Ameliorative effects of a phosphodiesterase 10A inhibitor, MR1916 on l-DOPA-induced dyskinesia in parkinsonian rats

Arakawa, Keita; Yuge, Natsuko; Maehara, Shunsuke

doi:10.1007/s43440-020-00060-y

Cited by 8 publications

(9 citation statements)

References 25 publications

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“…administration of nonselective PDE inhibitors, such as zaprinast or the sildenafil analogue UK-343664, has been reported to diminish the occurrence of AIMs and prevent the L-DOPA-induced reduction in cyclic nucleotides in models of parkinsonian rodents (Giorgi et al, 2008;Picconi et al, 2011). Our group (Guimarães et al, 2022;Padovan-Neto & West, 2017), along with others (Arakawa et al, 2020;Beck et al, 2018;Matłoka et al, 2022), has shown that PDE10A inhibitors decrease the severity of AIMs in a preclinical model of PD. Contrary to Bortolanza et al (2016), we observed no interference of SNP with AIMs, potentially resulting from methodological divergences.…”

Section: Discussionmentioning

confidence: 71%

“…Compounds that reduce NO levels (e.g., nNOS or sGC inhibitors) exhibit antidyskinetic activity in both rodent (Bariotto‐dos‐Santos et al, 2019; Padovan‐Neto et al, 2009; Solís et al, 2015; Takuma et al, 2012) and non‐human primate (Herrero et al, 2023) models of PD. NO donors such as sodium nitroprusside (SNP) and molsidomine (Bortolanza et al, 2016; Solís et al, 2015) along with PDE inhibitors (Arakawa et al, 2020; Beck et al, 2018; Guimarães et al, 2022; Matłoka et al, 2022; Padovan‐Neto & West, 2017) also exhibited antidyskinetic activity in rodent models of PD.…”

Section: Introductionmentioning

confidence: 99%

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Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

Ribeiro,

Guimarães,

Bariotto‐dos‐Santos

et al. 2024

Eur J of Neuroscience

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Levodopa (L‐DOPA) is the classical gold standard treatment for Parkinson's disease. However, its chronic administration can lead to the development of L‐DOPA‐induced dyskinesias (LIDs). Dysregulation of the nitric oxide–cyclic guanosine monophosphate pathway in striatal networks has been linked to deficits in corticostriatal transmission in LIDs. This study investigated the effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on behavioural and electrophysiological outcomes in sham‐operated and 6‐hydroxydopamine‐lesioned rats chronically treated with vehicle or L‐DOPA, respectively. In sham‐operated animals, systemic administration of SNP increased the spike probability of putative striatal medium spiny neurons (MSNs) in response to electrical stimulation of the primary motor cortex. In 6‐hydroxydopamine‐lesioned animals, SNP improved the stepping test performance without exacerbating abnormal involuntary movements. Additionally, SNP significantly increased the responsiveness of putative striatal MSNs in the dyskinetic striatum. These findings highlight the critical role of the NO signalling pathway in facilitating the responsiveness of striatal MSNs in both the intact and dyskinetic striata. The study suggests that SNP has the potential to enhance L‐DOPA's effects in the stepping test without exacerbating abnormal involuntary movements, thereby offering new possibilities for optimizing Parkinson's disease therapy. In conclusion, this study highlights the involvement of the NO signalling pathway in the pathophysiology of LIDs.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

Ribeiro,

Guimarães,

Bariotto‐dos‐Santos

et al. 2024

Eur J of Neuroscience

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“…A bar test was performed. MR1916 has good bioavailability and brain penetration in rats [43]; non-cataleptic doses previously increased striatal cAMP and cGMP levels and improved cognitive performance and motor control in models of schizophrenia [44] and dyskinesias [43,45]. MR1916 (synthesized by Mochida Pharmaceuticals) (0, 0.1, 0.4, and 0.8 µmol/kg) free base, dissolved in 10% (w/v) 2 -hydroxypropyl-β-cyclodextrin (HPBC, Thermo Fisher Scientific, Waltham, MA) in Nanopure water was injected intraperitoneally (1 mg/mL).…”

Section: Bar Testmentioning

confidence: 99%

Effects of the Phosphodiesterase 10A Inhibitor MR1916 on Alcohol Self-Administration and Striatal Gene Expression in Post-Chronic Intermittent Ethanol-Exposed Rats

Bertotto,

Lampson-Stixrud,

Sinha

et al. 2024

Cells

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Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats (n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers (Pde10a, Drd1, Drd2, Penk, and Tac1) and immediate-early genes (IEG) (Fos, Fosb, ΔFosb, and Egr1) in EtOH-naïve (n = 5–6/grp) and post-CIE (n = 6–8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1, Fos, and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking.

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“…PDE4 inhibition could have therapeutic potential in PD Arakawa (2020) 87 6-OHDA rat model • MR1916 (PDE10A inhibitor) reduced LID without affecting the antiparkinsonian effects induced by L-dopa Regulation of striatal cyclic nucleotides by PDE10A inhibition could be a useful therapeutic approach for LID Kim (2020) 67 MPTP mouse model • MP-10 (PF-2545920; ie, a PDE10A inhibitor) decreased dopaminergic cell death and microglial activation…”

Section: Parkinson's Diseasementioning

confidence: 99%

“… 85 Importantly, administration of the PDE inhibitor zaprinast (nonselective inhibitor of PDEs 5, 6, 9, 10, and 11) effectively reduced LID severity, preventing cyclic nucleotides level decrement. 85 Moreover, UK‐343664 (ie, a PDE5 inhibitor) and MR1916 (ie, a PDE10A inhibitor) have also been reported to attenuate LID in 6‐OHDA rats 86 , 87 and parkinsonian monkeys, 88 suggesting that PDE could, in fact, be targeted for preventing or treating LID in PD.…”

Section: Huntington's Diseasementioning

confidence: 99%

The Emerging Role of Phosphodiesterases in Movement Disorders

2021

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A BS TRACT: Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the hydrolysis and inactivation of the cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate, which act as intracellular second messengers for many signal transduction pathways in the central nervous system. Several classes of PDE enzymes with specific tissue distributions and cyclic nucleotide selectivity are highly expressed in brain regions involved in cognitive and motor functions, which are known to be implicated in neurodegenerative diseases, such as Parkinson's disease and Huntington's disease. The indication that PDEs are intimately involved in the pathophysiology of different movement disorders further stems from recent discoveries that mutations in genes encoding different PDEs, including PDE2A, PDE8B, and PDE10A, are responsible for rare forms of monogenic parkinsonism and chorea. We here aim to provide a translational overview of the preclinical and clinical data on PDEs, the role of which is emerging in the field of movement disorders, offering a novel venue for a better understanding of their pathophysiology. Modulating cyclic nucleotide signaling, by either acting on their synthesis or on their degradation, represents a promising area for development of novel therapeutic approaches. The study of PDE mutations linked to monogenic movement disorders offers the opportunity of better understanding the role of PDEs in disease pathogenesis, a necessary step to successfully benefit the treatment of both hyperkinetic and hypokinetic movement disorders.

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Ameliorative effects of a phosphodiesterase 10A inhibitor, MR1916 on l-DOPA-induced dyskinesia in parkinsonian rats

Cited by 8 publications

References 25 publications

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa‐induced dyskinesias

Effects of the Phosphodiesterase 10A Inhibitor MR1916 on Alcohol Self-Administration and Striatal Gene Expression in Post-Chronic Intermittent Ethanol-Exposed Rats

The Emerging Role of Phosphodiesterases in Movement Disorders

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