PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity

Rombaut, Ben; Kessels, Sofie; Schepers, Melissa; Tiane, Assia; Paes, Dean; Solomina, Yevgeniya; Piccart, Elisabeth; Hove, Daniël L.A. van den; Brône, Bert; Prickaerts, Jos; Vanmierlo, Tim

doi:10.7150/thno.50701

Cited by 16 publications

(6 citation statements)

References 209 publications

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“…In addition, pan-PDE4 inhibition also reduced the pro-inflammatory cytokine production of TNFα, IL-1β, iNOS, and NF-κβ [146]. Moreover, PDE4 inhibition has also been reported to enhance cognition and lead to neuroplasticity in AD as elaborated on in a review by Rombaut et al [138,147]. The effect of pan-PDE4 inhibition in rodent models of AD is similar to the effect seen in ischemic stroke.…”

Section: Functional Read-outsmentioning

confidence: 85%

Neuroinflammation in Ischemic Stroke: Inhibition of cAMP-Specific Phosphodiesterases (PDEs) to the Rescue

et al. 2021

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Ischemic stroke is caused by a thromboembolic occlusion of a major cerebral artery, with the impaired blood flow triggering neuroinflammation and subsequent neuronal damage. Both the innate immune system (e.g., neutrophils, monocytes/macrophages) in the acute ischemic stroke phase and the adaptive immune system (e.g., T cells, B cells) in the chronic phase contribute to this neuroinflammatory process. Considering that the available therapeutic strategies are insufficiently successful, there is an urgent need for novel treatment options. It has been shown that increasing cAMP levels lowers neuroinflammation. By inhibiting cAMP-specific phosphodiesterases (PDEs), i.e., PDE4, 7, and 8, neuroinflammation can be tempered through elevating cAMP levels and, thereby, this can induce an improved functional recovery. This review discusses recent preclinical findings, clinical implications, and future perspectives of cAMP-specific PDE inhibition as a novel research interest for the treatment of ischemic stroke. In particular, PDE4 inhibition has been extensively studied, and is promising for the treatment of acute neuroinflammation following a stroke, whereas PDE7 and 8 inhibition more target the T cell component. In addition, more targeted PDE4 gene inhibition, or combined PDE4 and PDE7 or 8 inhibition, requires more extensive research.

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Section: Functional Read-outsmentioning

confidence: 85%

Neuroinflammation in Ischemic Stroke: Inhibition of cAMP-Specific Phosphodiesterases (PDEs) to the Rescue

et al. 2021

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“…In DLPFC, we found 7 synaptic proteins that lost rhythmicity in OUD and 11 synaptic proteins that gained rhythmicity (Fig. 5D; e.g., USO1, NSDHL, PDE1C [101], Fig. 5E).…”

Section: Altered Diurnal Rhythms Of the Synaptic Proteome In Dlpfc An...mentioning

confidence: 93%

Circadian rhythm disruptions associated with opioid use disorder in the synaptic proteomes of the human dorsolateral prefrontal cortex and nucleus accumbens

Puig

Xue

Salisbury

et al. 2023

Preprint

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Opioid craving and the vulnerability to relapse is associated with severe and persistent disruptions to sleep and circadian rhythms. Investigations into the cellular and molecular pathways in the human brain underlying the relationship between circadian rhythms and OUD remain limited. In human subjects with OUD, previous transcriptomics work implicated a role for circadian regulation of synaptic processes in key cognitive- and reward-related brain regions, dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc). To provide further insights into the synaptic alterations associated with OUD, we used mass-spectrometry based proteomics to deeply profile protein alterations in tissue homogenates and synaptosomes from both NAc and DLPFC of unaffected and OUD subjects. Between unaffected and OUD subjects, we identified 43 differentially expressed (DE) proteins in NAc homogenates and 55 DE proteins in DLPFC homogenates. In synaptosomes, we found 56 DE proteins in NAc of OUD subjects and 161 DE proteins in DLPFC. Examining synaptosome enrichment of specific proteins enabled us to identify brain region- and synapse-specific pathway alterations in NAc and DLPFC associated with OUD. Across both regions, we found OUD-associated protein alterations primarily in pathways involved in GABAergic and glutamatergic synaptic functions, as well as circadian rhythms. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24-hour cycle, we were able to map circadian-related changes in the synaptic proteomes in NAc and DLPFC associated with OUD. In OUD, TOD analysis revealed significant circadian changes in endoplasmic reticulum to Golgi vesicle-mediated transport and protein membrane trafficking in NAc synapses, accompanied by changes in platelet derived growth factor receptor beta signaling in DLPFC synapses. Together, our results lend further support for molecular disruption of circadian regulation of synaptic signaling in the human brain as a key factor in opioid addiction.

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“…Increasing evidence has demonstrated that activated PDE2A hydrolyzes cAMP and terminates signaling delivery [27]. The balance of the cAMP concentration plays an important role in central nervous system development [28,29]. We examined the concentration of cAMP in gliomas when PDE2A was overexpressed and found that PDE2A greatly reduced cAMP generation (Fig.…”

Section: Pde2a Decreased Camp Generation and Suppressed Wnt/β-catenin Signaling To Regulate Gsc Stemnessmentioning

confidence: 99%

miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

Ren

Zhao

et al. 2021

Int. J. Biol. Sci.

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Rationale:The malignant phenotypes of glioblastomas (GBMs) are primarily attributed to glioma stem cells (GSCs). Our previous study and other reports have suggested that both miR-139 and its host gene PDE2A are putative antitumor genes in various cancers. The aim of this study was to investigate the roles and mechanisms of miR-139/PDE2A in GSC modulation. Methods: Clinical samples were used to determine miR-139/PDE2A expression. Patient-derived glioma stem-like cells (PD-GSCs) were stimulated for immunofluorescent staining, sphere formation assays and orthotopic GBM xenograft models. Bioinformatic analysis and further in vitro experiments demonstrated the downstream molecular mechanisms of miR-139 and PDE2A. OX26/CTX-conjugated PEGylated liposome (OCP) was constructed to deliver miR-139 or PDE2A into glioma tissue specifically. Results: We demonstrated that miR-139 was concomitantly transcribed with its host gene PDE2A. Both PDE2A and miR-139 indicated better prognosis of gliomas and were inversely correlated with GSC stemness. PDE2A or miR-139 overexpression suppressed the stemness of PD-GSCs. FZD3 and β-catenin, which induced Wnt/β-catenin signaling activation, were identified as targets of miR-139 and mediated the effects of miR-139 on GSCs. Meanwhile, PDE2A suppressed Wnt/β-catenin signaling by inhibiting cAMP accumulation and GSK-3β phosphorylation, thereby modulating the self-renewal of PD-GSCs. Notably, Notch1, which is also a target of miR-139, suppressed PDE2A/miR-139 expression directly via downstream Hes1, indicating that miR-139 promoted its own expression by the miR-139-Notch1/Hes1 feedback circuit. Expectedly, targeted overexpression miR-139 or PDE2A in glioma with OCP system significantly repressed the stemness and decelerated glioma progression. Conclusions: Our findings elaborate on the inhibitory functions of PDE2A and miR-139 on GSC stemness and tumorigenesis, which may provide new prognostic markers and therapeutic targets for GBMs.

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PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity

Cited by 16 publications

References 209 publications

Neuroinflammation in Ischemic Stroke: Inhibition of cAMP-Specific Phosphodiesterases (PDEs) to the Rescue

Neuroinflammation in Ischemic Stroke: Inhibition of cAMP-Specific Phosphodiesterases (PDEs) to the Rescue

Circadian rhythm disruptions associated with opioid use disorder in the synaptic proteomes of the human dorsolateral prefrontal cortex and nucleus accumbens

miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

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