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1.
Free radicals have gained wide acceptance as mediators of cerebral ischemic injury. It has previously been reported that a spin trap nitrone, alpha-phenyl-N-tert-butyl nitrone (PBN), can reduce infarct volumes in rats subjected to either permanent or transient focal cerebral ischemia. A recent study has demonstrated that NXY-059, a novel free radical trapping nitrone compound, has a neuroprotective effect against transient focal cerebral ischemia. This study was designed to determine the effect of NXY-059 in a rodent model of permanent focal cerebral ischemia. Male spontaneously hypertensive rats were subjected to permanent middle cerebral artery occlusion (MCAO) by placement of a microaneurysm clip on the middle cerebral artery (MCA). Animals were divided into three groups: (1) physiological saline given as a 1 ml/kg i.v. bolus administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 0.5 ml/h of physiological saline for 24 h (n=10); (2) 30 mg/kg, 1 ml/kg, i.v. bolus of NXY-059 dissolved in physiological saline administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 30 mg/kg/h, 0.5 ml/h, of NXY-059 for 24 h (n=9); (3) 60 mg/kg, 1 ml/kg, i.v. bolus of NXY-059 dissolved in physiological saline administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 60 mg/kg/h, 0.5 ml/h, of NXY-059 for 24 h (n=12). Infarction was quantified after a survival period of 24 h. Differences in infarct volume were examined with one-way ANOVA following Dunnet's multiple comparison test. The percentage of cortical infarction in the saline control group was 22.6 +/- 6.8% (mean+/-S.D.) of contra-lateral hemisphere, and in the 30 mg/kg/h NXY-059-treated group was 17.4% +/- 6.8% (NS). Plasma concentration (microM/l) of NXY-059 in the 30 mg/kg/h group was 80.2 +/- 52.2 (n=9), while in the 60 mg/kg/h group plasma concentration (microM/l) of NXY-059 was 391.0 +/- 207.0 (n=10). Infarction in the 60 mg/kg/h NXY-059-treated group was significantly reduced (P=0.009) to 14.5 +/- 5%. Our preliminary data demonstrate that administration of NXY-059 (60 mg/kg/h for 24 h) ameliorates cortical infarction in rats subjected to permanent focal cerebral ischemia with 24 h survival. 相似文献
2.
Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. 总被引:9,自引:0,他引:9
S Kuroda R Tsuchidate M L Smith K R Maples B K Siesj? 《Journal of cerebral blood flow and metabolism》1999,19(7):778-787
Recent results have demonstrated that the spin trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN) reduces infarct volume in rats subjected to 2 hours of middle cerebral artery occlusion, even when given 1 to 3 hours after the start of recirculation. In the current study, the authors assessed the effect of NXY-059, a novel nitrone that is more soluble than PBN. Loading doses were given of 0.30, 3.0, or 30 mg x kg(-1) followed by 0.30, 3.0, or 30 mg x kg(-1) x h(-1) for 24 or 48 hours. Dose-response studies showed that when treatment was begun 1 hour after recirculation, 0.30 mg x kg(-1) had a small and 30 mg x kg(-1) a marked effect on infarct volume. At equimolar doses (3.0 mg x kg(-1) for NXY-059 and 1.4 mg x kg(-1) for PBN), NXY-059 was more efficacious than PBN. Similar results were obtained when a recovery period of 7 days was allowed. The window of therapeutic opportunity for NXY-059 was 3 to 6 hours after the start of recirculation. Studies of the transfer constant of [14C]NXY-059 showed that, in contrast to PBN, this more soluble nitrone penetrates the blood-brain barrier less extensively. This fact, and the pronounced antiischemic effect of NXY-059, suggest that the delayed events leading to infarction may be influenced by reactions occurring at the blood-endothelial interface. 相似文献
3.
Oxygen free radical generation may have important secondary damaging effects after the onset of cerebral ischemia. Free radical scavengers have been used successfully in attenuating neuronal damage in the reperfusion period in transient forebrain ischemia. There are limited data on effectiveness in models of focal ischemia. Two free radical scavengers, alpha-phenyl-n-tert-butyl-nitrone (PBN) and N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN), have been shown to reduce oxidative-stress-induced neuronal injury. Whereas PBN has been demonstrated to reduce infarct volume in focal ischemia, neuroprotection has not been evaluated with S-PBN. The present study was designed to evaluate the neuroprotective effect of PBN and S-PBN compared to vehicle in a focal embolic middle cerebral artery (MCA) cerebral ischemia model in rats. Wistar rats were randomly divided into three groups (n = 10 each group). Animals in the control group received vehicle and those in the treatment groups were treated with PBN or S-PBN (both 100 mg/kg/day x 3 days, intraperitoneally) starting 2 h after the introduction of an autologous thrombus into the right-side MCA. The neurological outcome was observed and compared before and after treatment and between groups. The percentage of cerebral infarct volume was estimated from 2,3, 5-triphenyltetrazolium chloride stained coronal slices 72 h after the ischemic insult. Two-hour postischemia administration of PBN or S-PBN significantly improved neurobehavioral scores at 24 h following MCA embolization (both P < 0.01). The percentage of infarct volume for animals receiving vehicle was 32.8 +/- 9.4%. Two-hour delayed administration of PBN and S-PBN achieved a 35.4% reduction in infarct volume in treatment groups when compared with animals receiving vehicle (PBN vs control, 21.2 +/- 10.9% vs 32.8 +/- 9.4%; P < 0.05; S-PBN vs control, 21.2 +/- 13.1%, (P < 0.05). These data indicate that free radical generation may be involved in brain damage in this model and 2-h delayed postischemia treatment with PBN and S-PBN may have neuroprotective effects in focal cerebral ischemia. As S-PBN does not normally cross the blood-brain barrier, the neuroprotection evident in this study may be explained by entry into the brain via damaged vessels. 相似文献
4.
N Marklund T Lewander F Clausen L Hillered 《Journal of cerebral blood flow and metabolism》2001,21(11):1259-1267
In previous studies, the authors showed that the nitrone radical scavenger alpha-phenyl-N- tert -butyl nitrone (PBN) and its sulfo-derivative, 2-sulfo-phenyl-N- tert -butyl nitrone (S-PBN), attenuated cognitive disturbance and reduced tissue damage after traumatic brain injury (TBI) in rats. In the current study, the production of reactive oxygen species (ROS) after TBI was monitored with microdialysis and the 4-hydroxybenzoic acid (4-HBA) trapping method. A single dose of PBN (30 mg/kg) or an equimolar dose of S-PBN (47 mg/kg) was administered intravenously 30 minutes before a controlled cortical contusion injury in rats. Plasma and brain tissue drug concentrations were analyzed at the end of the microdialysis experiment (3 hours after injury) and, in a separate experiment with S-PBN, at 30 and 60 minutes after injury. Traumatic brain injury caused a significant increase in ROS formation that lasted for 60 minutes after the injury as evidenced by increased 3,4-dihydroxybenzoic acid (3,4-DHBA) concentrations in the dialysate. PBN and S-PBN equally and significantly attenuated the posttraumatic increase in 3,4-DHBA formation. High PBN concentrations were found bilaterally in brain tissue up to 3 hours after injury. In contrast, S-PBN was rapidly cleared from the circulation and was not detectable in brain at 30 minutes after injury or at any later time point. The results suggest that scavenging of ROS after TBI may contribute to the neuroprotective properties observed with nitrone spin-trapping agents. S-PBN, which remained undetectable even in traumatized brain tissue, reduced ROS production to the same extent as PBN that readily crossed the blood-brain barrier. This finding supports an important role for ROS production at the blood-endothelial interface in TBI. 相似文献
5.
The status epilepticus (SE) induced in rats by lithium-pilocarpine (Li-pilo) shares many common features with soman-induced SE including extensive limbic neuropathology. Reactive oxygen species are hypothesized to play a role in the SE induced neuropathology and we propose that the free radical scavengers alpha-phenyl-N-tert-butyl nitrone (PBN) and N-tert-butyl-alpha-(2 sulfophenyl) nitrone (S-PBN) may be neuroprotective. PBN or S-PBN were administered either immediately following pilocarpine (exposure treatment) or 5 min after the onset of SE as determined by ECoG activity. SE was allowed to continue for 3 h before termination with propofol. The rats were sacrified 24 h following pilocarpine administration. S-PBN induced minor effects to reduce SE duration and improve neurological deficit 24 h following pilocarpine administration. One hundred and fifty milligrams per kilograms PBN administered 5 min after SE onset produced significant neuroprotection in the parietal, occipital, perirhinal and piriform cortices as well as the lateral amygdala. One hundred and fifty milligrams per kilograms S-PBN was neuroprotective only in the occipital and perirhinal cortex while 300 mg/kg S-PBN exacerbated cortical neuropathology. S-PBN administered 5 min after SE onset exacerbated neuropathology in thalamic regions. In contrast, PBN and S-PBN administered as exposure treatment exacerbated neuropathology in thalamic and CA3 regions. The differential neuroprotective effects of PBN and S-PBN may be the result of the poor brain penetration by S-PBN. The results suggest that free radical scavenger activity is neuroprotective in cortical regions during cholinergic convulsions. Regional variations in drug-induced neuroprotectant activity in Li-pilo SE are common and suggest multiple mechanisms of neuropathology. 相似文献
6.
Effect of NXY-059 on secondary mitochondrial dysfunction after transient focal ischemia; comparison with cyclosporin A 总被引:3,自引:0,他引:3
The free radical trapping agents NXY-059 and alpha-phenyl-N-tert.-butylnitrone (PBN) markedly reduce infarct volume, even when given 1 or 3 h after the start of recirculation, following 2 h of middle cerebral artery (MCA) occlusion in rats. Their anti-ischemic effects are shared by the two immunosuppressants cyclosporin A (CsA) and FK506. Interestingly, CsA causes an additional reduction in infarct volume when given after only 5 min of recirculation, possibly reflecting blockade of a mitochondrial permeability transition (MPT) pore. PBN, CsA and FK506 are known to ameliorate the secondary dysfunction of mitochondrial function, as assessed in vitro, which occurs during the first 4-6 h of recirculation. The present experiments were undertaken to assess whether NXY-059 reduces tissue damage by acting directly on mitochondrial membranes, and provided that this is the case, if blockade of an MPT is involved. The results were compared to those of CsA, which thus served as a reference compound. NXY-059 was given i.v. after 5 min and 1 h, and CsA after 5 min of recirculation. Both NXY-059 and CsA reduced infarct volumes to about 30% of control, prevented the secondary decline in mitochondrial respiratory function during recirculation, and reduced the mitochondrial release of cytochrome c after 6 and 24 h of recirculation. However, NXY-059 failed to block the effect of Ca(2+) on mitochondrial swelling in vitro, as CsA did. Furthermore, NXY-059, given after 5 min of recirculation, did not reproduce the effects of CsA. The results thus suggest that NXY-059 exerts its effects on mitochondria by indirect mechanisms. 相似文献
7.
Coadministration of NXY-059 and tenecteplase six hours following embolic strokes in rabbits improves clinical rating scores 总被引:2,自引:0,他引:2
Currently, the only FDA-approved treatment for acute ischemic stroke (AIS) is the thrombolytic, tissue plasminogen activator (tPA; alteplase; activase). It has been proposed that both the spin trap agent NXY-059 (cerovive) and tenecteplase (TNK-tPA), which are currently in phase II clinical trials, may also be useful for the treatment of ischemic stroke. However, there is little information available concerning the dose-response profiles or therapeutic window for NXY-059 in a validated embolic stroke model, nor is there information available pertaining to the effects of combining NXY-059 with tenecteplase. Thus, we determined the pharmacological profile of NXY-059 on behavioral outcome following small clot embolic strokes in rabbits when administered alone or in combination with tenecteplase. Male New Zealand white rabbits were embolized by injecting a suspension of small blood clots into cerebral circulation via a carotid catheter. NXY-059 (0.1-100 mg/kg) was infused intravenously (IV), 1 h following embolization, whereas control rabbits received infusions of saline. We also determined the therapeutic window for NXY-059 by administering the drug 1, 3, or 6 h following embolic strokes. Lastly, in combination studies, NXY-059 was given concomitantly with tenecteplase 1 or 6 h following embolization. In the vehicle control group, the P(50) value (milligrams of clots that produce behavioral deficits in 50% of the rabbits) measured 24 h following embolism was 1.20 +/- 0.15 mg, and this was increased by 100-134% if NXY-059 (1-100 mg/kg) was administered following embolization. If NXY-059 was administered beginning 3 or 6 h following embolization, there was no significant behavioral improvement. If NXY-059 (100 mg/kg) and tenecteplase (0.9 mg/kg) were administered concomitantly 1 h postembolization, we did not measure any additional behavioral improvement compared to either drug alone. However, if the drugs were administered 6 h following embolization, we measured a statistically significant reduction of behavioral deficits. This study shows that NXY-059 is neuroprotective over a wide range if administered early following an embolic stroke. In addition, the study shows that NXY-059 can be administered in combination with tenecteplase to provide additional behavioral improvement at extended delays following embolization. 相似文献
8.
Savitz SI 《Experimental neurology》2007,205(1):20-25
Neuroprotection represents a failed strategy to improve outcome after acute ischemic stroke (AIS). However, most neuroprotective drugs have been inadequately studied in animal stroke models, which led to the creation of the STAIR guidelines on preclinical and clinical testing of therapeutics for AIS. NXY-059, a free radical spin trap agent, was felt by many to have followed these criteria and it was recently shown to improve outcome in AIS patients in the SAINT I trial. However, the repeat, SAINT II trial was a neutral study, the results of which cast doubt on neuroprotection as a viable strategy for AIS. A critical analysis of the NXY-059 preclinical data, however, reveals several shortcomings that have not been addressed in the literature. This report contends that the preclinical evaluation of NXY-059 lacked strenuous testing and was not shown to reproducibly lead to robust protection in extended time windows in clinically relevant stroke models, at several different academic research laboratories. The clinical trials of NXY-059 were inadequately designed, in part, because of inappropriate treatment windows and inclusion of diverse stroke patients. Future neuroprotective agents need more rigorous testing in animal models of focal cerebral ischemia and appropriate evaluation in clinical studies that better match the preclinical data. 相似文献
9.
Diazoxide preconditioning attenuates global cerebral ischemia-induced blood-brain barrier permeability 总被引:6,自引:0,他引:6
Brain edema formation due to blood-brain barrier (BBB) disruption is a major consequence of cerebral ischemia. Previously, we demonstrated that targeting mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) protects neuronal tissues in vivo and in vitro, however, the effects of mitoK(ATP) openers on cerebral endothelial cells and on BBB functions have never been examined. We investigated the effects of mitoK(ATP) channel opener diazoxide on BBB functions during ischemia/reperfusion injury (I/R). Rats were treated with 6, 20 or 40 mg/kg diazoxide ip for 3 days then exposed to global cerebral ischemia for 30 min. BBB permeability was assessed by administering Evan's-blue (EB) and Na-fluorescein (NaF) at the beginning of the 30 min reperfusion. I/R increased BBB permeability for the large molecular weight EB (ng/mg) in the cortex (control: 146 +/- 12, n = 7; I/R: 1049 +/- 152, n = 11) which was significantly attenuated in diazoxide-treated rats (575 +/- 99, n = 9; 582 +/- 104, n = 8; 20 and 40 mg/kg doses). Diazoxide pretreatment also significantly inhibited the extravasation of the low molecular weight NaF. Edema formation in the cortex was also decreased after diazoxide pretreatment. In cultured cerebral endothelial cells, diazoxide depolarized the mitochondrial membrane, suggesting a direct diazoxide effect on the endothelial mitochondria. Our results demonstrate that preconditioning of cerebral endothelium with diazoxide protects the BBB against ischemic stress. 相似文献
10.
Ginsberg MD 《Stroke; a journal of cerebral circulation》2007,38(6):1967-1972
The SAINT II Trial, a large randomized multicenter clinical trial of the putative neuroprotectant, NXY-059, failed to demonstrate a treatment benefit in acute ischemic stroke. The further development of this agent was suspended. The implications of this outcome are considered from several perspectives, including: (1) the marginally positive antecedent trial, SAINT I, and the critical commentary stimulated by it, which called attention to its interpretively challenging primary outcome measure--a shift in the full-scale modified Rankin scale score--and to other statistical shortcomings; (2) the cogency of the STAIR recommendations, to which the development of NXY-059 closely adhered; and (3) the inherent physiochemical shortcomings of NXY-059 as a neuroprotective agent--its polar, nonlipophilic nature, poor blood-brain barrier penetrability, nonphysiological oxidation potential, and low potency. Caution is urged, however, regarding the unwarranted adoption of a nihilistic view toward neuroprotection on the part of the stroke community in view of the abundant preclinical evidence demonstrating proof-of-principle of the feasibility of neuroprotection, as well as the multiplicity of biochemical and molecular neuroprotective targets. The author offers the personal example of a translational journey in which a promising neuroprotectant agent targeting multiple injury mechanisms, high-dose albumin therapy, has proceeded successfully from preclinical studies that established efficacy through a pilot clinical trial that demonstrated safety and offered strong suggestions of clinical efficacy, leading to a large multicenter clinical trial currently in progress. 相似文献
11.
背景:诸多研究证实,短暂性脑缺血预处理可诱导脑缺血耐受。然而,脑缺血耐受的内源性保护机制尚未明确。
目的:观察脑缺血预处理诱导脑缺血耐受大鼠再灌注不同时间窗血脑屏障通透性改变及基质金属蛋白酶9表达的变化。
方法:将Wistar大鼠随机分为3组,缺血预处理组采用线栓法阻塞大脑中动脉10 min建立局灶性缺血预处理模型,分别在缺血预处理后1,3,7,14,21 d进行再次缺血2 h;模型组不进行缺血预处理,假手术组不阻塞血管。于再灌注22 h进行神经功能检测,采用TTC染色测定脑梗死体积,通过测定渗出血管外的伊文思蓝含量来评价血脑屏障通透性的变化,免疫组织化学和原位杂交法检测基质金属蛋白酶9蛋白及mRNA的表达。
结果与结论:与模型组比较,缺血预处理组1,3,7 d亚组的神经功能评分、脑梗死体积、血脑屏障通透性、脑含水量以及基质金属蛋白酶9蛋白和mRNA表达均明显减小/降低(P < 0.05或P < 0.01),其中以3 d亚组降低最为明显。提示缺血预处理诱导了脑缺血耐受,预缺血诱导的血脑屏障通透性改变以及基质金属蛋白酶9表达减低在脑缺血耐受中发挥重要作用。 相似文献
12.
S. Chapat V. Frey N. Claperon C. Bouchaud F. Puisieux P. Couvreur P. Rossignol J. Delattre 《Brain research bulletin》1991,26(3):339-342
This study was performed to elucidate the mechanism by which adenosine triphosphate (ATP) encapsulated into liposomes was able to protect against experimental brain ischemia in the rat. After intracarotidal administration of liposomally entrapped ATP, the ATP blood level increased dramatically whereas no change was observed after administration of free ATP. This suggested that liposomes may protect ATP from its degradation by endothelial ectonucleotidases. On the other hand, it was observed that after administration of liposomally entrapped carboxyfluorescein (CF) to ischemic rats, the distribution of the brain fluorescence under the form of numerous punctiform structures was completely different from the diffuse fluorescence obtained with free CF injections. These data suggest that under certain hypoxic conditions the blood-brain barrier is open allowing the liposomes to reach the cerebral parenchyma. The mechanism of brain uptake is, however, still unclear: endothelial tight junctions opening or endothelial transcytosis. 相似文献
13.
Stilbazulenyl nitrone,a novel antioxidant,is highly neuroprotective in focal ischemia 总被引:1,自引:0,他引:1
Ginsberg MD Becker DA Busto R Belayev A Zhang Y Khoutorova L Ley JJ Zhao W Belayev L 《Annals of neurology》2003,54(3):330-342
Azulenyl nitrones are novel chain-breaking antioxidants with low oxidation potentials and high lipophilicity-properties favoring their efficacy as neuroprotectants. We tested the second-generation azulenyl nitrone, stilbazunenlyl nitrone (STAZN), in focal ischemic stroke. Physiologically monitored rats received 2 hours of middle cerebral artery occlusion by intraluminal suture, resulting in substantial cortical and striatal infarcation. Neurobehavior was quantified on a standard battery, and brains were perfusion-fixed for quantitative histopathology at 3 days. In 3 independent series, rats were treated at either 2h + 4h, or 2h + 4h + 24h + 48h, after onset of ischemia; vehicle-treated rats received dimethylsulfoxide or saline. All animals (n = 52) developed high-grade neurological deficits (score 11 of 12) during ischemia, which improved, in STAZN-treated rats, within 1-1.5 h of the initial dose and fell to a median score of 3 at 72 h, compared to 8 in vehicle rats. STAZN treatment reduced mean cortical infarct volume by 64-97%, and total infarct volume by 42-72%. In over one-half of STAZN-treated animals, cortical infarction was virtually abolished. Regression analysis predicted that STAZN would confer approximately 50% cortical neuroprotection even in the most severely affected cases. The potency of STAZN was orders-of-magnitude greater than other nitrones such as NXY-059. These results suggest that STAZN has great promise for ischemic stroke. 相似文献
14.
《中国神经再生研究》2014,(15)
Danhong injection(DHI),a Chinese Materia Medica standardized product extracted from Radix Salviae miltiorrhizae and Flos Carthami tinctorii,is widely used in China for treating acute ischemic stroke.In the present study,we explored the neuroprotective efficacy of DHI in a rat model of temporary middle cerebral artery occlusion,and evaluated the potential mechanisms underlying its effects.Pretreatment with DHI(0.9 and 1.8 mL/kg)resulted in a significantly smaller infarct volume and better neurological scores than pretreatment with saline.Furthermore,DHI significantly reduced the permeability of the blood-brain barrier,increased occludin protein expression and decreased neutrophil infiltration,as well as profoundly suppressing the upregulation of matrix metallopeptidase-9 expression seen in rats that had received vehicle.Matrix metallopeptidase-2 expression was not affected by ischemia or DHI.Moreover,DHI(1.8 mL/kg)administered 3 hours after the onset of ischemia also improved neurological scores and reduced infarct size.Our results indicate that the neuroprotective efficacy of DHI in a rat model of cerebral ischemia-reperfusion injury is mediated by a protective effect on the blood-brain barrier and the reversal of neutrophil infiltration. 相似文献
15.
VEGF protects brain against focal ischemia without increasing blood--brain permeability when administered intracerebroventricularly. 总被引:5,自引:0,他引:5
Dilaver Kaya Yasemin Gürsoy-Ozdemir Muge Yemisci Ne?e Tuncer Sevin? Aktan Turgay Dalkara 《Journal of cerebral blood flow and metabolism》2005,25(9):1111-1118
Delayed administration of vascular endothelial growth factor (VEGF) promotes functional recovery after focal cerebral ischemia. However, early intravenous injection of VEGF increases blood-brain barrier (BBB) leakage, hemorrhagic transformation and infarct volume whereas its application to cortical surface is neuroprotective. We have investigated whether or not early intracerebroventricular administration of VEGF could replicate the neuroprotective effect observed with topical application and the mechanism of action of this protection. Mice were subjected to 90 mins middle cerebral artery (MCA) occlusion and 24 h of reperfusion. Vascular endothelial growth factor (8 ng, intracerebroventricular) was administered 1 or 3 h after reperfusion. Compared with the vehicle-treated (intracerebroventricular) group, VEGF decreased the infarct volume along with BBB leakage in both treatment groups. Neurologic disability scores improved in parallel to the changes in infarct volume. Independently of the decrease in infarct size, VEGF also reduced the number of TUNEL-positive apoptotic neurons. Phospo-Akt levels were significantly higher in ischemic hemispheres of the VEGF-treated mice. Contrary to intracerebroventricular route, intravenous administration of VEGF (15 microg/kg) enhanced the infarct volume as previously reported for the rat. In conclusion, single intracerebroventricular injection of VEGF protects brain against ischemia without adversely affecting BBB permeability, and has a relatively long therapeutic time window. This early neuroprotective action, observed well before recovery-promoting actions such as angiogenesis, possibly involves activation of the PI-3-Akt pathway. 相似文献
16.
Atticus H Hainsworth Nasrin Bhuiyan A Richard Green 《Journal of cerebral blood flow and metabolism》2008,28(1):24-28
Disodium 2,4-sulphophenyl-N-tert-butylnitrone (NXY-059) is a novel free radical-trapping compound that is neuroprotective in both rodent and primate models of acute ischaemic stroke. Neuroprotection in vitro by NXY-059 has not been reported previously, and we have now investigated whether such an effect can be detected using a simple cell culture model of neurotoxicity. Neuron-like cells of the neuroblastoma-derived clonal cell line N1E-115 were exposed to the free radical-generating agent sodium nitroprusside (SNP), which produced a concentration-dependent reduction in mitochondrial complex II activity 24 h later (EC(50) approximately 100 micromolar). Cell death induced by SNP (100 micromolar), assessed either by an increased proportion of apoptotic nuclear morphology or by mitochondrial complex II activity, was inhibited by a cocktail of known antioxidants (ascorbate, reduced glutathione, and dithiothreitol, all at 100 micromolar) but not by NXY-059 at a concentration known to be neuroprotective in vivo (300 micromolar). Disodium 2,4-sulphophenyl-N-tert-butylnitrone was also without effect on H(2)O(2)-mediated cytotoxicity. These results support recent data suggesting that in vivo NXY-059 probably acts at the neurovascular unit rather than at an intracellular site as a neuroprotective agent. 相似文献
17.
Green AR Lanbeck-Vallén K Ashwood T Lundquist S Lindström Böö E Jonasson H Campbell M 《Brain research》2006,1072(1):224-226
The penetration of the free radical trapping neuroprotectant NXY-059 into the brain has been examined in rats subjected to permanent middle cerebral artery occlusion (pMCAO). NXY-059 (125 mg/kg bolus followed by 125 mg/kg/h) was infused for 4 h 45 min starting 15 min after right pMCAO or sham operation. At 5 h, there was a similar plasma total NXY-059 concentration (μmol/L) in both groups [sham: 623 ± 44 (6); pMCAO: 605 ± 43 (5)] and a similar drug concentration (nmol/g) in the right cortex [sham: 6.92 ± 1.05 (6); pMCAO: 6.14 ± 2.18 (6)]. A subsequent experiment in normal rats, infusing NXY-059 at both a similar and higher concentration (252 mg/kg bolus and 252 mg/kg/h), demonstrated that the concentration of NXY-059 in cortex increased linearly with respect to the plasma concentration. These data demonstrate that NXY-059 does penetrate brain tissue in control animals and ischemic tissue of animals subjected to pMCAO. 相似文献
18.
Shaoxia Wang ;Hong Guo ;Xumei Wang ;Lijuan Chai ;Limin Hu ;Tao Zhao ;Buchang Zhao ;Xiaoxu Tan ;Feifei Jia 《中国神经再生研究》2014,9(15):1453-1459
Danhong injection (DHI), a Chinese Materia Medica standardized product extracted from Radix Salviae miltiorrhizae and Flos Carthami tinctorii, is widely used in China for treating acute isch-emic stroke. In the present study, we explored the neuroprotective efficacy of DHI in a rat model of temporary middle cerebral artery ocdusion, and evaluated the potential mechanisms under-lying its effects. Pretreatment with DHI (0.9 and 1.8 mL/kg) resulted in a significantly smaller infarct volume and better neurological scores than pretreatment with saline. Furthermore, DHI significantly reduced the permeability of the blood-brain barrier, increased occludin protein expression and decreased neutrophil infiltration, as well as profoundly suppressing the upreg-ulation of matrix metallopeptidase-9 expression seen in rats that had received vehicle. Matrix metallopeptidase-2 expression was not affected by ischemia or DHI. Moreover, DHI (1.8 mL/kg) administered 3 hours after the onset of ischemia also improved neurological scores and reduced infarct size. Our results indicate that the neuroprotective efficacy of DHI in a rat model of cerebral ischemia-reperfusion injury is mediated by a protective effect on the blood-brain barrier and the reversal of neutrophil infiltration. 相似文献
19.
血脑屏障内皮细胞与细胞间粘附分子-1在鼠脑缺血性脑水肿发生机制中的作用 总被引:12,自引:0,他引:12
目的研究缺血性脑水肿病理过程中血脑屏障内皮细胞及其细胞间粘附分子-1(intercellularadhesionmolecule-1,ICAM-1)的表达与血脑屏障通透性的关系.方法用电镜技术和免疫组织化学方法观察脑缺血过程中大鼠血脑屏障内皮细胞超微结构及其ICAM-1的表达和对镧离子的通透性改变.结果脑缺血后1h,缺血区脑组织血脑屏障内皮细胞未见ICAM-1表达,但电镜下可见内皮细胞轻度肿胀.3h,ICAM-1开始表达,缺血区脑组织轻度水肿,内皮细胞肿胀.至12h,ICAM-1表达达到高峰,脑组织严重水肿,内皮细胞、神经细胞及胶质细胞明显肿胀;内皮细胞胞饮小泡包含有被吞噬的镧离子,有些镧离子进入紧密连接间隙.72h,ICAM-1表达已明显减少,脑组织水肿仍较重,内皮细胞严重破坏,大量镧离子漏出血管外,进入脑实质.结论脑缺血后血脑屏障的破坏与ICAM-1的表达密切相关,提示ICAM-1参与血脑屏障内皮细胞的破坏过程,而且这些改变在缺血性脑水肿的病理过程中起重要作用. 相似文献
20.
Samuel Valable Joan Montaner Anita Bellail Vincent Berezowski Julien Brillault Romeo Cecchelli Didier Divoux Eric T Mackenzie Myriam Bernaudin Simon Roussel Edwige Petit 《Journal of cerebral blood flow and metabolism》2005,25(11):1491-1504
After cerebral ischemia, angiogenesis, by supplying for the deficient perfusion, may be a beneficial process for limiting neuronal death and promoting tissue repair. In this study, we showed that the combination of Ang-1 and vascular endothelial growth factor (VEGF) provides a more adapted therapeutic strategy than the use of VEGF alone. Indeed, we showed on a focal ischemia model that an early administration of VEGF exacerbates ischemic damage, because of its effects on blood-brain barrier (BBB) permeability. In contrast, a coapplication of Ang-1 and VEGF leads to a significant reduction of the ischemic and edema volumes by 50% and 42%, respectively, in comparison with VEGF-treated mice. We proposed that Ang-1 blocks the BBB permeability effect of VEGF in association with a modulation of matrix metalloproteinase (MMP) activity. Indeed, we showed on both ischemic in vivo and BBB in vitro models that VEGF enhances BBB damage and MMP-9 activity and that Ang-1 counteracts both effects. However, we also showed a synergic angiogenic effect of Ang-1 and VEGF in the brain. Taken together, these results allow to propose that, in cerebral ischemia, the combination of Ang-1 and VEGF could be used early to promote the formation of mature neovessels without inducing side effects on BBB permeability. 相似文献