Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain

Moretti, Raffaella; Leger, Pierre‐Louis; Besson, Valérie; Csaba, Zsolt; Pansiot, Julien; Criscio, Lorena Di; Gentili, Andrea; Titomanlio, Luigi; Bonnin, Philippe; Baud, Olivier; Charriaut‐Marlangue, Christiane

doi:10.1186/s12974-016-0560-4

Cited by 52 publications

(50 citation statements)

References 35 publications

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“…Data suggest that by 2-6 h after HI insult blood flow was restored to near normal in all brain regions of neonatal mice [22] . Studies using acute applications of sildenafil exhibit an influence on the distribution of brain perfusion with enhanced blood flow to the ischemic hemisphere in the neonatal rat [7] but not in neonatal [8] and adult mice [23] . Whereas lesion volumes remained unchanged after middle cerebral artery occlusion followed by PDE5 inhibition in adult mice [23,24] , the degree of tissue loss decreased after 8 days in neonatal mice injured by permanent middle cerebral artery occlusion [8] .…”

Section: Discussionmentioning

confidence: 99%

“…Studies using acute applications of sildenafil exhibit an influence on the distribution of brain perfusion with enhanced blood flow to the ischemic hemisphere in the neonatal rat [7] but not in neonatal [8] and adult mice [23] . Whereas lesion volumes remained unchanged after middle cerebral artery occlusion followed by PDE5 inhibition in adult mice [23,24] , the degree of tissue loss decreased after 8 days in neonatal mice injured by permanent middle cerebral artery occlusion [8] . In our model, results revealed no improvement in histological scoring after sildenafil treatment independently of the frequency of injections, and we did not detect any hindrance of progression, apparent by an increased injury score at P47 suggesting that sildenafil does not prevent lesion enlargement.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, sildenafil treatment in postnatal day 7 (P7) rats and P9 mice reduced brain damage after HI insult but dosing and timing of administration after hypoxia-ischemia seem to be critical. Sildenafil at lower doses is neuroprotective to the developing brain whereas in higher doses it increases infarct volume and mortality suggesting a narrow window of opportunity [7,8] . Mechanisms of action for cGMP and sildenafil on neurogenesis and differentiation of neuronal stem cells are not well defined.…”

Section: Introductionmentioning

confidence: 99%

“…Mechanisms of action for cGMP and sildenafil on neurogenesis and differentiation of neuronal stem cells are not well defined. Induction of cerebral vasodilation by PDE5 inhibition after HI injury as a potential mechanism seems to be species dependent and does not fully explain the neuroprotective properties of sildenafil [7][8][9] . Elevated levels of cGMP induced by sildenafil treatment lead to activation of downstream targets which have fundamental roles in neurogenesis and synaptic plasticity such as the cGMP/PKG/CREB/BDNF and PI3K/Akt/GSK-3β signaling pathways [10] .…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Associated with these beneficial effects, sildenafil had anti-inflammatory effects, reducing astrogliosis and GFAP-positive cell density and decreasing microglial density. A very recent study by Moretti et al [204] also demonstrated that sildenafil modulates neuroinflammation in the ischemia model induced in C57BL/6 mice P9 pups by permanent middle cerebral artery occlusion. Animals were treated with a single dose of sildenafil (Viagra ® , Pfizer, 10 mg/kg i.p., given 5 min after artery occlusion), which provided a reduction of the mean lesion 8 days after ischemia; also, it reduced the number of GFAP-positive cells, decreased microglial density, and modulated the M1 and M2 profiles of microglia/macrophages in the late phase after ischemia.…”

Section: Strokementioning

confidence: 90%

The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

Peixoto¹,

Nunes²,

Rapôso³

2017

Mechanisms of Neuroinflammation

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The nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling appears to play a key role in inhibiting neuroinflammation and preventing the activation of a proapoptotic pathway, thereby promoting neural cell survival. In addition, evidence indicates that cGMP/protein kinase G (PKG) pathway is involved in the modulation of glial cell activity. Phosphodiesterase 5 (PDE5), which hydrolyzes cGMP in the inactive form, 5ʹGMP, is present throughout the body and brain and has emerged as a potential therapeutic target for diseases related to neuroinflammatory and neurodegenerative processes, since their inhibition leads to accumulation of cGMP. The objective of this chapter is to review current knowledge of NO/cGMP signaling pathways on neuroinflammation and the potential therapeutic use of PDE5 inhibitors (PDE5-Is) in neurological diseases. The extensive, while recent, literature on the effects of PDE-Is on Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and stroke has been reviewed.

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Monitoring the apical growth characteristics of hairy roots using non‐invasive laser speckle contrast imaging

Schott

Bley

Walter

et al. 2021

Engineering in Life Sciences

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Hairy roots are used to produce plant agents and additives. Due to their heterogeneous structure and growth characteristics, it is difficult to determine growthrelated parameters continuously and in real time. Laser speckle contrast analysis is widely used as a non-destructive measurement technique in material testing or in medical technology. This type of analysis is based on the principle that moving objects or particles cause fluctuations in stochastic interference patterns known as speckle patterns. They are formed by the random backscattering of coherent laser light on an optically rough surface. A Laser Speckle Imager, which is well established for speckle studies of hemodynamics, was used for the first time for non-invasive speckle measurements on hairy roots to study dynamic behavior in plant tissue. Based on speckle contrast, a specific flux value was defined to map the dynamic changes in the investigated tissue. Using this method, we were able to predict the formation of lateral strands and to identify the growth zone in the apical root region, as well as dividing it into functional regions. This makes it possible to monitor physiological processes in the apical growth zone in vivo and in real time without labeling the target structures.

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Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain

Cited by 52 publications

References 35 publications

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

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

The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

Monitoring the apical growth characteristics of hairy roots using non‐invasive laser speckle contrast imaging

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