Sildenafil Mediates Blood-Flow Redistribution and Neuroprotection After Neonatal Hypoxia-Ischemia

Abstract

The goal of this study was to test the hypothesis that boosting NO-cGMP signaling through PDE-5 inhibition with sildenafil would enhance microcirculatory CBF, reduce ipsilateral Background and Purpose-The best conceivable treatment for hypoxia-ischemia (HI) is the restoration of blood flow to the hypoxic-ischemic region(s). Our objective was to examine whether boosting NO-cGMP signaling using sildenafil citrate, a phosphodiesterase-type 5 inhibitor, could modify cerebral blood flow and reduce lesions in the developing brain. Methods-HI was induced in P7 Sprague-Dawley rats by unilateral carotid artery occlusion and hypoxia, and followed by either PBS or sildenafil. Blood-flow velocities were measured by ultrasound imaging with sequential Doppler recordings to evaluate collateral recruitment. Cell death, blood-brain barrier integrity, and glial activation were analyzed by immunohistochemistry. Motor behavior was evaluated using an open-field device adapted to neonatal animals. Results-Sildenafil citrate (10 mg/kg) induced collateral patency, reduced terminal dUTP nick-end labeling-positive cells, reactive astrogliosis, and macrophage/microglial activation at 72 hours and 7 days post-HI. Sildenafil also reduced the number of terminal dUTP nick-end labeling-positive endothelial cells within lesion site. Seven days after HI and sildenafil treatment, tissue loss was significantly reduced, and animals recovered motor coordination. Conclusions-Our findings strongly indicate that sildenafil citrate treatment, associated with a significant increase in cerebral blood flow, reduces HI damage and improves motor locomotion in neonatal rats. Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.

Sildenafil Improves Functional and Structural Outcome of Retinal Injury Following Term Neonatal Hypoxia-Ischemia

“…[41][42][43][44][45] Thus, in the short term, sildenafil may help restore the blood flow to the affected retina. In fact, Charriaut-Marlangue et al 46 demonstrated a blood flow increase in the common carotid artery contralateral to the ligated side after a single administration of intraperitoneal sildenafil immediately following an HI insult in a premature rat model of neonatal HIE. However, in our study, sildenafil was administered with a 12-hour delay and continued for 7 days; thus, a process other than acute vasodilation is likely involved.…”

“…[10][11][12][13][14][15][48][49][50][51][52] In a premature rat model of brain injury, sildenafil has been shown to decrease neuronal apoptosis and microglial activation. 46 Because neuronal apoptosis has been shown to peak at 24 hours after HI in the neonatal retina, 2 the sildenafil administered 12 hours after HI may have limited apoptosis and further degeneration by its possible antiapoptotic and anti-inflammatory effects, which have been observed in the adult rat brain. 11,15,48,49,51 Further investigations are needed to determine the exact mechanisms underlying the beneficial effects of sildenafil on retinal function and structure.…”

“…We administered sildenafil by oral route instead of the intraperitoneal or subcutaneous route described in most of the previous animal experiments, 14,16,17,31,46 because oral sildenafil is the most commonly used route with human newborns. It is safe to assume that oral sildenafil reaches the retina, as it has been demonstrated to transiently affect the ERG in healthy human subjects 1 hour after intake.…”

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

“…However, it is not clear if sildenafil induces oligodendrogenesis or if it inhibits cell death/apoptosis or both. Myelin protection and oligodendrocyte proliferation have also been demonstrated in ischemic models [147,148], and several studies showed that PDE5-Is inhibit apoptosis in central neurological disease models [122,148,149].…”

“…In 2014, Charriaut-Marlang et al [148] surgically induced ischemia model in P7 Sprague-Dawley rat pups by occlusion in the right common carotid artery and tested sildenafil. The animals were treated with a single dose of Viagra ® (Pfizer, 10 or 5 mg/kg i.p.).…”