sildenafil-citrate and Stroke

The structural underpinning responsible for neuroplasticity and neurorestoration under physiological and pathophysiological conditions is only beginning to be elucidated. It is evident that life-long neurogenesis occurs in the human brain, with experimental data supporting its upregulation following an insult (eg, stroke) and/or in response to pharmacological therapy. Sildenafil, a PDE5 inhibitor currently marketed for the treatment of erectile dysfunction, enhances neurorestoration in rat models of stroke, as measured by neurogenesis, synaptogenesis and angiogenesis. This neurorestorative effect is associated with improved outcome despite no observed effect on brain infarct size. This neurorestorative effect has also been observed in both young and old animals, and is demonstrable even if therapy is initiated 1 week post-stroke. The extended therapeutic window and novel mechanism of action of neurorestorative therapies, such as sildenafil, warrant further investigation for the treatment of stroke.

Topics: Animals; Humans; Neuroprotective Agents; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke; Sulfones; Vasodilator Agents

Sildenafil is the first internationally approved drug for erectile dysfunction. Unsupervised and non-prescribed use of sildenafil among young Indian population has increased in last few years. Sildenafil helps in erection of penis by inhibiting the action of Phosphodiesterase-5 (PDE-5) enzyme, present in the vasculature of corpus cavernosum muscle and lengthens the duration of erection. Documented adverse effects of sildenafil are headache, flushing, nasal congestion, dyspepsia, and slight decrease in systolic and diastolic blood pressure. We present a rare case of sudden death due to cerebrovascular hemorrhage after sildenafil use and concomitant alcohol intake. The history is that a 41-year-old male with no significant past medical and surgical history was staying at a hotel room with a female friend; he had consumed 2 tablets of sildenafil (50 mg each) and alcohol at night. Next morning, he developed uneasiness following which he was taken to the Hospital where he was declared dead on arrival. The important autopsy findings include edematous brain with about 300 g of clotted blood in the right basal ganglia extending to bilateral ventricles, and in pons region. Other significant findings on microscopic examination were hypertrophic ventricular wall of heart, fatty changes in liver and acute tubular necrosis and hypertensive changes in the kidney. The findings are discussed in the light of the literature about the lethal complications of combined use of sildenafil and alcohol including cerebrovascular accidents. As a forensic pathologist it is the duty of the doctor to execute meticulous autopsy along with ancillary investigations including toxicological analysis and to correlate all these findings to determine the possible effects of drugs when present, so as to gather knowledge about potentially fatal drugs and further create public awareness regarding the same.

Topics: Adult; Erectile Dysfunction; Ethanol; Female; Humans; Male; Piperazines; Purines; Sildenafil Citrate; Stroke

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

To evaluate the effect of bevacizumab and sildenafil on stroke parameters in a mouse model, middle cerebral artery occlusion was induced in male C57Bl/6 mice using an intra-arterial filament method. The filament was removed after 60 minutes, and the mice were immediately given a single intraperitoneal injection of saline, bevacizumab, or sildenafil. An additional group of mice (n = 7) received bevacizumab 6 h after MCAO induction. The mice were euthanized 24 hours later and evaluated for infarct area and brain edema using triphenyltetrazolium chloride staining and ImageJ. In the saline-treated mice (n = 16), total stroke volume was 19.20 ± 6.38 mm(3), mean penumbra area was 4.5 ± 2.03 mm(3), and hemispheric asymmetry was 106.5%. Corresponding values in the bevacizumab group (n = 19) were 17.79 ± 5.80 mm(3), 7.3 ± 3.5 mm(3), and 108.6%; in the delayed (6 h) bevacizumab injected mice (n = 7) they were 9.80 ± 8.00 mm(3), 2.4 ± 2.0 mm(3), and 98.2%; and in the sildenafil group (n = 16) they were 18.42 ± 5.41 mm(3), 5.7 ± 2.02 mm(3), and 109.9%. The bevacizumab group had a significantly larger mean penumbra area when given immediately and smaller total stroke area in both groups than the saline- (p = 0.03) and sildenafil-treated (p = 0.003) groups. Only delayed bevacizumab group had reduced edema. Bevacizumab, injected immediately or delayed after injury, exerts a neuroprotective/salvage effect, whereas immediate treatment with sildenafil does not. Inflammation may play a role in the neuroprotective effect.

Topics: Angiogenesis Inhibitors; Animals; Bevacizumab; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Sildenafil Citrate; Stroke; Treatment Outcome; Vasodilator Agents

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

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.. 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.. 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.. 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.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cell Survival; Disks Large Homolog 4 Protein; GPI-Linked Proteins; Infarction, Middle Cerebral Artery; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Myelin Proteins; Nerve Growth Factor; Nerve Net; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type I; Nogo Receptor 1; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Receptor, trkA; Receptor, trkB; Receptors, Cell Surface; Recovery of Function; Reperfusion Injury; Sildenafil Citrate; Stroke; Sulfones; Synapses; Synaptophysin

The aim of this study was to test the hypothesis that a combination of atorvastatin and sildenafil promotes recovery in an additive manner after ischemic stroke in mice.. Adult C57BL/6 mice (n = 67) were subjected to transient middle cerebral artery occlusion. Vehicle-control (H2O), atorvastatin (0.3 mg/kg), sildenafil (0.3 mg/kg), or combined atorvastatin (0.3 mg/kg) and sildenafil (0.3 mg/kg) were administrated via oral gavage daily for 6 days starting 24 hrs after ischemia. Behavioral studies including neurologic score and adhesive removal test were performed before surgery and on postoperative days 1 and 7; cylinder test was performed before surgery and on postoperative day 7. Mice were killed after 7 days and brain slices were stained with hematoxylin and eosin to measure the infarct volume.. The combination group performed significantly better in the adhesive removal test (mean ± SD) (50 ± 54 secs) as compared with the control group (147 ± 109 secs) (P < 0.05) and to atorvastatin (144 ± 102 secs) (P < 0.05) but did not show statistically significant improvement as compared with sildenafil (107 ± 115 secs) (P = 0.148). There were no significant differences among the groups in neurologic score and cylinder test. There was no significant difference in the infarct volume.. The data suggest that combined atorvastatin and sildenafil generates a better functional outcome as compared with atorvastatin-only treatment, but not sildenafil-only treatment, in one of multiple variables tested.

Topics: Animals; Atorvastatin; Behavior, Animal; Drug Therapy, Combination; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mice, Inbred C57BL; Neuropsychological Tests; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrroles; Recovery of Function; Sildenafil Citrate; Stroke; Sulfones

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

Sildenafil provides restorative therapeutic benefits in the treatment of experimental stroke. The majority of experimental studies on treatment of stroke have been performed in young animals; however, stroke is primarily a disease of the aged. Thus, using MRI, we evaluated the effects of sildenafil treatment of embolic stroke in aged animals.. Aged male Wistar rats (18 months) were subjected to embolic stroke and treated daily with saline (n=10) or with sildenafil (n=10) initiated at 24 hours and subsequently for 7 days after onset of ischemia. MRI measurements were performed at 24 hours and weekly to 6 weeks after embolization.. MRI and histological measurements demonstrated that sildenafil treatment of aged rats significantly enhanced angiogenesis and axonal remodeling after stroke compared to saline-treated aged rats. Local cerebral blood flow in the angiogenic area was elevated and expansion of the ipsilateral ventricle and, consequently, brain atrophy was significantly reduced in the sildenafil-treated rats.. Treatment of embolic stroke in aged rats with sildenafil significantly augments angiogenesis and axonal remodeling, which increased local blood flow and reduced expansion of the ipsilateral ventricle 6 weeks after stroke compared to control aged rats. MRI can be used to investigate brain repair after stroke in aged rats.

Topics: Animals; Brain; Cerebrovascular Circulation; Intracranial Embolism; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neovascularization, Physiologic; Piperazines; Purines; Rats; Rats, Wistar; Recovery of Function; Sildenafil Citrate; Stroke; Sulfones; 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

This study uses T(2)* weighted imaging (T2*WI) to measure the temporal evolution of cerebral angiogenesis in rats subjected to embolic stroke up to 6 weeks after stroke onset with or without sildenafil treatment. Method- Male Wistar rats were subjected to embolic stroke and treated with saline (n=10) or with sildenafil (n=11), with treatment initiated at 24 hours and continued daily for 7 days after onset of ischemia. T2*WI measurements were performed at 24 hours after embolization and weekly up to 6 weeks using a 7-Tesla system. Histological measurements were obtained at 6 weeks after MRI scans.. Using T2*WI, cerebral angiogenesis was detected starting from 4 weeks and from 2 weeks after onset of embolic stroke in saline and sildenafil treated rats, respectively. Significant differences in the temporal and spatial features of angiogenesis after embolic stroke up to 6 weeks after onset of stroke were found between saline and sildenafil treated rats and were identified with T2*WI. MRI permeability parameter, K(i), complementarily detected angiogenesis after ischemia in embolic stroke rats. Sildenafil treatment of stroke rats significantly enhanced the angiogenesis, as confirmed histologically.. T2*WI can quantitatively measure the temporal evolution of angiogenesis in rats subjected to embolic stroke. Compared to control rats, sildenafil treatment significantly increased angiogenesis in treated animals up to 6 weeks after stroke.

Topics: Animals; Brain; Brain Mapping; Cerebral Arteries; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Intracranial Embolism; Male; Microcirculation; Neovascularization, Physiologic; Piperazines; Predictive Value of Tests; Purines; Rats; Rats, Wistar; Recovery of Function; Sildenafil Citrate; Stroke; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

Interaction between angiogenesis and axonal remodeling after stroke was dynamically investigated by MRI in rats with or without sildenafil treatments. Male Wistar rats were subjected to embolic stroke and treated daily with saline (n=10) or with sildenafil (n=11) initiated at 24 h and subsequently for 7 days after onset of ischemia. T(2)(*)-weighted imaging, cerebral blood flow (CBF), and diffusion tensor imaging (DTI) measurements were performed from 24 h to 6 weeks after embolization. T(2)(*) and fractional anisotropy (FA) maps detected angiogenesis and axonal remodeling after stroke, respectively, starting from 1 week in sildenafil-treated rats. Areas demarcated by MRI with enhanced angiogenesis, elevated local CBF, and augmented axonal remodeling were spatially and temporally matched, and FA values were significantly correlated with the corresponding CBF values (R=0.66, P<4 x 10(-5)) at 6 weeks after stroke. Axonal projections were reorganized along the ischemic boundary after stroke. These MRI measurements, confirmed by histology, showed that sildenafil treatment simultaneously enhanced angiogenesis and axonal remodeling, which were MRI detectable starting from 1 week after stroke in rats. The spatial and temporal consistency of MRI metrics and the correlation between FA and local CBF suggest that angiogenesis, by elevating local CBF, promotes axonal remodeling after stroke.

Topics: Animals; Axons; Brain; Cerebrovascular Circulation; Intracranial Embolism; Magnetic Resonance Angiography; Male; Neovascularization, Physiologic; Piperazines; Purines; Rats; Rats, Wistar; Recovery of Function; Sildenafil Citrate; Stroke; Sulfones; Time Factors; Vasodilator Agents

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

Topics: Altitude Sickness; Erectile Dysfunction; Heart Diseases; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Raynaud Disease; Sildenafil Citrate; Stroke; Sulfones; Vasodilator Agents

Sildenafil citrate has been shown to enhance neurogenesis, angiogenesis, synaptogenesis, and neurological outcome by augmentation of cyclic guanosine monophosphate (cGMP) levels in animal models of ischemic stroke. Whether sildenafil citrate may be helpful for recovery in human stroke is unknown at this time.. A 41-year-old woman with locked-in syndrome due to pontine infarction began receiving 150 mg of oral sildenafil citrate daily on a compassionate use basis in August 2003 and continues treatment at this time. Magneto-encephalography (MEG) was performed at 12 and 17 months after stroke.. No serious adverse events have occurred. Significant milestone recoveries including standing, use of both arms, talking, and full return of swallowing have occurred, particularly after nine months of treatment. The MEG showed a significantly increased amplitude in the somatosensory cortex.. Daily use of high dose sildenafil citrate appears to be safe in this patient with stroke resulting in locked-in syndrome. Further studies will be required to establish safety and efficacy.

Topics: Adult; Basilar Artery; Brain Stem Infarctions; Cerebral Angiography; Cyclic GMP; Dose-Response Relationship, Drug; Evoked Potentials, Somatosensory; Female; Humans; Magnetoencephalography; Manipulation, Chiropractic; Neovascularization, Physiologic; Nerve Regeneration; Neuronal Plasticity; Phosphodiesterase Inhibitors; Piperazines; Pons; Purines; Quadriplegia; Recovery of Function; Sildenafil Citrate; Stroke; Sulfones; Treatment Outcome; Vertebral Artery Dissection; Vertebrobasilar Insufficiency

Advanced age is associated with a decrease in brain plasticity compared with the young adult. Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor promotes brain plasticity and improves functional outcome after stroke in the young animal. Here, we test the hypothesis that sildenafil provides restorative therapeutic benefit to the aged animal.. Male Wistar rats (aged, 18-month old; young, 3-month old) were subjected to embolic stroke. Saline or sildenafil was administered daily at a dose of 2 mg/kg orally or 10 mg/kg subcutaneously for 7 consecutive days starting 24 hour after stroke onset.. Aged rats exhibited significant impairment of functional recovery and reductions of vascular density, and endothelial cell proliferation compared with young rats. Aged rats treated with sildenafil at a dose of 10 mg/kg but not 2 mg/kg, showed significant improvements of functional recovery and concomitant increases in cortical cyclic guanosine 3',5'-cyclic monophosphate (cGMP) level, vascular density, endothelial cell proliferation, and synaptogenesis compared with aged rats treated with saline. In young rats, treatment with sildenafil at a dose of 2 or 10 mg/kg significantly enhanced functional recovery and amplified brain plasticity compared with young rats treated with saline.. Age is associated with reduction of angiogenesis, and poor neurological functional recovery after stroke. However, treatment of aged stroke rats with sildenafil improves functional recovery that is likely fostered by enhancement of angiogenesis and synaptogenesis.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aging; Animals; Bromodeoxyuridine; Cell Proliferation; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelium, Vascular; Immunohistochemistry; Male; Neovascularization, Pathologic; Neuronal Plasticity; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sodium Chloride; Stroke; Sulfones; Synapses; Synaptophysin; Time Factors; Treatment Outcome

We investigated the effects of NO on angiogenesis and the synthesis of vascular endothelial growth factor (VEGF) in a model of focal embolic cerebral ischemia in the rat. Compared with control rats, systemic administration of an NO donor, DETANONOate, to rats 24 hours after stroke significantly enlarged vascular perimeters and increased the number of proliferated cerebral endothelial cells and the numbers of newly generated vessels in the ischemic boundary regions, as evaluated by 3-dimensional laser scanning confocal microscopy. Treatment with DETANONOate significantly increased VEGF levels in the ischemic boundary regions as measured by ELISA. A capillary-like tube formation assay was used to investigate whether DETANONOate increases angiogenesis in ischemic brain via activation of soluble guanylate cyclase. DETANONOate-induced capillary-like tube formation was completely inhibited by a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Blocking VEGF activity by a neutralized antibody against VEGF receptor 2 significantly attenuated DETANONOate-induced capillary-like tube formation. Moreover, systemic administration of a phosphodiesterase type 5 inhibitor (Sildenafil) to rats 24 hours after stroke significantly increased angiogenesis in the ischemic boundary regions. Sildenafil and an analog of cyclic guanosine monophosphate (cGMP) also induced capillary-like tube formation. These findings suggest that exogenous NO enhances angiogenesis in ischemic brain, which is mediated by the NO/cGMP pathway. Furthermore, our data suggest that NO, in part via VEGF, may enhance angiogenesis in ischemic brain.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Brain; Bromodeoxyuridine; Cell Division; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Guanylate Cyclase; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Donors; Nitroso Compounds; Piperazines; Purines; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Stroke; Sulfones; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

In a sequential clinical trial, accrual of data on patients often continues after the stopping criterion for the study has been met. This is termed "overrunning." Overrunning occurs mainly when the primary response from each patient is measured after some extended observation period. The objective of this article is to compare two methods of allowing for overrunning. In particular, simulation studies are reported that assess the two procedures in terms of how well they maintain the intended type I error rate. The effect on power resulting from the incorporation of "overrunning data" using the two procedures is evaluated.

Topics: Biometry; Calcium Channel Blockers; Clinical Trials as Topic; Data Interpretation, Statistical; Erectile Dysfunction; Humans; Isradipine; Male; Models, Statistical; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Stroke; Sulfones; Time Factors; Vasodilator Agents

Topics: Humans; Hypotension; Ischemic Attack, Transient; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Stroke; Sulfones; Vasodilator Agents

We tested the hypothesis that sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, promotes functional recovery and neurogenesis after stroke.. Male Wistar rats were subjected to embolic middle cerebral artery occlusion. Sildenafil (Viagra) was administered orally for 7 consecutive days starting 2 or 24 hours after stroke onset at doses of 2 or 5 mg/kg per day. Ischemic rats administered the same volume of tap water were used as a control group. Functional outcome tests (foot-fault, adhesive removal) were performed. Rats were killed 28 days after stroke for analysis of infarct volume and newly generated cells within the subventricular zone and the dentate gyrus. Brain cGMP levels, expression of PDE5, and localized cerebral blood flow were measured in additional rats.. Treatment with sildenafil significantly (P<0.05) enhanced neurological recovery in all tests performed. There was no significant difference of infarct volume among the experimental groups. Treatment with sildenafil significantly (P<0.05) increased numbers of bromodeoxyuridine-immunoreactive cells in the subventricular zone and the dentate gyrus and numbers of immature neurons, as indicated by betaIII-tubulin (TuJ1) immunoreactivity in the ipsilateral subventricular zone and striatum. The cortical levels of cGMP significantly increased after administration of sildenafil, and PDE5 mRNA was present in both nonischemic and ischemic brain.. Sildenafil increases brain levels of cGMP, evokes neurogenesis, and reduces neurological deficits when given to rats 2 or 24 hours after stroke. These data suggest that this drug that is presently in the clinic for sexual dysfunction may have a role in promoting recovery from stroke.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Behavior, Animal; Brain; Bromodeoxyuridine; Cell Count; Cell Division; Cerebrovascular Circulation; Corpus Striatum; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dentate Gyrus; Disease Models, Animal; Lateral Ventricles; Male; Nerve Regeneration; Neurons; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Recovery of Function; RNA, Messenger; Sildenafil Citrate; Stroke; Sulfones; Treatment Outcome

Topics: Humans; Ischemic Attack, Transient; Magnetic Resonance Imaging; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke; Sulfones