Stimulation of Neural Stem Cell Proliferation by Inhibition of Phosphodiesterase 5

Santos, Ana Isabel; Carreira, Bruno P.; Nobre, Rui Jorge; Carvalho, Caetana M.; Araújo, Inês M.

doi:10.1155/2014/878397

Cited by 28 publications

(19 citation statements)

References 43 publications

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“…Several studies have also reported the proneurogenic effect of sildenafil on SVZ-derived cell culture [33] and in animal models of brain injury [32]. Santos et al [17] have also recently reported that three different PDE5 inhibitors are able to increase the levels of cGMP in SVZ cells and stimulate cell proliferation through the ERK/MAPK pathway in adult mice. However, to our knowledge, the effect of iNO on the developing SVZ was never investigated.…”

Section: Discussionmentioning

confidence: 99%

“…This study suggests that modulating the cell fate of endogenous NPCs in the developing brain could be an interesting strategy to promote repair. In addition, increasing evidence supports the relationship between the level of guanosine 3′,5′ cyclic monophosphate (cGMP), the main effector of NO biological effects, and the ability of the SVZ to produce NPCs [17]. Here, we ask the question whether iNO could promote the proliferation of NPCs within the SVZ in the uninjured developing brain.…”

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat

Duy¹,

Pham²,

Pansiot³

et al. 2015

Dev Neurosci

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Several lines of evidence demonstrate that inhaled nitric oxide (iNO) not only acts locally on the pulmonary vasculature but also has remote effects on the mature and developing brain under basal or pathological conditions by modulating cerebral blood flow and microvascularization, white matter maturation, inflammation, and subsequent brain repair. Previously, consistent studies demonstrated that increased levels of guanosine 3′,5′ cyclic monophosphate (cGMP), the main effector of biological effect induced by nitric oxide (NO), significantly augment proliferation and neuronal differentiation of adult neural progenitor cells (NPCs). In the present study, we ask the question whether iNO could promote the proliferation of NPCs in the uninjured developing brain. We first reported that iNO exposure at a concentration of 20 ppm during the first 7 days of life was associated with a significant but transient elevation of brain cGMP concentration 2 h after the onset of iNO exposure and a subsequent increase in myelin content of the developing white matter at postnatal day (P) 10. Using BrDu labelling and colabelling with specific cell-type markers we found that iNO exposure of rat pups results in an increased NPC proliferation in several layers of the subventricular zone (SVZ) at both early (30 h) and late (P7) time points. These proliferating NPCs were found to be sustainably viable and subsequently differentiated into oligodendroglial cells in the developing white matter and cortex. We also found that NG2 immunoreactivity around vessel walls, labeling pericyte cells, was increased in NO-exposed rat pups in the periventricular SVZ. In conclusion, iNO appears to act on oligodendrocyte progenitor cells, leading to increased density of mature oligodendrocytes and myelin content in the immature rat brain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat

Duy¹,

Pham²,

Pansiot³

et al. 2015

Dev Neurosci

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“…Indenopyrazole 21, a compound containing the indenopyrazole framework, was found to strongly inhibit HIF-1α transcriptional activity without affecting HIF-1α protein accumulation and HIF-1 heterodimerization 65. YC-1, an antiplatelet aggregation agent, was shown to dissociate the binding of HIFα T-CAD to p300 co-activator, leading to the repression of HIF transcriptional activity; YC-1 could also impair HIFα protein accumulation 2666. FM19G11, a novel chemical entity, significantly repressed p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation, by inhibiting histone acetylation 5567…”

Section: Hif Inhibitors For Cancer Therapymentioning

confidence: 99%

Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy

2017

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Hypoxia is frequently observed in solid tumors and also one of the major obstacles for effective cancer therapies. Cancer cells take advantage of their ability to adapt hypoxia to initiate a special transcriptional program that renders them more aggressive biological behaviors. Hypoxia-inducible factors (HIFs) are the key factors that control hypoxia-inducible pathways by regulating the expression of a vast array of genes involved in cancer progression and treatment resistance. HIFs, mainly HIF-1 and -2, have become potential targets for developing novel cancer therapeutics. This article reviews the updated information in tumor HIF pathways, particularly recent advances in the development of HIF inhibitors. These inhibitors interfere with mRNA expression, protein synthesis, protein degradation and dimerization, DNA binding and transcriptional activity of HIF-1 and -2, or both. Despite efforts in the past two decades, no agents directly inhibiting HIFs have been approved for treating cancer patients. By analyzing results of the published reports, we put the perspectives at the end of the article. The therapeutic efficacy of HIF inhibitors may be improved if more efforts are devoted on developing agents that are able to simultaneously target HIF-1 and -2, increasing the penetrating capacity of HIF inhibitors, and selecting suitable patient subpopulations for clinical trials.

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“…Wang et al [11] were able to show that sildenafil increased phosphorylated Akt, which was associated with increases in phosphorylated GSK-3 and induction of neurogenesis in adult neural progenitor cells suggesting an important role of GSK-3 in neurogenesis. These effects of sildenafil on phosphorylated Akt are specific, as sildenafil did not change expression of phosphorylated ERK1/2 [11,12] . In addition, GSK-3 is also an important component of Wnt/β-catenin pathway signaling, which regulates neurogenesis during development [13,14] .…”

Section: Introductionmentioning

confidence: 99%

Sildenafil Enhances Quantity of Immature Neurons and Promotes Functional Recovery in the Developing Ischemic Mouse Brain

Engels

Elting²,

Braun³

et al. 2017

Dev Neurosci

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Background: Hypoxic-ischemic (HI) injury to the developing brain occurs in 1 out of 1,000 live births and remains a major cause of significant morbidity and mortality. A large number of survivors suffer from long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after HI insult are not clearly understood, and preventive measures or clinical treatments are nonexistent or not sufficiently effective in the clinical setting. Sildenafil as a specific phosphodiesterase 5 inhibitor leads to increased levels of the second messenger cyclic guanosine monophosphate (cGMP) and promotes functional recovery and neurogenesis after ischemic injury to the adult brain. Objective: Here, we investigated the effect of sildenafil treatment on activation of intracellular signaling pathways, histological and neurogenic response including functional recovery after an ischemic insult to the developing brain. Design/Methods: Nine-day-old C57BL/6 mice were subjected either to sham operation or underwent ligation of the right common carotid artery followed by hypoxia (8%) for 60 min. Animals were either administered sildenafil (10 mg/kg, i.p.) or vehicle 2 h after hypoxia. A subgroup of animals received multiple injections of 10 mg/kg daily on 5 consecutive days. Pups were either perfusion fixed at postnatal days 14 or 47 for immunohistochemical analysis, or brains were dissected 2, 6, 12, and 24 h after the end of hypoxia and analyzed for cGMP, pAkt, pGSK-3β, and β-catenin by means of ELISA or immunoblotting. In addition, behavioral studies using the wire hang test and elevated plus maze were conducted 21 and 38 days after HI injury. Results: Based on cresyl violet staining, single or multiple sildenafil injections did not reveal any differences in injury scoring compared to sham animals. However, cerebral levels of cGMP were altered after sildenafil therapy. Treatment significantly increased numbers of immature neurons, as indicated by doublecortin immunoreactivity in the ipsilateral subventricular zone and striatum. In addition, animals treated with sildenafil after HI insult demonstrated improved functional recovery. pAkt, pGSK-3β, and β-catenin levels vary after HI injury but additional sildenafil treatment had no impact on protein expression compared to the level of sham controls. Conclusions: Here, we report that treatment with sildenafil after HI insult did not improve histological brain injury scores. Nevertheless, our results suggest involvement of the cGMP and PI3K/Akt/GSK-3β signaling pathway with promotion of a neurogenic response and reduction of neurological deficits. In summary, sildenafil may have a role in promoting recovery from HI injury in the developing brain.

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Stimulation of Neural Stem Cell Proliferation by Inhibition of Phosphodiesterase 5

Cited by 28 publications

References 43 publications

Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat

Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat

Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy

Sildenafil Enhances Quantity of Immature Neurons and Promotes Functional Recovery in the Developing Ischemic Mouse Brain

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