Role of phosphodiesterases in neurological and psychiatric disease

Hebb, Andrea L.O.; Robertson, Harold A.

doi:10.1016/j.coph.2006.08.014

Cited by 71 publications

(51 citation statements)

References 66 publications

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“…In fact, cAMP and cGMP play their phosphodiesterase (PDE)-inhibitory role by activating cell cycle proteins, after the imbalance between antioxidants and oxidation that is initiated under chronic stress [17]. Medications that raise the levels of cAMP can reduce the levels of proinflammatory mediators and elevate anti-inflammatory mediator levels.…”

Section: Introductionmentioning

confidence: 99%

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

El-Haggar

Eissa

Mostafa

et al. 2018

Psychother Psychosom

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Background: There is evidence for an association between major depressive disorder (MDD) and both inflammatory and phosphodiesterase (PDE) pathways. This study aimed to evaluate the adjunct role of the PDE inhibitor pentoxifylline (PTX), a compound with anti-inflammatory properties, in the treatment of adult patients with MDD. Methods: This was a prospective, 12-week, double-blind study of parallel groups. Eighty adult outpatients who met the DSM-IV criteria for MDD participated in the trial. Patients were required to have a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 18. Patients were allocated randomly: 40 received escitalopram 20 mg/day plus placebo while the other 40 received escitalopram 20 mg/day plus PTX (400 mg b.i.d.). Patients were assessed by a psychiatrist at baseline, and 4, 8, and 12 weeks after the medication had been started. The serum levels of TNF-α, IL-6, IL-10, BDNF, 8-OHdG, and serotonin were measured at baseline and after therapy. Results: After 8 and 12 weeks, the PTX group showed a statistically significantly greater improvement in HAM-D score compared to the control group (least squares mean difference [LSMD] –3.29, p = 0.000 and LSMD –3.49, p = 0.000, respectively). Moreover, the PTX group showed a statistically significantly greater reduction in the serum levels of TNF-α, IL-6, IL-10, and 8-OHdG along with a statistically significant increase in the levels of BDNF and serotonin in comparison with the control group after the treatment. Conclusion: The findings of this study suggest that PTX could be a promising adjunct to antidepressants in the treatment of MDD patients.

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Section: Introductionmentioning

confidence: 99%

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

El-Haggar

Eissa

Mostafa

et al. 2018

Psychother Psychosom

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“…Even so, chemical inhibitors of PDEs, and in some cases chemical activators, are seen as potential therapeutic compounds for the treatment of a variety of conditions including neurological diseases such as anxiety, depression, and Alzheimer's disease; inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension; metabolic diseases such as diabetes and obesity; and other conditions such as memory loss, chronic lymphocytic leukemia, prostate cancer, and erectile dysfunction. [2][3][4][5][6][7][8][9] We describe here the development of a cell-based screen for identifying both chemical inhibitors and activators of cAMP PDEs using a simple growth assay in the fission yeast…”

Section: Introductionmentioning

confidence: 99%

Development of a Fission Yeast-Based High-Throughput Screen to Identify Chemical Regulators of cAMP Phosphodiesterases

et al. 2008

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Cyclic nucleotide phosphodiesterases (PDEs) comprise a superfamily of enzymes that serve as drug targets in many human diseases. There is a continuing need to identify high-specificity inhibitors that affect individual PDE families or even subtypes within a single family. The authors describe a fission yeast-based high-throughput screen to detect inhibitors of heterologously expressed adenosine 3′,5′-cyclic monophosphate (cAMP) PDEs. The utility of this system is demonstrated by the construction and characterization of strains that express mammalian PDE2A, PDE4A, PDE4B, and PDE8A and respond appropriately to known PDE2A and PDE4 inhibitors. High-throughput screens of 2 bioactive compound libraries for PDE inhibitors using strains expressing PDE2A, PDE4A, PDE4B, and the yeast PDE Cgs2 identified known PDE inhibitors and members of compound classes associated with PDE inhibition. The authors verified that the furanocoumarin imperatorin is a PDE4 inhibitor based on its ability to produce a PDE4-specific elevation of cAMP levels. This platform can be used to identify PDE activators, as well as genes encoding PDE regulators, which could serve as targets for future drug screens. (Journal of Biomolecular Screening 2008:62-71)

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“…PDE10A is therefore an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function (9), including Parkinson disease (10), Huntington disease (11,12), schizophrenia (13,14), memory disorders (15), depression, and addiction (16). Animal models of Huntington disease have shown that PDE10A expression is an extremely sensitive marker of striatal neuron loss (12,17), and Parkinson disease models have been used to demonstrate possible roles of PDE10A in both the early motor symptoms and the late complications of Parkinson disease due to prominent PDE10A-dependent dysregulation of corticostriatal signaling (10,18).…”

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confidence: 99%

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: ¹⁸F-MNI-659 and ¹⁸F-MNI-654

et al. 2014

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Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ( 18 F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ( 18 F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A. Methods: Eleven healthy volunteers participated in this study ( 18 F-MNI-654 test-retest, 2 men; 18 F-MNI-659 test-retest, 4 men and 1 woman; 18 F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for 18 F-MNI-654 and over 3.5 h for 18 F-MNI-659, and pharmacokinetic modeling with plasma-and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for 18 F-MNI-659 and radiation dosimetry estimated with OLINDA. Results: Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time-activity data demonstrated that 18 F-MNI-654 kinetics were much slower than 18 F-MNI-659 kinetics. For 18 F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BP ND ), supporting noninvasive quantification, with test-retest variability less than 10% and intraclass correlation greater than 0.9. The 18 F-MNI-659 effective dose was estimated at 0.024 mSv/MBq. Conclusion: PET imaging in the human brain with 2 novel PDE10A 18 F tracers is being reported. Noninvasive quantification of 18 F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, 18 F-MNI-659 kinetics are fast enough for a good estimate of BP ND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, 18 F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.

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Role of phosphodiesterases in neurological and psychiatric disease

Cited by 71 publications

References 66 publications

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

Development of a Fission Yeast-Based High-Throughput Screen to Identify Chemical Regulators of cAMP Phosphodiesterases

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: ¹⁸F-MNI-659 and ¹⁸F-MNI-654

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Role of phosphodiesterases in neurological and psychiatric disease

Cited by 71 publications

References 66 publications

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

Development of a Fission Yeast-Based High-Throughput Screen to Identify Chemical Regulators of cAMP Phosphodiesterases

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: 18F-MNI-659 and 18F-MNI-654

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In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: ¹⁸F-MNI-659 and ¹⁸F-MNI-654