Phosphodiesterase‐5 Inhibitors: Action on the Signaling Pathways of Neuroinflammation, Neurodegeneration, and Cognition

Peixoto, Christina Alves; Nunes, Ana Karolina Santana; García‐Osta, Ana

doi:10.1155/2015/940207

Cited by 78 publications

(76 citation statements)

References 232 publications

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“…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] . Glycogen synthase kinase-3 (GSK-3) as a downstream target of Akt is inhibited by activation of Akt by inducing its phosphorylation.…”

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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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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“…PDE5 inhibitors including sildenafil, tadalafil, and vardenafil, are primarily used as pharmacological agents for the treatment of erectile dysfunction, but they also have a potential therapeutic application for the treatment of neurovascular dysfunction, neuroinflammatory and neurodegenerative diseases by inducing accumulation of cGMP and activation of cGMP dependent protein kinase, e.g., protein kinase G, signaling pathways [236,237]. Clinical study demonstrates that PDE5 inhibitors are safe and generally well tolerated with no serious side effects in patients.…”

Section: Phosphodiesterase-5 Inhibitorsmentioning

confidence: 99%

Diabetic Cardiovascular Neuropathy

Serhiyenko¹,

Publisher²,

Serhiyenko³

2018

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Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus, that is strongly associated with increased risk of cardiovascular mortality. Although it is common complication, the significance of CAN has not been fully appreciated and there are no unified treatment algorithms for today. In this review we have analyzed the existing data about the known risk factors, screening and diagnostic algorithm, staging of CAN and possible treatment, including effectiveness of lifestyle modification, intensive glycemic control; treatment of diabetic dyslipidemia; antioxidants; vitamins; correction of vascular endothelial dysfunction; prevention and treatment of thrombosis; treatment of orthostatic hypotension. Conclusion 88References 89 Abbreviations list 108Victoria Serhiyenko, Alexandr Serhiyenko 7 ABOUT THE AUTHORSVictoria A Serhiyenko, MD, PhD in Medicine Sciences, DMSc, Associate Professor of the Department of Endocrinology, Lviv National Medical University named by Danylo Halitsky, Lviv, Ukraine. At the moment she is working on the problems concerted with the revelation of the correlating connections between activities of some metabolic, hormonal and other parameter, and state of the proand anti-inflammatory factors in blood in patients with diabetes mellitus which depends on the character of diabetic complications. The second part of his scientific work is the research of the effectively of the benfotiamine in treatment and prevention of diabetic complications in clinical practice.Victoria Serhiyenko has published 238 scientific papers. These works are devoted to the problems of pathogenesis, diagnosis and treatment, prevention of the diabetic cardiovascular autonomic neuropathy.Alexandr A Serhiyenko, MD, PhD in Medicine Sciences, DMSc, Professor of the Department of Endocrinology, Lviv National Medical University named by Danylo Halitsky, Lviv, Ukraine. At the moment he is working on the problems concerted with the revelation of the correlating connections between activities of some metabolic parameters in patients with diabetes mellitus which depends on the character of diabetic complications. The second part of her scientific work is the research of the effectively of the benfotiamine in treatment and prevention of diabetic complications in clinical practice.Alexandr Serhiyenko has published 613 scientific papers. These works are devoted to the problems of pathogenesis, diagnosis and treatment, prevention of the diabetic complications.

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“…Alternatively, some unrelated drugs may work to combat AD pathologies. For example, phosphodiesterase‐5 inhibitors (including sildenafil, vardenafil, tadalafil), used to treat pulmonary hypertension, have demonstrated an ability to reduce expression of amyloid precursor protein cleaving enzymes, leading to sustained reduction of Aβ levels [46]. In a transgenic murine model expressing human amyloid precursor protein and presenilin‐1, phosphodiesterase‐5 inhibitors halted and even rescued memory deficits, in addition to alleviating AD pathologies [47].…”

Section: Clinic Day Variablesmentioning

confidence: 99%

The hidden variables problem in Alzheimer's disease clinical trial design

Liyanage

Santos

Weaver

2018

A&D Transl Res & Clin Interv

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As the leading cause of dementia worldwide, Alzheimer's disease has garnered intense academic and clinical interest. Yet, trials in search of a disease-modifying therapy have failed overwhelmingly. We suggest that, in part, this may be attributable to the influence of disruptive variables inherent to the framework of a clinical trial. Specifically, we observe that everyday factors such as diet, education, mental exertion, leisure participation, multilingualism, sleep, trauma, and physical activity, as well as clinical/study parameters including environment, family coaching, concurrent medications, and illnesses may serve as potent confounders, disruptors, or sources of bias to an otherwise significant drug-disease interaction. This perspective briefly summarizes the potential influence of these hidden variables on the outcomes of clinical trials and suggests strategies to abate their impact.

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Phosphodiesterase‐5 Inhibitors: Action on the Signaling Pathways of Neuroinflammation, Neurodegeneration, and Cognition

Cited by 78 publications

References 232 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

Diabetic Cardiovascular Neuropathy

The hidden variables problem in Alzheimer's disease clinical trial design

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