Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in neonatal rats

BACKGROUND: Perinatal stroke is a common human disease. Neonatal brains are immature and engaged in active synaptogenesis. Preconditioning adult rats with the volatile anesthetic isoflurane induces neuroprotection. Whether isoflurane preconditioning induces neuroprotection in neonates is not known. METHODS: Seven-day-old Sprague-Dawley rats had left common carotid arterial ligation followed by hypoxia with 8% oxygen for 1, 2, or 2.5 h at 37 degrees C. Isoflurane preconditioning with 1 or 1.5% isoflurane for 30 min was performed at 24 h before the brain hypoxia/ischemia. The inducible nitric oxide synthase inhibitor aminoguanidine (200 mg/kg, intraperitoneally) was administered 30 min before the isoflurane pretreatment. The weight ratio of left to right cerebral hemispheres at 7 days after the brain hypoxia/ischemia was calculated. The mortality during the period from cerebral hypoxia/ischemia to 7 days afterwards was monitored. In another experiment, 6-day-old rats were exposed to 1.5% isoflurane for 30 min. The cerebral hemispheres were removed at various time points for Western analysis of inducible nitric oxide synthase. RESULTS: The mortality was about 40% in neonates with brain hypoxia/ischemia for 2 h or 2.5 h and was not altered by isoflurane preconditioning. The weight ratio of left/right cerebral hemispheres in the survivors was 0.99 +/- 0.02, 0.65 +/- 0.19, and 0.86 +/- 0.15 (n = 7-18) for the rats in control, brain hypoxia/ischemia for 2.5 h, and isoflurane preconditioning plus brain hypoxia/ischemia for 2.5 h groups, respectively (P < 0.05 for the comparisons between control versus brain hypoxia/ischemia and brain hypoxia/ischemia versus isoflurane preconditioning plus brain hypoxia/ischemia). This isoflurane preconditioning-induced neuroprotection was abolished by aminoguanidine (the weight ratio was 0.61 +/- 0.18, n = 12). Isoflurane induced a time-dependent increase in the inducible nitric oxide synthase proteins. CONCLUSIONS: Isoflurane preconditioning induces neuroprotection in neonatal rats. This neuroprotection is inducible nitric oxide synthase-dependent.     

Isoflurane Preconditioning Induces Neuroprotection That Is Inducible Nitric Oxide Synthase-dependent in Neonatal Rats

Background: Perinatal stroke is a common human disease. Neonatal brains are immature and engaged in active synaptogenesis. Preconditioning adult rats with the volatile anesthetic isoflurane induces neuroprotection. Whether isoflurane preconditioning induces neuroprotection in neonates is not known.

Methods: Seven-day-old Sprague-Dawley rats had left common carotid arterial ligation followed by hypoxia with 8% oxygen for 1, 2, or 2.5 h at 37[degrees]C. Isoflurane preconditioning with 1 or 1.5% isoflurane for 30 min was performed at 24 h before the brain hypoxia/ischemia. The inducible nitric oxide synthase inhibitor aminoguanidine (200 mg/kg, intraperitoneally) was administered 30 min before the isoflurane pretreatment. The weight ratio of left to right cerebral hemispheres at 7 days after the brain hypoxia/ischemia was calculated. The mortality during the period from cerebral hypoxia/ischemia to 7 days afterwards was monitored. In another experiment, 6-day-old rats were exposed to 1.5% isoflurane for 30 min. The cerebral hemispheres were removed at various time points for Western analysis of inducible nitric oxide synthase.

Results: The mortality was about 40% in neonates with brain hypoxia/ischemia for 2 h or 2.5 h and was not altered by isoflurane preconditioning. The weight ratio of left/right cerebral hemispheres in the survivors was 0.99 +/- 0.02, 0.65 +/- 0.19, and 0.86 +/- 0.15 (n = 7-18) for the rats in control, brain hypoxia/ischemia for 2.5 h, and isoflurane preconditioning plus brain hypoxia/ischemia for 2.5 h groups, respectively (P < 0.05 for the comparisons between control versus brain hypoxia/ischemia and brain hypoxia/ischemia versus isoflurane preconditioning plus brain hypoxia/ischemia). This isoflurane preconditioning-induced neuroprotection was abolished by aminoguanidine (the weight ratio was 0.61 +/- 0.18, n = 12). Isoflurane induced a time-dependent increase in the inducible nitric oxide synthase proteins.     

Isoflurane Preconditioning Reduces the Rat NR8383 Macrophage Injury Induced by Lipopolysaccharide and Interferon [gamma]

Background: Isoflurane exposure before an insult can reduce the insult-induced injury in various organs. This phenomenon is called isoflurane preconditioning. The authors hypothesize that isoflurane can precondition macrophages, cells that travel to all tissues and are important in the host defense and inflammation responses.

Methods: Rat NR8383 macrophages were pretreated with or without 1-3% isoflurane for 1 h at 30 min before they were incubated with or without 100 ng/ml lipopolysaccharide plus 50 U/ml interferon [gamma] for 24 h. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry was performed after cells were stained with annexin V and propidium iodide. Inducible nitric oxide synthase protein expression in macrophages was quantified by Western blotting.

Results: Lipopolysaccharide plus interferon [gamma] decreased cell viability by approximately 50%. This decrease was dose-dependently inhibited by aminoguanidine, an inducible nitric oxide synthase inhibitor. Lipopolysaccharide plus interferon [gamma] caused inducible nitric oxide synthase expression. This expression was inhibited by pretreatment with 2% but not 1% or 3% isoflurane. Isoflurane at 2% inhibited lipopolysaccharide plus interferon [gamma]-induced accumulation of nitrite, an oxidation product of nitric oxide. Pretreatment with 2% but not 1% or 3% isoflurane improved cell viability. Lipopolysaccharide plus interferon [gamma] increased the number of propidium iodide-positive staining cells. This increase was attenuated by 2% isoflurane pretreatment. The protective effect of 2% isoflurane was abolished by chelerythrine, calphostin C, or bisindolylmaleimide IX, protein kinase C inhibitors.     

Neuroanesthesia and Intensive Care Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists

PURPOSE: To investigate the role of the adenosine A1 receptor in the rapid tolerance to cerebral ischemia induced by isoflurane preconditioning. METHODS: Seventy-five rats were randomly assigned into five groups (n = 15 each): Control, 8-cyclopentyl-1,3-dipropulxanthine (DPCPX), Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups. All animals underwent right middle cerebral artery occlusion (MCAO) for two hours. Isoflurane preconditioning was conducted one hour before MCAO in Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups by exposing the animals to 1.5% isoflurane in 98% oxygen for one hour. In the Control and DPCPX groups, animals were exposed to 98% oxygen one hour before MCAO for one hour. A selective adenosine A1 receptor antagonist, DPCPX, was administered (0.1 mg x kg(-1)) 15 min before isoflurane/oxygen exposure in the DPCPX and DPCPX+Isoflurane groups to evaluate the effect of adenosine A1 receptor antagonist on isoflurane preconditioning. Dimethyl sulfoxide, the solvent of DPCPX, was administered (1 mL x kg(-1)) 15 min before isoflurane exposure in the Vehicle+Isoflurane group. Neurological deficit scores and brain infarct volumes were evaluated 24 hr after reperfusion. RESULTS: Animals in the Isoflurane and Vehicle+Isoflurane groups developed lower neurological deficit scores and smaller brain infarct volumes than the Control group (P < 0.01). Animals in the DPCPX+Isoflurane group developed higher neurological deficit scores and larger brain infarct volumes than the Isoflurane and Vehicle+Isoflurane groups (P < 0.01). CONCLUSION: The present study demonstrates that preconditioning with isoflurane reduces focal cerebral ischemic injury in rats, and the adenosine A1 receptor antagonist (DPCPX) attenuates the neuroprotection induced by isoflurane preconditioning.     

Isoflurane Alters Energy Substrate Metabolism to Preserve Mechanical Function in Isolated Rat Hearts following Prolonged No-Flow Hypothermic Storage

Background: Isoflurane enhances mechanical function in hearts subject to normothermic global or regional ischemia. The authors examined the effectiveness of isoflurane in preserving mechanical function in hearts subjected to cardioplegic arrest and prolonged hypothermic no-flow storage. The role of isoflurane in altering myocardial glucose metabolism during storage and reperfusion during these conditions and the contribution of adenosine triphosphate-sensitive potassium (KATP) channel activation in mediating the functional and metabolic effects of isoflurane preconditioning was determined.

Methods: Isolated working rat hearts were subjected to cardioplegic arrest with St. Thomas' II solution, hypothermic no-flow storage for 8 h, and subsequent aerobic reperfusion. The consequences of isoflurane treatment were assessed during the following conditions: (1) isoflurane exposure before and during storage; (2) brief isoflurane exposure during early nonworking poststorage reperfusion; and (3) isoflurane preconditioning before storage. The selective mitochondrial and sarcolemmal KATP channel antagonists, 5-hydroxydecanoate and HMR 1098, respectively, were used to assess the role of KATP channel activation on glycogen consumption during storage in isoflurane-preconditioned hearts.

Results: Isoflurane enhanced recovery of mechanical function if present before and during storage. Isoflurane preconditioning was also protective. Isoflurane reduced glycogen consumption during storage under the aforementioned circumstances. Storage of isoflurane-preconditioned hearts in the presence of 5-hydroxydecanoate prevented the reduction in glycogen consumption during storage and abolished the beneficial effect of isoflurane preconditioning on recovery of mechanical function.     

Isoflurane exerts a short-term but not a long-term preconditioning effect in neonatal rats exposed to a hypoxic-ischaemic neuronal injury

Background: Isoflurane has been shown to induce tolerance against ischaemic injury in adult rodents. Although the delayed preconditioning effect of isoflurane has been demonstrated in neonatal rat pups, the acute preconditioning effects of isoflurane remained undetermined. The present study was therefore conducted to evaluate the acute preconditioning efficacy of isoflurane in neonatal rats subjected to a hypoxic-ischaemic (HI) injury.
Methods: Post-natal day 7 pups were exposed to 1 or 2% isoflurane in oxygen for either 30, 60 or 90 min. Fifteen minutes after isoflurane exposure, the pups were subjected to an HI injury induced by left common carotid artery ligation and exposure to 8% oxygen for 2 h. Pups not exposed to isoflurane or not subjected to HI served as controls. Histopathologic injury to the cortex and hippocampus was evaluated 7 and 49 days after HI.
Results: Isoflurane 2% exposure for 60 or 90 min before HI induced tolerance in the hippocampus and the number of normal neurons in the CA1 sector 7 days after HI was significantly greater than in non-preconditioned animals. This protective efficacy of isoflurane preconditioning was not observed 49 days after HI.
Conclusions: Exposure of 2% isoflurane for at least 60 min is required to induce tolerance against HI injury in rat pups. However, this neuroprotective efficacy results in only transient neuroprotection.     

The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits

Brief exposure to isoflurane or repetitive, transient ischemia during early reperfusion after prolonged coronary artery occlusion protects against myocardial infarction by inhibiting the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP during delayed ischemic preconditioning occurred concomitant with enhanced expression of the antiapoptotic protein B cell lymphoma-2 (Bcl-2). We tested the hypothesis that Bcl-2 mediates myocardial protection by isoflurane or brief ischemic episodes during reperfusion in rabbits (n = 91) subjected to a 30-min left anterior descending coronary artery occlusion followed by 3 h reperfusion. Rabbits received 0.9% saline, isoflurane (0.5 or 1.0 minimum alveolar concentration, MAC) administered for 3 min before and 2 min after reperfusion, 3 cycles of postconditioning ischemia (10 or 20 s each) during early reperfusion, 0.5 MAC isoflurane plus 3 cycles of postconditioning ischemia (10 s), or the direct mPTP inhibitor cyclosporin A (CsA, 10 mg/kg) in the presence or absence of the selective Bcl-2 inhibitor HA14-1 (2 mg/kg, i.p.). Isoflurane (1.0, but not 0.5, MAC) and postconditioning ischemia (20 s but not 10 s) significantly (P < 0.05) reduced infarct size (mean +/- sd, 21% +/- 4%, 43% +/- 7%, 19% +/- 7%, and 39% +/- 11%, respectively, of left ventricular area at risk) as compared with control (44% +/- 4%). Isoflurane (0.5 MAC) plus 10 s postconditioning ischemia and CsA alone also exerted protection. HA14-1 alone did not affect infarct size nor block protection produced by CsA but abolished reductions in infarct size caused by 1.0 MAC isoflurane, 20 s postconditioning ischemia, and 0.5 MAC isoflurane plus 10 s postconditioning ischemia. The results suggest that Bcl-2 mediates isoflurane-induced and ischemic postconditioning by indirectly modulating mPTP activity in vivo.     

Isoflurane alters energy substrate metabolism to preserve mechanical function in isolated rat hearts following prolonged no-flow hypothermic storage

BACKGROUND: Isoflurane enhances mechanical function in hearts subject to normothermic global or regional ischemia. The authors examined the effectiveness of isoflurane in preserving mechanical function in hearts subjected to cardioplegic arrest and prolonged hypothermic no-flow storage. The role of isoflurane in altering myocardial glucose metabolism during storage and reperfusion during these conditions and the contribution of adenosine triphosphate-sensitive potassium (K(atp)) channel activation in mediating the functional and metabolic effects of isoflurane preconditioning was determined. METHODS: Isolated working rat hearts were subjected to cardioplegic arrest with St. Thomas' II solution, hypothermic no-flow storage for 8 h, and subsequent aerobic reperfusion. The consequences of isoflurane treatment were assessed during the following conditions: (1) isoflurane exposure before and during storage; (2) brief isoflurane exposure during early nonworking poststorage reperfusion; and (3) isoflurane preconditioning before storage. The selective mitochondrial and sarcolemmal K(atp) channel antagonists, 5-hydroxydecanoate and HMR 1098, respectively, were used to assess the role of K(atp) channel activation on glycogen consumption during storage in isoflurane-preconditioned hearts. RESULTS: Isoflurane enhanced recovery of mechanical function if present before and during storage. Isoflurane preconditioning was also protective. Isoflurane reduced glycogen consumption during storage under the aforementioned circumstances. Storage of isoflurane-preconditioned hearts in the presence of 5-hydroxydecanoate prevented the reduction in glycogen consumption during storage and abolished the beneficial effect of isoflurane preconditioning on recovery of mechanical function. CONCLUSIONS: Isoflurane provides additive protection of hearts subject to cardioplegic arrest and prolonged hypothermic no-flow storage and favorably alters energy substrate metabolism by modulating glycolysis during ischemia. The effects of isoflurane preconditioning on glycolysis during hypothermic no-flow storage appears to be associated with activation of mitochondrial K(atp) channels.     

Isoflurane protects renal function against ischemia and reperfusion through inhibition of protein kinases, JNK and ERK

Isoflurane has a pharmacological preconditioning effect against ischemia in the heart and brain, but whether this also occurs in the kidney is unclear. In this study, we investigated pharmacological preconditioning by isoflurane in the rat kidney. In the isoflurane preconditioning group (1.5% isoflurane for 20 min before renal ischemia) serum creatinine (1.2 +/- 0.7 and 1.1 +/- 0.2 mg/dL) and blood urea nitrogen (99 +/- 29 and 187 +/- 31 mg/dL) were significantly smaller at 24 and 48 h after reperfusion than in the nonpreconditioning group (creatinine; 2.4 +/- 1.2 and 2.9 +/- 0.9 mg/dL, urea; 62 +/- 19 and 79 +/- 20 mg/dL). We also investigated the intracellular signal transduction involved in isoflurane preconditioning in the kidney. The activities of the stress protein kinases, JNK and ERK but not p38, were significantly less in the kidneys of the preconditioning group than in those of the nonpreconditioning group (P < 0.05). We conclude that isoflurane has a preconditioning effect against renal ischemia/reperfusion injury when administered before ischemia. Inhibition of the protein kinases, JNK and ERK, might be involved in the mechanisms of isoflurane preconditioning.     

异氟烷预处理改善内毒素诱导大鼠急性肺损伤和死亡率

背景异氟烷预处理对肺脏促炎症介质和多种内毒素诱导的急性肺损伤后生存率的作用鲜有系统报道。我们研究异氟烷预处理对脂多糖诱导的大鼠急性肺损伤的作用。方法雄性SD大鼠重250—300g,随机被分为4组：假手术组,即假手术-空白组（腹腔注射盐水）空白预处理（100％O2）;假手术．异氟烷组,假手术大鼠用异氟烷预处理;LPS组,即空白．LPS组,腹腔注射脂多糖,空白预处理;ISO—LAP组,腹腔注射脂多糖大鼠,异氟烷预处理。腹腔注射脂多糖,诱导内毒素血症,异氟烷预处理在注射内毒素前30分给予1．4％处理,然后观察动物6小时,监测动脉压、心率、血气。肺损伤程度通过肺湿／干比、伊文思蓝染料外渗、组织学检测评估。同时,检测肺脏NO、TNF-α、IL-1β、IL-6水平,另外,进行生存分析和肺iNOS（诱导NO合酶）基因表达检测。结果脂多糖诱导系统性低血压和重型肺损伤,以急性肺损伤程度增加、伴随肺功能的改变、肺组织NO、TNF-α、IL-1β、IL-6水平升高为证。异氧烷预处理减弱了系统性低血压和急性肺损伤发展,调节脂多糖诱导的肺脏硝酸盐／亚硝酸盐升高和促炎症介质释放,提高败血症大鼠生存率。iNOS表达可被脂多糖处理上调,被异氟烷预处理下调。结论异氟烷预处理可减弱肺脏促炎症介质释放,减少重度败血症大鼠死亡率,其保护作用可能由部分抑制iNOS—NO信号通路活性所介导.     

初生期异氟烷暴露对小鼠脑细胞发育、成年期行为、学习和记忆的影响

背景 异氟烷等吸入麻醉药广泛地应用于婴幼儿.异氟烷、咪达唑仑以及氧化亚氮暴露后,新生小鼠神经变性和神经认知功能损害的一些研究,已经引起越来越多人对儿科麻醉安全问题的关注.新生小鼠异氟烷暴露较长时间会触发可致神经认知功能损害的低血糖症.本研究即检测初生期异氟烷暴露和血糖对小鼠的脑细胞存活力、自主活动能力以及空间学习记忆能...     

MCI-186 prevents spinal cord damage and affects enzyme levels of nitric oxide synthase and Cu/Zn superoxide dismutase after transient ischemia in rabbits

OBJECTIVE: The mechanism of spinal cord injury is believed to be related to the vulnerability of spinal motor neuron cells against ischemia. We tested whether MCI-186, which is useful for treating ischemic damage in the brain, can protect against ischemic spinal cord damage. METHODS: After induction of ischemia, MCI-186 or vehicle was injected intravenously. Cell damage was analyzed by observing the function of the lower limbs and by counting the number of motor neurons. To investigate the mechanism by which MCI-186 prevents ischemic spinal cord damage, we observed the immunoreactivity of Cu/Zn superoxide dismutase, neuronal nitric oxide synthase, and endothelial nitric oxide synthase. RESULTS: MCI-186 eased the functional deficits and increased the number of motor neurons after ischemia. The induction of neuronal nitric oxide synthase was significantly reduced by the treatment with MCI-186. Furthermore, the increase in the induction of endothelial nitric oxide synthase and Cu/Zn superoxide dismutase was more pronounced. CONCLUSION: These results indicate that MCI-186 may protect motor neurons from ischemic injury by reducing neuronal nitric oxide synthase and increasing endothelial nitric oxide synthase. MCI-186 may be a strong candidate for use as a therapeutic agent in the treatment of ischemic spinal cord injury.     

Postconditioning with Isoflurane Reduced Ischemia-induced Brain Injury in Rats

Background: Preexposure of brain to isoflurane, a commonly used anesthetic, induces ischemic tolerance. This phenomenon is called isoflurane preconditioning. However, it is not known whether isoflurane application after ischemia provides neuroprotection.

Methods: Corticostriatal slices (400 [mu]m) freshly prepared from adult male Sprague-Dawley rats were subjected to a 15-min oxygen-glucose deprivation (OGD; to simulate ischemia in vitro). Isoflurane was applied after OGD. Brain slices were harvested 2 h after OGD for measuring 2,3,5-triphenyltetrazolium chloride (TTC) conversion to quantify cell injury. Adult male Sprague-Dawley rats were also subjected to middle cerebral arterial occlusion for 90 min and then treated with or without 2% isoflurane for 60 min started at the onset of reperfusion. The infarct volumes, neurologic deficit scores, and performance on rotarod were evaluated at 24 h after the onset of reperfusion.

Results: Isoflurane applied immediately after the 15-min OGD for 30 min dose-dependently reversed the OGD-induced decrease of TTC conversion. The TTC conversion was 34 +/- 16% and 58 +/- 28% of the control, respectively, for OGD alone and OGD plus 2% isoflurane (P < 0.05, n = 12). Application of 2% isoflurane for 30 min started at 10 min after the OGD also reduced the OGD-decreased TTC conversion. The presence of 0.3 [mu]m glibenclamide, a general adenosine 5'-triphosphate-sensitive potassium channel blocker, or 500 [mu]m 5-hydroxydecanoic acid, a mitochondrial adenosine 5'-triphosphate-sensitive potassium channel blocker, during the application of 2% isoflurane abolished the isoflurane preservation of TTC conversion. Application of isoflurane during reperfusion also improved neurologic outcome after brain ischemia.     

Isoflurane does not produce a second window of preconditioning against myocardial infarction in vivo

The administration of a volatile anesthetic shortly before a prolonged ischemic episode exerts protective effects against myocardial infarction similar to those of ischemic preconditioning. A second window of preconditioning (SWOP) against myocardial infarction can also be elicited by brief episodes of ischemia when this occurs 24 h before prolonged coronary artery occlusion. Whether remote exposure to a volatile anesthetic also causes delayed myocardial protection is unknown. We tested the hypothesis that the administration of isoflurane 24 h before ischemia produces a SWOP against infarction. Barbiturate-anesthetized dogs (n = 25) were instrumented for measurement of hemodynamics, including aortic and left ventricular (LV) pressures and LV +dP/dt(max), and subjected to a 60-min left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size and coronary collateral blood flow were assessed with triphenyltetrazolium chloride staining and radioactive microspheres, respectively. Two groups of dogs received 1.0 minimum alveolar anesthetic concentration isoflurane for 30 min or 6 h that was discontinued 30 min (acute) or 24 h (delayed) before ischemia and reperfusion, respectively. A control group of dogs did not receive isoflurane. Infarct size was 27% +/- 3% of the LV area at risk in the absence of pretreatment with isoflurane. Acute, but not remote, administration of isoflurane reduced infarct size (12% +/- 1% and 31% +/- 3%, respectively). No differences in hemodynamics or transmural myocardial perfusion during or after occlusion were observed between groups. The results indicate that isoflurane does not produce a SWOP when administered 24 h before prolonged myocardial ischemia in vivo. IMPLICATIONS: Isoflurane mimics the beneficial effects of ischemic preconditioning by protecting myocardium against infarction when it is administered shortly before a prolonged ischemic episode. However, unlike ischemic preconditioning, isoflurane does not produce a second window of protection 24 h after administration in dogs.     

吸入性麻醉药异氟醚对大鼠脑缺血/再灌注损伤的保护作用

目的 研究异氟醚预处理对大鼠脑缺血/再灌注损伤的可能保护机制.方法 采用四动脉结扎法建立大鼠脑缺血模型.分别在缺血前随机分为假手术组、直接脑缺血/再灌注组、吸入2 h 1.5 MAC异氟醚脑缺血/再灌注组和吸入纯氧2h脑缺血/再灌注对照组,全脑缺血15 min后再分别复灌3 d和5 d.复灌3 d的大鼠断头取海马进行JNK3的免疫印迹和免疫沉淀;复灌5 d的大鼠用焦油紫染色法检测海马CA1区的细胞.结果 复灌3 d后,缺血前吸入1.5 MAC异氟醚组的大鼠组其JNl.的活性明显低于直接缺血对照组和吸入纯氧对照组(P<0.05);复灌5 d后,缺血前吸入1.5 MAC异氟醚可有效降低大鼠海马CA1区锥体细胞的死亡(P<0.05).结论 1.5 MAc异氟醚对大鼠脑缺血/再灌注损伤有确切的保护作用;JNK信号通路可能介导了异氟醚对缺血性脑损伤的保护作用.     

异氟醚对大鼠海马高级糖基化终末产物受体表达的影响

目的 探讨异氟醚对大鼠海马高级糖基化终末产物受体(RAGE)表达的影响.方法 雄性老龄SD大鼠45只,月龄24月;雄性成年SD大鼠45只,月龄4月,分为老龄组和成年组(n=45),每组再分为3个亚组(n=15):老龄对照组(OC组)和成年对照组(AC组)吸入含30%氧气的空氧混合气体;老龄单次吸入异氟醚组(OS组)和成年单次吸入异氟醚组(AS组)吸入1.5%异氟醚2 h;老龄多次吸入异氟醚组(OR组)和成年多次吸入异氟醚组(AR组)吸入1.5%异氟醚3次,2 h/次,每天1次.吸入异氟醚后1 d各组随机取8只大鼠行Morris水迷宫实验测定认知功能,余大鼠处死取海马,采用RT-PCR法检测RAGE mRNA的表达水平,免疫组织化学法检测RAGE蛋白的表达水平.结果 与OC组比较,OS组和OR组认知功能减退,海马RAGE mRNA及其蛋白的表达上调(P＜0.05);与AC组比较,AS组和AR组认知功能减退,AR组海马RAGE mRNA及其蛋白的表达上调(P＜0.05);与OS组比较,OR组认知功能减退,海马RAGE mRNA表达上调(P＜0.05);与AS组比较,AR组认知功能减退,海马RAGE mRNA及其蛋白的表达上调(P＜0.05).结论 异氟醚可导致老龄和成年大鼠认知功能降低,尤其对老龄大鼠影响明显,可能与其上调海马RAGE表达有关.     

The initiating factors of late preconditioning in skeletal muscle.

PURPOSE: The goal of these studies was to determine the initiating factors for late preconditioning in the microcirculation of skeletal muscle. MATERIALS AND METHODS: The cremaster muscle of male Sprague-Dawley rats underwent 4 h of ischemia and then 60 min of reperfusion. Ischemic preconditioning (IPC) consisted of 45 min of ischemia but was done 24 h before the 4 h of ischemia. To mimic the effects of IPC in the late phase, adenosine (ADO) or sodium nitroprusside (SNP) was given 24 h before the prolonged ischemia via local intraarterial infusion. To block the effects of IPC in the late phase, 8-sulfophenyl-theophylline (a nonspecific ADO receptor blocker) or N(W)-nitro-l-arginine (a nonselective nitric oxide synthase antagonist) was given prior to IPC. Microvascular response to IPC and pharmacological preconditioning were determined by measuring arteriole diameters and capillary perfusion using intravital microscopy. RESULTS: Administration of ADO or SNP on day 1 without IPC produced a similar microvascular protection against prolonged ischemia/reperfusion on day 2 as that induced by IPC alone. In contrast, blocking ADO receptors or nitric oxide synthase on day 1 just prior to IPC eliminated the IPC-induced microvascular protection seen on day 2. In addition, inhibition of nitric oxide synthase on day 1 diminished the protection induced by ADO, but blocking ADO receptors on day 1 did not compromise the protection induced by SNP. CONCLUSION: The results from these studies suggest that up regulation of ADO is the initiating factor with secondary up regulation of nitric oxide in late preconditioning. Both ADO and nitric oxide contribute to initiating microvascular protection in the late phase of IPC.     

异氟醚预处理对大脑中动脉闭塞大鼠胶质细胞中Toll样受体4表达的影响

目的观察异氟醚预处理对大脑中动脉闭塞(MCAO)模型大鼠胶质细胞中Toll样受体4(TLR4)表达的影响。方法雄性SD大鼠48只,体重250～300g,随机均分为三组:假手术组(S组)、MCAO模型组(M组)、异氟醚预处理组(I组)。2h后进行再灌注,再灌注24h后进行神经功能评分,检测脑梗死容积,分别测定每个视野内TLR4与星形胶质细胞标记物(GFAP)共存阳性细胞数和TLR4与小胶质细胞标记物(OX42)共存阳性细胞数。结果与M组相比,I组神经功能评分降低,脑梗死容积减少,GFAP和OX42阳性细胞数均减少(P<0.05)。结论异氟醚预处理具有脑保护作用,抑制TLR4的表达及胶质细胞的活化可能是其作用机制之一。