Dataset Information

Neuroprotection by sildenafil: neuronal networks potentiation in acute experimental stroke.

ABSTRACT:

Aims

Sildenafil, a phosphodiesterase type 5 inhibitor, has been found to produce functional recovery in ischemic rats by increasing the cGMP level and triggering neurogenesis. The aim of this study was to investigate further sildenafil mechanisms.

Methods

Male Sprague-Dawley rats underwent middle cerebral artery occlusion and reperfusion, followed by intraperitoneal or intravenous treatment of sildenafil starting 2 h later. Behavioral tests were performed on day 1 or day 7 after reperfusion, while cerebral infarction, edema, Nissl staining, Fluoro-Jade B staining, and electron microscopy studies were carried out 24 h poststroke. The cGMP-dependent Nogo-66 receptor (Nogo-R) pathway, synaptophysin, PSD-95/neuronal nitric oxide synthases (nNOS), brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB), and nerve growth factor (NGF)/tropomyosin-related kinase A (TrkA) were measured.

Results

Sildenafil enhanced neurological recovery and inhibited infarction, even following delayed administration 4 h after stroke onset. Furthermore, sildenafil reduced the loss of neurons and modulated the expressions of the cGMP-dependent Nogo-R pathway. Moreover, sildenafil protected the structure of synapses and mediated the expressions of synaptophysin, PSD-95/nNOS, BDNF/TrkB, and NGF/TrkA.

Conclusions

Sildenafil produces significant neuroprotective effects on injured neurons in acute stroke, and these are mediated by the cGMP-dependent Nogo-R pathway, NGF/TrkA, and BDNF/TrkB.

SUBMITTER: Chen XM

PROVIDER: S-EPMC6493202 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

Neuroprotection by sildenafil: neuronal networks potentiation in acute experimental stroke.

Chen Xue-Mei XM Wang Nan-Nan NN Zhang Tian-Yu TY Wang Fang F Wu Chun-Fu CF Yang Jing-Yu JY

CNS neuroscience & therapeutics 20130830 1

<h4>Aims</h4>Sildenafil, a phosphodiesterase type 5 inhibitor, has been found to produce functional recovery in ischemic rats by increasing the cGMP level and triggering neurogenesis. The aim of this study was to investigate further sildenafil mechanisms.<h4>Methods</h4>Male Sprague-Dawley rats underwent middle cerebral artery occlusion and reperfusion, followed by intraperitoneal or intravenous treatment of sildenafil starting 2 h later. Behavioral tests were performed on day 1 or day 7 after r ...[more]

PMID: 24034153

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Project description:BackgroundMagnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents.MethodsWe randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability).ResultsAmong the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (±SD) age was 69±13 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7±1.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P=0.28 by the Cochran-Mantel-Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P=1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P=0.95) or all serious adverse events.ConclusionsPrehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. (Funded by the National Institute of Neurological Disorders and Stroke; FAST-MAG ClinicalTrials.gov number, NCT00059332.).

Dataset Information

Neuroprotection by sildenafil: neuronal networks potentiation in acute experimental stroke.

Aims

Methods

Results

Conclusions

Publications

Neuroprotection by sildenafil: neuronal networks potentiation in acute experimental stroke.

Similar Datasets

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