Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival

Medina‐Rodriguez, Eva M.; Arenzana, Francisco Javier; Pastor, Jesús; Redondo, Miriam; Palomo, Valle; Sola, Rafael G.; Gil, Carmen; Martı́nez, Ana; Bribián, Ana; Castro, Fernando de

doi:10.1007/s00018-013-1340-2

Cited by 57 publications

(54 citation statements)

References 78 publications

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“…However, inhibition of GSK3 alone, with TDZD8, shows no effects on OPC proliferation or differentiation, in spite of improved OPC survival. Previous results exclusively targeting inhibition of PDE7 with the quinazoline TC3.6, enhances OPC differentiation less efficiently than the dual inhibitor VP1.1539. The mechanism of action of dual PDE7-GSK3 inhibition on remyelination is likely specific to OPCs, as treatment did not modify microglial or astrocyte number, at least in the cuprizone in viv o model.…”

Section: Discussionmentioning

confidence: 85%

“…Previously, we have shown that PDE7 is expressed in OPCs and that PDE7 inhibitors (including VP1.15) enhance OPC differentiation and survival in vitro 39. However, the dual PDE7-GSK3 inhibitor VP3.15 was designed and synthesized as a drug-like molecule with a better safety profile, and improved pharmacodynamic and pharmacokinetic properties3643 (Tables 1 and 2).…”

Section: Resultsmentioning

confidence: 99%

“…We isolated OPCs, as previously described3977. Briefly, a stock papain solution was prepared containing (0.9 g/ml; Worthington Biochemical), L-cysteine (0.2 mg/ml; Sigma), and EDTA (0.2 mg/ml; Sigma) in Hank’s Balanced Salt Solution (HBSS; Invitrogen) without Ca 2+ and Mg2.…”

Section: Methodsmentioning

confidence: 99%

“…Although their effect on remyelination remains unknown, previous data from our group have shown that PDE7 inhibitors favour the differentiation and survival of mouse cortical OPCs and the differentiation of adult human OPCs in vitro 39. PDE7 inhibition leads to an enhancement of the intracellular levels of cAMP without intolerable gastrointestinal side effects40, making them potential and attractive therapeutic agents.…”

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confidence: 99%

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Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

Medina‐Rodriguez

Bribián

Boyd

et al. 2017

Sci Rep

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Multiple Sclerosis (MS) is a neurodegenerative disease where immune-driven demyelination occurs with inefficient remyelination, but therapies are limited, especially those to enhance repair. Here, we show that the dual phosphodiesterase (PDE)7- glycogen synthase kinase (GSK)3 inhibitor, VP3.15, a heterocyclic small molecule with good pharmacokinetic properties and safety profile, improves in vivo remyelination in mouse and increases both adult mouse and adult human oligodendrocyte progenitor cell (OPC) differentiation, in addition to its immune regulatory action. The dual inhibition is synergistic, as increasing intracellular levels of cAMP by cyclic nucleotide PDE inhibition both suppresses the immune response and increases remyelination, and in addition, inhibition of GSK3 limits experimental autoimmune encephalomyelitis in mice. This combination of an advantageous effect on the immune response and an enhancement of repair, plus demonstration of its activity on adult human OPCs, leads us to propose dual PDE7-GSK3 inhibition, and specifically VP3.15, as a neuroprotective and neuroreparative disease-modifying treatment for MS.

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Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

Medina‐Rodriguez

Bribián

Boyd

et al. 2017

Sci Rep

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“…Medina-Rodriguez et al (2013) showed that PDE7 inhibition could enhance oligodendrocyte precursor (OPC) survival and accelerate their differentiation in vitro. Treatment with PDE7 inhibitors TC3.6 and VP1.15 also showed promising results for remyelination [295]. Furthermore, Gonzalez-Garcia et al reported the effect of Rolipram and TC3.6 on experimental autoimmune encephalomyelitis (EAE).…”

Section: The Utility Of Pde Inhibitors For Neuroprotection and Neumentioning

confidence: 99%

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

Knott

Assi

Rao

et al. 2017

IJMS

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A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic.

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R‐Ras1 and R‐Ras2 regulate mature oligodendrocyte subpopulations

Alcover‐Sanchez,

Garcia‐Martin,

Paleo‐García

et al. 2024

Glia

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In the mammalian central nervous system, axonal myelination, executed by mature oligodendrocytes (MOLs), enables rapid neural transmission. Conversely, myelin deficiencies are hallmark features of multiple sclerosis, optic neuromyelitis, and some leukodystrophies. Recent studies have highlighted that MOLs are heterogeneous; however, how MOL subpopulations are specified and balanced in physiological settings is poorly understood. Previous works have demonstrated an essential role of the small GTPases R‐Ras1 and R‐Ras2 in the survival and myelination of oligodendrocytes. In this study, we aimed to determine how R‐Ras1 and R‐Ras2 contribute to the heterogeneity of MOL subpopulations. Our results evidence that R‐Ras1 and R‐Ras2 affect specification into the distinct subpopulations MOL1, MOL2, and MOL5/6, which in turn vary in their dependence of these GTPases. In R‐Ras1 and/or R‐Ras2 mutant mice, we observed an increase in the MOL1 subpopulation and a decrease in the MOL2 and MOL5/6 subpopulations. We identified R‐Ras1 and R‐Ras2 as key elements in balancing the heterogeneity of MOLs. Our results contribute to the understanding of the molecular mechanisms underlying the heterogeneity of MOLs and the myelination processes, which is crucial for innovating regenerative therapies for nervous system disorders.

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Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival

Cited by 57 publications

References 78 publications

Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

Promoting in vivo remyelination with small molecules: a neuroreparative pharmacological treatment for Multiple Sclerosis

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

R‐Ras1 and R‐Ras2 regulate mature oligodendrocyte subpopulations

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