Phosphodiesterase 5 inhibitor, zaprinast, selectively increases cerebral blood flow in the ischemic penumbra in the rat brain

BACKGROUND: Guanosine 3', 5'-cyclic monophosphate (cGMP) acts as a relaxant second messenger in the cerebral vessels. cGMP-specific phosphodiesterase type 5 (PDE5) inhibitor increases intracellular cGMP levels. This study investigated the effect of the PDE5 inhibitor on the ischemic brain.METHODS: Regional cerebral blood flow (rCBF), cGMP concentration, and infarction volume were measured in the rat middle cerebral artery occlusion model. Ten minutes after ischemia, the animals received an intravenous (i.v.) infusion of vehicle (phosphate-buffered saline), PDE5 inhibitor, zaprinast (10 mg/kg), or nitric oxide donor, S-nitroso-N-acetyl-penicillamine (SNAP, 100 microg/kg). rCBF was measured continuously by laser-Doppler flowmetry in the ischemic penumbra of the ischemic and contralateral sides under continuous blood pressure monitoring. cGMP concentrations were determined using the enzyme immunoassay and infarct volumes were estimated by 2,3,5-triphenyltetrazolium chloride staining.RESULTS: The administration of zaprinast significantly increased rCBF in the ischemic brain compared with the pre-drug control value despite the decreased mean blood pressure, whereas it did not affect rCBF in the contralateral side. The cGMP concentration was significantly higher in the ischemic cortex compared with the contralateral side. SNAP infusion increased the cGMP concentration in the bilateral cortices to a similar extent. The volume of cerebral infarction was significantly decreased by zaprinast administration.CONCLUSIONS: The PDE5 inhibitor zaprinast may selectively increase CBF in the ischemic brain via increased cGMP levels, thus providing a new strategy against acute cerebral infarction.     

Early reperfusion improves the recovery of contralateral electrophysiological diaschisis following focal cerebral ischemia in rats

Abstract

Objectives: We evaluated electrophysiological benefits of reperfusion following ischemic stroke.

Methods: Rats received either transient proximal occlusion of the right middle cerebral artery for 30 (Group I, n=8) or 90 minutes (Group II, n=8) or permanent thermocoagulation of the distal right middle cerebral artery (Group III, n=6). Neurobehavioral outcome and somatosensory evoked potentials (SSEPs) were examined before and at 7 days after the onset of brain ischemia. Brain infarction was assessed after the rats were euthanized.

Results: Before ischemia, stable SSEPs were consistently recorded. At 7 days post-insult, Group III (permanent occlusion) had the greatest reduction in the SSEPs recorded ipsilaterally and contralaterally. Groups I and II (transient ischemic groups) also had depressant SSEPs recorded from the ipsilateral ischemic and the contralateral intact brain (electrophysiological diaschisis). However, prolonged ischemia resulted in greater brain infarction and increased neurological deficits in addition to greater reductions in the ipsilateral and the contralateral SSEPs.

Conclusion: Early reperfusion facilitates the electrophysiological recovery in both ipsilateral lesional and the contralateral intact brain, which may be closely relevant to post-injury brain rewiring. We also demonstrated that contralateral electrophysiological diaschisis could be greatly reversed by early reperfusion and is independent of the lesion size of striatum.     

Type V phosphodiesterase expression in cerebral arteries with vasospasm after subarachnoid hemorrhage in a canine model

Abstract

Cyclic GMP (cGMP) mediates smooth muscle relaxation in the central nervous system. In subarachnoid hemorrhage (SAH), decreases in intrinsic nitric oxide (NO) cause cerebral vasospasms due to the regulation of cGMP formation by NO-mediated pathways. As phosphodiesterase type V (PDE V) selectively hydrolyzes cGMP, we hypothesized that PDE V may function in the initiation of vasospasm. This study sought to identify the altered PDE V expression and activity in the vasospastic artery in a canine SAH model. We also used this system to examine possible therapeutic strategies to prevent vasospasm. Using a canine model of SAH, we induced cerebral vasospasm in the basilar artery (BA). Following angiographic confirmation of vasospasm on day 7, PDE V expression was immunohistochemically identified in smooth muscle cells of the vasospastic BA but not in cells of a control artery. The isolation of PDE enzymes using a sepharose column confirmed increased PDE V activity in the vasospastic artery only through both inhibition studies, using the highly selective PDE V inhibitor, sildenafil citrate, and Western blotting. Preliminary in vivo experiment using an oral PDE V inhibitor at 0.83 mg kg^-1 demonstrated partial relaxation of the spastic BA. PDE V activity was increased from control levels within the BA seven days after SAH. PDE V expression was most prominent in smooth muscle cells following SAH. These results suggest that clinical administration of a PDE V inhibitor may be a useful therapeutic tool in the prevention of vasospasm following SAH. [Neurol Res 2002; 24: 607-612]     

Simultaneous LC-MS/MS analysis of the biomarkers cAMP and cGMP in plasma, CSF and brain tissue

The cyclic nucleotides cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) are important second messengers. They are useful biomarkers to indicate biological activity of drugs such as phosphodiesterase (PDE) inhibitors which block the degradation of these nucleotides. Here, we established a fast and sensitive method for the simultaneous analysis of cAMP and cGMP by LC-MS/MS with broad applicability. The limit of detection is 50 pM. Linearity is given in a range of 0.5-500 nM for both nucleotides, with a high intra- and inter-assay precision and accuracy and an analysis time of 3.5 min. We validated the suitability of the method by pharmacological modulation of cAMP or cGMP concentrations in mice with the PDE4 inhibitor rolipram and the PDE5 inhibitor zaprinast. Rolipram significantly increased cAMP concentrations in plasma, CSF and brain tissue. Zaprinast increased cGMP concentrations in plasma but not in brain tissue, which is in accordance with its blood brain barrier permeability. In conclusion, the LC-MS/MS method described here could be a valuable analytical tool for investigating pharmacodynamic effects of PDE inhibitors and to monitor disease-related changes of cAMP and cGMP in the periphery as well as in the central nervous system.     

A nonNMDA antagonist,GYKI 52466 improves microscopic O2 balance in the cortex during focal cerebral ischemia

Abstract

This study was performed to test whether GYKI 52466, a nonNMDA receptor antagonist; would improve microregional oxygen supply and consumption balance in the focal cerebral ischemic area. Rats were anesthetized with 1.4% isoflurane. For the GYKI Group (n = 8), 10 min before middle cerebral artery (MCA) occlusion, a bolus of 5 mg kg^–1 of GYKI 52466 i.v. was administered and was followed by an infusion of 5 mg kg^–1 h^–1. For the Control Group (n = 8), the same volume of the vehicle was administered. One hour after MCA occlusion, regional cerebral blood flow (rCBF) was measured using the 14C-iodoantipyrine autoradiographic technique. Microscopic arterial and venous oxygen saturations were determined using microspectrophotometry. In the cortex contralateral to MCA occlusion, the average rCBF and the average 02 consumption were lower in the GYKI Group than in the Control Group (rCBF: GYKI 65.5 dh 24.1 ml 100 g^–1 min^–1 Control 97.7±33 A ml 100g^–1 min^–1; 02 consumption: GYKI 3.9 ± 1.2 ml 02 100 g 1 min^–1 Control 6.2 ±2.5 ml 02 100g 1 min^–1) without a significant difference in the number of veins with Sv02 < 50%. In the ischemic cortex, the number of veins with Sv02 < 50% was significantly smaller in the GYKI Group (21 veins out of 63) than in the Control Group (45 out of 59) without a significant difference in the average rCBF (GYKI 44.9±17.7, Control 29.7±10.4) or regional 02 consumption between these two groups (GYKI 3.3 ± 1.4, Control 2.7± 1.2). Our data demonstrated that GYKI 52466 was effective in improving microscopic 02 balance in the focal ischemic cortical area of the brain and it decreased 02 consumption in the non-ischemic cortex. [Neurol Res 1999; 21: 299-304]     

Effect of propentofylline on cerebral blood flow in a gerbil focal cerebral ischemia

BACKGROUND AND PURPOSE: Neuroprotection and improvement of cerebral blood flow are two basic principles of pharmacological intervention in acute stroke. Propentofylline, an adenosine uptake and phosphodiesterase inhibitor, has been shown to be neuroprotective in various models of cerebral ischemia. However, its effect on cerebral circulation in ischemic conditions is not yet fully elucidated. Present experiments were designed to investigate the effect of propentofylline on regional cerebral blood flow (rCBF) in the gerbil permanent focal cerebral ischemia model. METHODS: Focal cerebral ischemia in gerbils was produced by clipping one common carotid artery and contralateral external carotid artery. rCBF was measured in both parietal cortices concurrently by the hydrogen clearance. RESULTS: Propentofylline at 10 mg/kg administered intraperitoneally 30 min after induction of cerebral ischemia significantly increased rCBF in ischemic regions (increase of 94.6%). Effects were dose dependent. Higher dosage (30 mg/kg) induced reductions of ischemic rCBF, which were associated with significant decreases of mean arterial blood pressure. Lower dosage (5 mg/kg) was without significant effect. CONCLUSIONS: Results suggest that propentofylline at suitable dosage improves rCBF in ischemic brain areas. Taking into account neuroprotective potentials of propentofylline, results offer additional rationale for clinical trials investigating efficacy of propentofylline in treatment of acute stroke.     

Book Reviews

Abstract

Perfusion is thought to be impaired in brain edema due to reduced perfusion pressure. Brain edema therapy is assumed to improve perfusion. We assessed regional cerebral blood flow (rCBF)1 regional cerebral blood volume (rCBV) and mean transit time of blood (MIT) using perfusion-weighted magnetic resonance imaging (MRJ) in 75 patients showing acute local brain edema due to infarction or intracerebral hematoma. Patients were treated by intravenous infusion of 725 ml 40% sorbitol over 70 min. rCBFI rCBV and MIT in the edematous region were measured before and 30 min after treatment. Before treatment rCBF (46.5 ± 12.1 vs. 42.9 ± 10.5 ml 100 g^-1 min^-1)1 MIT (4.7 ± 1.9 vs. 4.0 ± 7.7 s) and rCBV (5.4 ± 1.7 vs. 4.7 ± 1.7 ml 100 g^-1) were significantly (p < 0.05) increased in the edematous region compared to th contralateral side. After treatment no significant differences could be found. We interpret the elevation of MIT and rCBV in the edema as signs of an autoregulative compensation of an impaired perfusion. rCBF is even over-compensated. After brain edema therapy perfusion seems normalised. This new MRI method appears as useful for measuring therapeutic effects on cerebral perfusion. [Neural Res 1998; 20: 474-478]     

A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression.

High-frequency stimulation (HFS) of corticostriatal glutamatergic fibers induces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of LTD can be mimicked by zaprinast, a selective inhibitor of cGMP phosphodiesterases (PDEs). Biochemical analysis shows that most of the striatal cGMP PDE activity is calmodulin-dependent and inhibited by zaprinast. The zaprinast-induced LTD occludes further depression by tetanic stimulation and vice versa. Both forms of synaptic plasticity are blocked by intracellular 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, indicating that an increased cGMP production in the spiny neuron is a key step. Accordingly, intracellular cGMP, activating protein kinase G (PKG), also induces LTD. Nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) and 7-nitroindazole monosodium salt (7-NINA) block LTD induced by either HFS or zaprinast, but not that induced by cGMP. LTD is also induced by the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine. SNAP-induced LTD occludes further depression by HFS or zaprinast, and it is blocked by intracellular ODQ but not by L-NAME. Intracellular application of PKG inhibitors blocks LTD induced by HFS, zaprinast, and SNAP. Electron microscopy immunocytochemistry shows the presence of NOS-positive terminals of striatal interneurons forming synaptic contacts with dendrites of spiny neurons. These findings represent the first demonstration that the NO/cGMP pathway exerts a feed-forward control on the corticostriatal synaptic plasticity.     

In vivo effects of phosphodiesterase inhibition on basal cyclic guanosine monophosphate levels in the prefrontal cortex, hippocampus and cerebellum of freely moving rats

We have characterized the various phosphodiesterases (PDE) that degrade cyclic GMP in the prefrontal cortex, hippocampus, and cerebellum using the microdialysis technique to measure in vivo extracellular cyclic GMP in awake rats. The following PDE blockers were used (100 and 1,000 microM): 8-methoxymethyl-IBMX (8-MM-IBMX), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), milrinone, rolipram, and zaprinast. For solubility reasons, sildenafil was tested only at 100 microM. All drugs were administered locally in the brain regions through the dialysis probe. At 100 microM, 8-MM-IBMX enhanced the cyclic nucleotide extracellular levels in the prefrontal cortex and hippocampus but not in the cerebellum; EHNA and milrinone were active only in the hippocampus; rolipram was devoid of any effect; zaprinast and sildenafil were effective in all three brain areas. At 1 mM, 8-MM-IBMX, milrinone, and zaprinast increased extracellular cyclic GMP in all the brain regions examined, EHNA became active also in the prefrontal cortex and rolipram showed a significant effect only in the cerebellum. This is the first in vivo functional study showing that, in cortex, PDE1, -2, and -5/9 degrade cGMP, with PDE9 probably playing a major role; in hippocampus, PDE5/9 and PDE1 are mainly involved and seem almost equally active, but PDE2 and -3 also contribute; in cerebellum, PDE5/9 are the main cGMP hydrolyzing enzymes, but also PDE1 and -4 significantly operate.     

Normobaric hyperoxia retards the evolution of ischemic brain tissue toward infarction in a rat model of transient focal cerebral ischemia

Objectives: Oxygen therapy has been long considered a logical therapy for ischemic stroke. Our previous studies showed that normobaric hyperoxia (normobaric hyperoxia (NBO), 95% O₂ with 5% CO₂) treatment during ischemia reduced ischemic neuronal death and cerebromicrovascular injury in animal stroke models. In this study, we studied the effects of NBO on the evolution of ischemic brain tissue to infarction in a rat model of transient focal cerebral ischemia.

Methods: Male Sprague-Dawley rats were given NBO (95% O₂) or normoxia (21% O₂) during 90-min filament occlusion of the middle cerebral artery (MCAO), followed by 3 or 22.5 h of reperfusion. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to evaluate the longitudinal evolution of tissue infarction.

Results： In normoxic rats, MCA-supplied cortical and striatal tissue was infarcted after 90-min MCAO with 22.5 h of reperfusion. NBO-treated rats showed a 61.4% reduction in infarct size and tissue infarction mainly occurred in the ischemic striatum. When infarction was assessed at an earlier time point, i.e. at 3 h of reperfusion, normoxic rats showed significantly smaller but mature infarction (no TTC staining, white color), with the infarction mainly occurring in the striatum. Unexpectedly, NBO-treated rats only showed immature lesion (partially stained by TTC, light white color) in the ischemic striatum, indicating that NBO treatment also retarded the process of neuronal death in the ischemic core. Of note, NBO-preserved striatal tissue underwent infarction after prolonged reperfusion.

Conclusions： Our results demonstrate that NBO treatment given during cerebral ischemia retards the evolution of ischemic brain tissue toward infarction and NBO-preserved cortical tissue survives better than NBO-preserved striatal tissue during the phase of reperfusion.     

Microalbuminuria in patients with acute ischemic stroke

ABSTRACT

Objective: Microalbuminuria could be detected in patients with acute stroke. However, the association between microalbuminuria and the severity of ischemic stroke has not been systematically investigated. This study aimed to systematically explore the prevalence of microalbuminuria in ischemic stroke patients, and the association of microalbuminuria with the severity of ischemic stroke, as well as the prognostic value of microalbuminuria in cerebral infarction patients.

Methods: 160 ischemic stroke patients and 54 controls were enrolled and clinical characteristics were recorded. Severity of stroke was assessed by NIHSS score at admission, and outcome was measured using mRS score. The concentration of urinary microalbumin was collected for each participant. Multiple linear regression analysis was performed to evaluate the relationship between microalbuminuria and the severity of ischemic stroke, and logistic regression analysis was employed to identify the prognostic value of microalbuminuria in ischemic stroke patients.

Results: The incidence of microalbuminuria in ischemic stroke patients was 36.88%. The concentration of urinary microalbumin increased with the increasing of cerebral infarction size, and was independently correlated with NIHSS score at admission and mRS score at 3 months after onset. In multivariate logistic regression analyses, microalbuminuria was one of the independent risk factors for poor prognosis of cerebral infarction patients.

Conclusions: MAU?was?found?in?approximately?one-third of patients with acute ischemic stroke. It was correlated with the severity of cerebral infarction at admission and clinical outcomes at 3 months after onset and could be used as a potential indicator of poor prognosis in ischemic stroke patients.     

Hippocampal cerebral blood flow increased following low-pressure hyperbaric oxygenation in firefighters with mild traumatic brain injury and emotional distress

Background

Recent evidence suggests that hyperbaric oxygenation (HBO), which has been used as an effective treatment for certain types of tissue injury, may change neural activities in the human brain and subsequently improve symptoms of psychiatric disorders. To scrutinize the neural mechanism of HBO in the human brain, we investigated whether 20 sessions of HBO changed regional cerebral blood flow (rCBF) of the limbic system in firefighters with mild traumatic brain injury (mTBI) and subjective emotional distress.

Methods

Twenty firefighters with mTBI and mild emotional distress were treated with HBO at a relatively low pressure of 1.3 atmospheres absolute for 45 min a day for 20 consecutive days (the mild emotional distress group). The rCBF of the limbic system was measured using an arterial spin labeling perfusion magnetic resonance imaging before and after the HBO. Analyses were performed on the data from fourteen individuals who completed the study and 14 age- and sex-matched healthy firefighters (the comparison group).

Results

Firefighters in the mild emotional distress group showed increase rCBF following HBO in a cluster encompassing the right hippocampal and parahippocampal regions (peak t = 4.31; cluster size = 248 mm³)(post-hoc analysis, z = 5.92, p < 0.001) that had lower rCBF relative to the comparison group at baseline (post-hoc analysis, t = ?2.20, p = 0.04).

Conclusion

The current study demonstrated that low-pressure HBO might increase rCBF of the hippocampal and parahippocampal regions, suggesting a potential underpinning mechanism of HBO in the human brain.

     

PAF受体拮抗剂对缺血/再灌注脑损害的作用研究

目的血小板活化因子(platelet activating factor，PAF)与缺血／再灌注(ischemic reperfusion，IR)脑损害有密切关系，此研究拟用PAF受体拮抗剂WEB2086对PAF、炎性细胞浸润及一氧化氮(NO)在脑IR损害中的作用和机制进行探讨。方法采用线栓法制成大鼠大脑中动脉IR模型，对IR脑组织NO含量、局部脑血流量(rCBF)、中性白细胞髓过氧化物酶(MPO)及脑梗死体积进行测定。结果：PAF受体拮抗剂WEB2086对IR脑组织NO的产生有明显影响．且可明显改善IR脑组织的rCBF和显著降低MPO活性，最终减轻局部IR脑损害。结论PAF受体拮抗剂WEB2086对IR脑组织的保护作用与NO有关。     

Troxerutin cerebroprotein hydrolysate injection ameliorates neurovascular injury induced by traumatic brain injury – via endothelial nitric oxide synthase pathway regulation

Abstract

Background: Neurovascular dysfunction caused by traumatic brain injury (TBI) is characterized by cerebralvascular damage, blood–brain barrier (BBB) breakdown, brain edema, etc. This study was designed to assess the protective role of 5 days troxerutin cerebroprotein hydrolysate (TCH) injection treatment against TBI, as well as the potential mechanism.

Methods: The weight-drop model of TBI in male Sprague-Dawley rats was chosen to induce TBI model, rats either with TCH or a vehicle via intraperitoneal injection were examined 3 days after TBI.

Results: TCH resulted in alleviation of neurological deficits, reduction of infarct volume, improvement of regional cerebral blood flow (rCBF), amelioration of neuronal death, astrocyte proliferation, endothelial cell loss, and BBB dysintegrity. These effects of TCH treatment against TBI were through endothelial nitric oxide synthase (eNOS) coupling/decoupling status adjustment, which not only increased nitric oxide (NO) level, but also decreased peroxynitrate level expression.

Conclusions: All the results indicated that TCH injection has multifaceted protective effects of neurovascular unit (NVU) against TBI via eNOS pathway regulation.     

Impaired cerebrovascular reactivity after cortical spreading depression in rats: Restoration by nitric oxide or cGMP

We investigated the role of the NO/cGMP system in the vasodilatory response to hypercapnia after cortical spreading depression (CSD) in barbiturate anesthetized rats in vivo. Regional cerebral blood flow (rCBF) was measured by laser Doppler flowmetry (LDF). Hypercapnia (arterial pCO2 50-60 mm Hg) increased rCBF by 2.8+/-1.0%/mm Hg (n = 34). Fifteen minutes after CSD, resting rCBF was reduced to 87%, and rCBF response to hypercapnia was abolished (p < 0.001, n = 28). Within 1 h after CSD, only little restoration of vascular reactivity occurred. Topical application of the NO-donors S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine (SIN1), or spermine/NO complex (Sperm/NO), or of the cell permeable guanosine 3',5'-cyclic monophosphate (cGMP) analogue 8-Br-cGMP reestablished resting rCBF to values measured before CSD, and reversed CSD-induced attenuation of the cerebrovascular response to hypercapnia. Restoration of resting rCBF to pre-CSD level by the NO-independent vasodilator papaverine had no effect on the attenuated hypercapnic response. In conclusion, we have shown that the compromised vascular reactivity to hypercapnia after CSD can be reversed to normal reactivity by restoration of the basal NO or cGMP concentration in the cortex, suggesting a reduction of the cerebrovascular NO or cGMP concentration following CSD.     

The influence of electro-acupuncture on neural plasticity in acute cerebral infarction

Abstract

Objective: To observe the effect of electro-acupuncture (EA) on dendritic spine and ephrin-A5 and to investigate the action of EA on neural plasticity after acute cerebral ischemic infarction.

Methods: Focal acute cerebral ischemia model was established by middle cerebral artery occlusion (MCAO) with electrocoagulation contralateral method. Ninety male Sprague–Dawley rats were randomly divided into sham operation (SO) group, MCAO group and EA treatment (ET) group. Golgi dying, double immunofluorescence method and RT-PCR were used to detect dendritic spine density, expression patterns of ephrin-A5 and the effect of EA on them at the end of the first, second and fourth week after ischemia.

Results: The dendritic spine density in MCAO group significantly decreased after ischemia (p<0.01). The dendritic spine density was raised in ET group in the corresponding time period (p<0.01) and among the ET groups. It was higher at the end of the fourth week than before (p<0.05). The signal of ephrin-A5 was detected mainly in neuron cytoplasm, and the mRNA expression in MCAO group and ET group increased compared to that in SO group (p<0.01). The mRNA expression in ET group at the first week was much higher than that in MCAO group (p<0.01). In ET groups, the mRNA expression of ephrin-A5 was down-regulated along with the time going (p<0.01).

Conclusion: It is possibly the regulation of the ephrin-A5 expression by which EA treatment improves the neural plasticity at the peri-infarct cerebral cortex in acute cerebral ischemia rat. There may be a time window in EA treatment for acute cerebral ischemia.     

NOS抑制剂对缺血再灌注脑组织rCBF及白细胞浸润的影响研究

目的应用非选择性NOS抑制剂L－NAME和选择性iNOS抑制剂AG治疗鼠大脑中动脉缺血再灌注损伤。通过对脑梗死体积、rCBF和白细胞浸润程度的观察，研究探讨不同类型NOS抑制剂治疗脑梗死的机制。方法采用线检法制作鼠大脑中动脉缺血再灌注模型，不同缺血及再灌注时间测定脑梗死体积、rCBF、缺血脑组织MPO酶活性。结果应用L－NAME（15mg／kg，ip）不但阻碍再灌注后rCBF的恢复，也增加缺血脑组织MPO酶活性（中性白细胞浸润增加），致脑梗死体积增加，脑损害加重；而AG（150mg／kg，ip）可有效降低脑梗死体积，且不影响rCBF的恢复和中性白细胞浸润。结论早期过度抑制神经元和内皮细胞NO对血流量的调节和抗白细胞粘附浸润作用可能是L-NAME加重缺血再灌注脑损害的重要原因之一，而选择性iNOS抑制剂有确切的脑保护作用。     

Phosphodiesterase type 5 inhibition coupled to strong reinforcement results in two periods of transient retention loss in the young chick

Previous behavioural studies which have administered phosphodiesterase type-5 (PDE5) inhibitors have consistently demonstrated improved retention. However, when young chicks were trained on a strongly reinforced passive avoidance task 100microM zaprinast caused two periods of transient retention loss. This is opposed to past findings and may suggest an effect on retrieval. It is hypothesised that the level of reinforcement is central to this phenomenon. The molecular corollary of this may be the need to maintain cGMP homeostasis such that strong reinforcement+zaprinast may impair retention through the production of excessive levels of cGMP. This was demonstrated by two challenge studies whereby increasing concentrations of 8-Br-cGMP were administered in the presence of the guanylate cyclase inhibitor ODQ (100microM; ic) resulting in an inverted "U-shaped" retention curve. These findings suggest a more complex role for PDE5 and cGMP in memory processing than previously described and question the role of PDE5 inhibitors as nootropes under all circumstances.     

Phosphodiesterase-5 Inhibitor Attenuates Anxious Phenotypes and Movement Disorder Induced by Mild Ischemic Stroke in Rats

ObjectivePatients with mild ischemic stroke experience various sequela and residual symptoms, such as anxious behavior and deficits in movement. Few approaches have been proved to be effective and safe therapeutic approaches for patients with mild ischemic stroke by acute stroke. Sildenafil (SIL), a phosphodiesterase-5 inhibitor (PDE5i), is a known remedy for neurodegenerative disorders and vascular dementia through its angiogenesis and neurogenesis effects. In this study, we investigated the efficacy of PDE5i in the emotional and behavioral abnormalities in rats with mild ischemic stroke. MethodsWe divided the rats into four groups as follows (n=20, respectively) : group 1, naïve; group 2, middle cerebral artery occlusion (MCAo30); group 3, MCAo30+SIL-pre; and group 4, MCAo30+SIL-post. In the case of drug administration groups, single dose of PDE5i (sildenafil citrate, 20 mg/kg) was given at 30-minute before and after reperfusion of MCAo in rats. After surgery, we investigated and confirmed the therapeutic effect of sildenafil on histology, immunofluorescence, behavioral assays and neural oscillations. ResultsSildenafil alleviated a neuronal loss and reduced the infarction volume. And results of behavior task and immunofluorescence shown possibility that anti-inflammation process and improve motor deficits sildenafil treatment after mild ischemic stroke. Furthermore, sildenafil treatment attenuated the alteration of theta-frequency rhythm in the CA1 region of the hippocampus, a known neural oscillatory marker for anxiety disorder in rodents, induced by mild ischemic stroke. ConclusionPDE5i as effective therapeutic agents for anxiety and movement disorders and provide robust preclinical evidence to support the development and use of PDE5i for the treatment of mild ischemic stroke residual disorders.