Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis

Schepers, Melissa; Paes, Dean; Tiane, Assia; Rombaut, Ben; Piccart, Elisabeth; Veggel, Lieve van; Gervois, Pascal; Wolfs, Esther; Lambrichts, Ivo; Brullo, Chiara; Bruno, Olga; Fedele, Ernesto; Ricciarelli, Roberta; ffrench‐Constant, Charles; Bechler, Marie E.; Schaik, Pauline van; Baron, Wia; Lefevere, Evy; Wasner, Kobi; Grünewald, Anne; Verfaillie, Cathérine; Baeten, Paulien; Broux, Bieke; Wieringa, Paul; Hellings, Niels; Prickaerts, Jos; Vanmierlo, Tim

doi:10.1016/j.bbi.2022.12.020

Cited by 23 publications

(23 citation statements)

References 108 publications

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“…In order to circumvent this pitfall, we investigated the potential of specific non-emetic PDE4B and PDE4D inhibitors, respectively A33 and Gebr32a. The PDE4B inhibitor A33 (3 mg/kg) and the PDE4D inhibitor Gebr32a (0.3 mg/kg) were administered at a dose previously demonstrated to diminish neuroinflammation or enhance myelin regeneration upon CNS pathology in the brain while circumventing emetic side effects [30]. We now show that the PDE4D inhibitor Gebr32a significantly improved functional recovery after SCI similarly to the pan PDE4 inhibitor roflumilast, whereas the PDE4B inhibitor A33 did not.…”

Section: Discussionmentioning

confidence: 77%

Amelioration of Functional and Histopathological Consequences after Spinal Cord Injury through Phosphodiesterase 4D (PDE4D) Inhibition

Schepers,

Hendrix,

Mussen

et al. 2023

Preprint

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Spinal cord injury (SCI) severely impacts the patient's quality of life. Two key strategies are currently being considered to improve clinical outcomes after SCI: modulation of the neuroinflammatory response, which exacerbates the primary injury, and stimulation of neuro-regenerative repair mechanisms to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.

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Section: Discussionmentioning

confidence: 77%

Amelioration of Functional and Histopathological Consequences after Spinal Cord Injury through Phosphodiesterase 4D (PDE4D) Inhibition

Schepers,

Hendrix,

Mussen

et al. 2023

Preprint

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“…In contrast, astrocyte reactivity can be affected and changed very quickly (within minutes to hours) in culture and therefore we choose to stimulate them for a maximum of 2 days. We would like to refer to our published protocols illustrating the time frame of these type of experiments 42–44 …”

Section: Methodsmentioning

confidence: 99%

“…We would like to refer to our published protocols illustrating the time frame of these type of experiments. [42][43][44] 2.9 | Immunocytochemistry:…”

Section: Opcs and Astrocytesmentioning

confidence: 99%

Therapeutic administration of mouse mast cell protease 6 improves functional recovery after traumatic spinal cord injury in mice by promoting remyelination and reducing glial scar formation

et al. 2023

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Traumatic spinal cord injury (SCI) most often leads to permanent paralysis due to the inability of axons to regenerate in the adult mammalian central nervous system (CNS). In the past, we have shown that mast cells (MCs) improve the functional outcome after SCI by suppressing scar tissue formation at the lesion site via mouse mast cell protease 6 (mMCP6). In this study, we investigated whether recombinant mMCP6 can be used therapeutically to improve the functional outcome after SCI. Therefore, we applied mMCP6 locally via an intrathecal catheter in the subacute phase after a spinal cord hemisection injury in mice. Our findings showed that hind limb motor function was significantly improved in mice that received recombinant mMCP6 compared with the vehicle-treated group. In contrast to our previous findings in mMCP6 knockout mice, the lesion size and expression

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“…In this context, the PDE4 isoenzyme is highly expressed in neurons, inflammatory and epithelial cells, and is involved in pulmonary, dermatological, and central nervous system diseases. In fact, PDE4Is show anti‐inflammatory ability in pre‐clinical models relevant to chronic obstructive pulmonary disease (COPD), [5–7] psoriasis, [8] and in neuro‐inflammation related disorders as multiple sclerosis [9] . PDE4 has four isotypes, PDE4A‐D.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, PDE4Is show anti-inflammatory ability in pre-clinical models relevant to chronic obstructive pulmonary disease (COPD), [5][6][7] psoriasis, [8] and in neuro-inflammation related disorders as multiple sclerosis. [9] PDE4 has four isotypes, PDE4A-D. Initially, PDE4B was reported as linked to anti-inflammatory role, while the PDE4I side effects, as vomiting, nausea, sedation and gastroesophageal reflexes, were attributed to PDE4D.…”

Section: Introductionmentioning

confidence: 99%

Scouting Different Phosphodiesterase 4 Inhibitor Chemotypes in Silico To Guide the Design of Anti‐inflammatory/Antioxidant Agents

et al. 2023

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During the last years, we developed a large library of new selective phosphodiesterase 4D inhibitors, maintaining the catechol portion of the well-known PDE4 inhibitor Rolipram, featuring different substitutions in place of the lactam group of this reference compound. Based on the X-ray analysis of PDE4 inhibitors (PDE4Is) previously synthesized by us and of naphthyridine-and naphthyridinone-containing derivatives exhibiting PDE4 inhibitory ability described in the literature, we designed and synthesized new compounds 1-3. All of them were screened in silico as putative PDE4Is, via molecular docking studies to exploit structural variation at the catechol group to gain further contacts especially with the flat aromatic residues (Phe506 and Phe538) of enzyme. Subsequent in silico prediction of ADMET properties and in vitro biological assays on platelets and endothelial cells are in good agreement with our previous data concerning the antioxidant/anti-inflammatory activity exhibited by our previous PDE4Is and similarly to other well-known PDE4Is.

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Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis

Cited by 23 publications

References 108 publications

Amelioration of Functional and Histopathological Consequences after Spinal Cord Injury through Phosphodiesterase 4D (PDE4D) Inhibition

Amelioration of Functional and Histopathological Consequences after Spinal Cord Injury through Phosphodiesterase 4D (PDE4D) Inhibition

Therapeutic administration of mouse mast cell protease 6 improves functional recovery after traumatic spinal cord injury in mice by promoting remyelination and reducing glial scar formation

Scouting Different Phosphodiesterase 4 Inhibitor Chemotypes in Silico To Guide the Design of Anti‐inflammatory/Antioxidant Agents

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