotonergic reuptake inhibitors. We have previously revealed the antidepressant-like properties of the iron chelator deferiprone in the 5-HTT knock-out (KO) mouse model of depression. Furthermore, deferiprone was found to alter neural activity in the prefrontal cortex of both wild-type (WT) and 5- HTT KO mice. In the current study, we examined the molecular effects of acute deferiprone treatment in the prefrontal cortex of both genotypes via phosphoproteomics. In WT mice treated with deferiprone, there were 22 differentially expressed phosphosites, with gene ontology analysis implicating cytoskeletal proteins. In 5-HTT KO mice treated with deferiprone, we found 33 differentially expressed phosphosites. Gene ontology analyses revealed phosphoproteins that were predominantly involved in synaptic and glutamatergic signalling. In a drug naive cohort, the analysis revealed 21 differentially expressed phosphosites in 5-HTT KO compared to WT mice. We confirmed the deferiprone-induced increase in Tyrosine hydroxylase serine 40 residue phosphorylation (pTH-Ser40) (initially revealed in our phosphoproteomics study) by western blots, with deferiprone increasing pTH-Ser40 expression in WT and 5-HTT KO mice. As glutamatergic and synaptic signalling are dysfunctional in 5-HTT KO mice (and are the target of fast-acting antidepressant drugs such as ketamine), these molecular effects may underpin deferiprone's antidepressant-like properties. Furthermore, dopaminergic signalling may also be involved in deferiprone's antidepressant-like properties.

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Effects of a Novel Psychomotor Stabilizer, IRL790, on Biochemical Measures of Synaptic Markers and Neurotransmission

Cited by 3 publications

References 37 publications

Dopamine D3 Receptor Plasticity in Parkinson’s Disease and L-DOPA-Induced Dyskinesia

Dopamine D3 Receptor Plasticity in Parkinson’s Disease and L-DOPA-Induced Dyskinesia

Phosphoproteomics implicates glutamatergic and dopaminergic signalling in the antidepressant-like properties of the iron chelator deferiprone

Phosphoproteomics implicates glutamatergic and dopaminergic signalling in the antidepressant-like properties of the iron chelator deferiprone

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