sildenafil-citrate and Brain-Ischemia

The authors performed a double-blind, placebo-controlled study in 28 patients to evaluate the effects of sildenafil on cerebral hemodynamics. A significant improvement of cerebrovascular reactivity, without any modification of other variables, was recorded 1 hour after the administration of 50 mg sildenafil. Further investigations are needed to evaluate whether cerebrovascular reactivity improvement could contribute to triggering sildenafil-induced migraine.

Topics: Aged; Brain Ischemia; Cerebral Arteries; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Double-Blind Method; Endothelial Cells; Humans; Male; Middle Aged; Migraine Disorders; Phosphodiesterase Inhibitors; Piperazines; Placebos; Purines; Sildenafil Citrate; Sulfones; Time Factors; Ultrasonography, Doppler, Transcranial; Vasodilation

Persistent low-level hemolysis (LLH) during continuous-flow mechanical circulatory support is associated with subsequent thrombosis. Free hemoglobin from ongoing hemolysis scavenges nitric oxide (NO) to create an NO deficiency which can augment platelet function leading to a prothrombotic state. The phosphodiesterase-5 inhibitor, sildenafil, potentiates NO signaling to inhibit platelet function. Accordingly, we investigated the association of sildenafil administration and thrombotic events in patients with LLH during Heart Mate II support.. A single-center review of all patients implanted with a Heart Mate II who survived to discharge (n=144). LLH was defined by a discharge lactate dehydrogenase level of 400 to 700 U/L. Patients were categorized as (1) LLH not on sildenafil, (2) LLH on sildenafil, (3) no LLH not on sildenafil, and (4) no LLH on sildenafil. Age, sex, platelet count, and mean platelet volume were similar between groups. Seventeen patients had either device thrombosis or ischemic stroke. Presence of LLH was associated with a greater risk of thrombosis (adjusted hazard ratio, 15; 95% confidence interval, 4.5-50;. Sildenafil is associated with reduced device thrombosis and ischemic stroke during ongoing LLH on Heart Mate II support.

Topics: Brain Ischemia; Chi-Square Distribution; Disease-Free Survival; Heart Failure; Heart-Assist Devices; Hemolysis; Humans; Kaplan-Meier Estimate; Mean Platelet Volume; Phosphodiesterase 5 Inhibitors; Proportional Hazards Models; Prosthesis Design; Protective Factors; Retrospective Studies; Risk Factors; Sildenafil Citrate; Stroke; Time Factors; Treatment Outcome

Perinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE-5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation.. Ischemia was induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or sildenafil intraperitoneal (i.p.) injections. Blood flow (BF) velocities were measured by ultrasound imaging with sequential Doppler recordings and laser speckle contrast imaging. Animals were euthanized, and brain tissues were obtained at 72 h or 8 days after pMCAo. Expression of M1- and M2-like microglia/macrophage markers were analyzed.. Although sildenafil (10 mg/kg) treatment potently increased cGMP concentrations, it did not influence early collateral recruitment nor did it reduce mean infarct volumes 72 h after pMCAo. Nevertheless, it provided a significant dose-dependent reduction of mean lesion extent 8 days after pMCAo. Suggesting a mechanism involving modulation of the inflammatory response, sildenafil significantly decreased microglial density at 72 h and 8 days after pMCAo. Gene expression profiles indicated that sildenafil treatment also modulates M1- (ptgs2, CD32 and CD86) and M2-like (CD206, Arg-1 and Lgals3) microglia/macrophages in the late phase after pMCAo. Accordingly, the number of COX-2(+) microglia/macrophages significantly increased in the penumbra at 72 h after pMCAo but was significantly decreased 8 days after ischemia in sildenafil-treated animals.. Our findings argue that anti-inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after pMCAo in neonatal mice. We propose that sildenafil treatment could represent a potential strategy for neonatal ischemic stroke treatment/recovery.

Topics: Animals; Animals, Newborn; Brain Ischemia; Disease Models, Animal; Immunohistochemistry; Mice; Mice, Inbred C57BL; Microglia; Phosphodiesterase Inhibitors; Polymerase Chain Reaction; Sildenafil Citrate

We previously reported that the phosphodiesterase-5 (PDE5) inhibitor sildenafil prevented neurodegeneration but not learning deficits in middle-aged rats that were subjected to the permanent, three-stage, four-vessel occlusion/internal carotid artery (4-VO/ICA) model of chronic cerebral hypoperfusion (CCH). In the present study, we examined whether the PDE3 inhibitor cilostazol alleviates the loss of long-term memory (i.e., retrograde amnesia) caused by CCH. The effect of sildenafil was then compared to cilostazol. Naive rats (12-15 months old) were trained in a non-food-rewarded eight-arm radial maze and subjected to CCH. One week later, retrograde memory was assessed for 5 weeks. Cilostazol (50mg/kg, p.o.) was administered for 42 days or 15 days, beginning approximately 45 min after the first occlusion stage. Sildenafil (3mg/kg, p.o.) was similarly administered for 15 days only. Histological examination was performed after behavioral testing. Chronic cerebral hypoperfusion caused persistent retrograde amnesia, which was reversed by cilostazol after both short-term and long-term treatment. This antiamnesic effect of cilostazol was sustained throughout the experiment, even after discontinuing treatment (15-day treatment group). This effect occurred in the absence of neuronal rescue. Sildenafil failed to prevent CCH-induced retrograde amnesia, but it reduced hippocampal cell death. Extending previous findings from this laboratory, we conclude that sildenafil does not afford memory recovery after CCH, despite its neuroprotective effect. In contrast, cilostazol abolished CCH-induced retrograde amnesia, an effect that may not depend on histological neuroprotection. The present data suggest that cilostazol but not sildenafil represents a potential strategy for the treatment of cognitive sequelae associated with CCH.

Topics: Aging; Amnesia, Retrograde; Animals; Brain Ischemia; Carotid Artery Diseases; Carotid Artery, Internal; Cell Death; Cilostazol; Disease Models, Animal; Male; Maze Learning; Memory, Long-Term; Neuroprotective Agents; Nootropic Agents; Pyramidal Cells; Rats, Wistar; Sildenafil Citrate; Tetrazoles

Topics: Brain Ischemia; Humans; Male; Middle Aged; Sildenafil Citrate; Stroke; Vasodilator Agents

Topics: Brain; Brain Ischemia; Carbolines; Coitus; Headache; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Paresis; Piperazines; Purines; Recurrence; Sildenafil Citrate; Smoking; Stroke; Sulfones; Tadalafil; Vasodilator Agents

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Brain Ischemia; Echocardiography, Transesophageal; Female; Foramen Ovale, Patent; Hemodynamics; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke; Sulfones; Treatment Outcome; Ultrasonography, Doppler, Transcranial

To dynamically investigate the long-term response of an ischemic lesion in rat brain to the administration of sildenafil, male Wistar rats subjected to embolic stroke were treated with sildenafil (n=11) or saline (n=10) at a dose of 10 mg/kg administered subcutaneously 24-h after stroke and daily for an additional 6 days. Magnetic resonance images were acquired and functional performance was measured in all animals at 1 day, 2 days and weekly for 6 weeks post-stroke. All rats were sacrificed 6 weeks after stroke and endothelial barrier antigen immunostaining was employed for morphological analysis and quantification of cerebral vessels. Map-ISODATA was computed from T(1), T(2) and T(1sat) maps. ISODATA derived tissue signatures characterize the degree of ischemic injury. Based on the map-ISODATA calculated at 6 weeks, the ischemic lesion for each animal was divided into two specific regions, the ischemic boundary and ischemic core. The temporal profiles of cerebral blood flow (CBF) and tissue signature were retrospectively tracked in these two regions and were compared with histological evaluation and functional outcome. After 1 week of sildenafil treatment, the ischemic lesion exhibited two significantly different regions, with higher CBF level and correspondingly, lower tissue signature value in the boundary region than in the core region. Sildenafil treatment did not significantly reduce the lesion size, but did enhance angiogenesis. Functional performance was significantly increased after sildenafil treatment compared with the control group. Administration of sildenafil to rats with embolic stroke enhances angiogenesis and selectively increases the CBF level in the ischemic boundary, and improves neurological functional recovery compared to saline-treated rats.

Topics: Animals; Antigens, Surface; Brain Ischemia; Cerebral Arteries; Cerebrovascular Circulation; Endothelial Cells; Intracranial Embolism and Thrombosis; Magnetic Resonance Imaging; Male; Neovascularization, Physiologic; Piperazines; Purines; Rats; Rats, Wistar; Recovery of Function; Sildenafil Citrate; Stroke; Sulfones; Treatment Outcome; Vasodilator Agents

Increasing age decreases the number of new neurons in the dentate gyrus and the subventricular zone (SVZ). Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, enhances neurogenesis in young rats. The present study tested the hypothesis that sildenafil augments neurogenesis in aged rats after focal cerebral ischemia. Nonischemic aged (18 months, n = 6) Wistar rats exhibited a significant reduction of actively proliferating and relatively quiescent cells in the SVZ measured by the number of minichromosome maintenance protein-2-positive (MCM-2+) cells, a marker of the proliferating cells, compared with nonischemic young (3-4 months, n = 8) rats. Occlusion of the middle cerebral artery did not increase the number of MCM-2+ cells in the SVZ of aged rats at 3 months after focal ischemia. However, treatment with sildenafil at a dose of 3 mg/kg (n = 8) daily for 7 consecutive days starting 7 days after focal ischemia significantly increased the number of MCM-2+ cells in the SVZ of aged rats compared with aged rats treated with saline (n = 8). Double immunostaining revealed that substantially more Ki67+ cells (a marker of proliferating cells) were doublecortin+ (a marker of migrating neuroblasts) in sildenafil-treated than in saline-treated aged animals. In addition, treatment with sildenafil significantly improved functional recovery compared with saline-treated rats. These data suggest that inhibition of PDE5 activity by sildenafil augments neurogenesis in the SVZ of aged ischemic rats, although these rats have reduced numbers of neural progenitor and stem cells in the SVZ.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aging; Animals; Brain Ischemia; Cell Division; Cell Proliferation; Cerebral Cortex; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Doublecortin Domain Proteins; Doublecortin Protein; Ki-67 Antigen; Male; Microtubule-Associated Proteins; Minichromosome Maintenance 1 Protein; Neuronal Plasticity; Neuropeptides; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Recovery of Function; Sildenafil Citrate; Stem Cells; Sulfones; Up-Regulation