Neuroprotection against surgically induced brain injury

BACKGROUND: Neurosurgical procedures are carried out routinely in health institutions across the world. A key issue to be considered during neurosurgical interventions is that there is always an element of inevitable brain injury that results from the procedure itself because of the unique nature of the nervous system. Brain tissue at the periphery of the operative site is at risk of injury by various means, including incisions and direct trauma, electrocautery, hemorrhage, and retractor stretch. METHODS/RESULTS: In the present review, we will elaborate upon this surgically induced brain injury and also present a novel animal model to study it. In addition, we will summarize preliminary results obtained by pretreatment with PP1, an Src tyrosine kinase inhibitor reported to have neuroprotective properties in in vivo experimental studies. Any form of pretreatment to limit the damage to the susceptible functional brain tissue during neurosurgical procedures may have a significant impact on patient recovery. CONCLUSION: This brief review is intended to raise the question of 'neuroprotection against surgically induced brain injury' in the neurosurgical scientific community and stimulate discussions.     

Neuroprotective effects of citicoline on brain edema and blood-brain barrier breakdown after traumatic brain injury

OBJECT: Cytidine 5'-diphosphocholine (CDPC), or citicoline, is a naturally occurring endogenous compound that has been reported to provide neuroprotective effects after experimental cerebral ischemia. However, in no study has such protection been shown after traumatic brain injury (TBI). In this study the authors examined the effect of CDPC on secondary injury factors, brain edema and blood-brain barrier (BBB) breakdown, after TBI. METHODS: After anesthesia had been induced in Sprague-Dawley rats by using 1.5% halothane, an experimental TBI was created using a controlled cortical impact (CCI) device with a velocity of 3 m/second, resulting in a 2-mm deformation. Four sham-operated control animals used for brain edema and BBB breakdown studies underwent the same surgical procedure, but received no injury. Brain edema was evaluated using the wet-dry method 24 hours postinjury, and BBB breakdown was evaluated by measuring Evans blue dye (EBD) extravasation with fluorescein 6 hours after TBI. The animals received intraperitoneal injections of CDPC (50, 100, or 400 mg/kg two times after TBI [eight-10 animals in each group]) or saline (eight animals) after TBI. Traumatic brain injury induced an increase in the percentage of water content and in EBD extravasation in the injured cortex and the ipsilateral hippocampus. No significant benefit from CDPC treatment was observed at a dose of 50 mg/kg. Cytidine 5'-diphosphocholine at a dose of 100 mg/kg attenuated EBD extravasation in both regions, although it reduced brain edema only in the injured cortex. In both regions, 400 mg/ kg of CDPC significantly decreased brain edema and BBB breakdown. CONCLUSIONS: This is the first report in which dose-dependent neuroprotective effects of CDPC have been demonstrated in the injured cortex as well as in the hippocampus, a brain region known to be vulnerable to injury, after experimental TBI. The results of this study suggest that CDPC is an effective neuroprotective agent on secondary injuries that appear following TBI.     

Inhibition of NR2B phosphorylation restores alterations in NMDA receptor expression and improves functional recovery following traumatic brain injury in mice

Traumatic brain injury (TBI) triggers a massive glutamate efflux, hyperactivation of N-methyl-D-aspartate receptors (NMDARs) and neuronal cell death. Previously it was demonstrated that, 15 min following experimentally induced closed head injury (CHI), the density of activated NMDARs increases in the hippocampus, and decreases in the cortex at the impact site. Here we show that CHI-induced alterations in activated NMDARs correlate with changes in the expression levels of the major NMDARs subunits. In the hippocampus, the expression of NR1, NR2A, and NR2B subunits as well as the GluR1 subunit of the AMPA receptor (AMPAR) were increased, while in the cortex at the impact site, we found a decrease in the expression of these subunits. We demonstrate that CHI-induced increase in the expression of NMDAR subunits and GluR1 in the hippocampus, but not in the cortex, is associated with an increase in NR2B tyrosine phosphorylation. Furthermore, inhibition of NR2B-phosphorylation by the tyrosine kinase inhibitor PP2 restores the expression of this subunit to its normal levels. Finally, a single injection of PP2, prior to the induction of CHI, resulted in a significant improvement in long-term recovery of motor functions observed in CHI mice. These results provide a new mechanism by which acute trauma contributes to the development of secondary damage and functional deficits in the brain, and suggests a possible role for Src tyrosine kinase inhibitors as preoperative therapy for planned neurosurgical procedures.     

Ghrelin prevents disruption of the blood-brain barrier after traumatic brain injury

Significant effort has been focused on reducing neuronal damage from post-traumatic brain injury (TBI) inflammation and blood-brain barrier (BBB)-mediated edema. The orexigenic hormone ghrelin decreases inflammation in sepsis models, and has recently been shown to be neuroprotective following subarachnoid hemorrhage. We hypothesized that ghrelin modulates cerebral vascular permeability and mediates BBB breakdown following TBI. Using a weight-drop model, TBI was created in three groups of mice: sham, TBI, and TBI/ghrelin. The BBB was investigated by examining its permeability to FITC-dextran and through quantification of perivascualar aquaporin-4 (AQP-4). Finally, we immunoblotted for serum S100B as a marker of brain injury. Compared to sham, TBI caused significant histologic neuronal degeneration, increases in vascular permeability, perivascular expression of AQP-4, and serum levels of S100B. Treatment with ghrelin mitigated these effects; after TBI, ghrelin-treated mice had vascular permeability and perivascular AQP-4 and S100B levels that were similar to sham. Our data suggest that ghrelin prevents BBB disruption after TBI. This is evident by a decrease in vascular permeability that is linked to a decrease in AQP-4. This decrease in vascular permeability may diminish post-TBI brain tissue damage was evident by decreased S100B.     

Reduction of ischemic brain injury in rats with normothermic and hyperthermic conditions

OBJECT: Statins have been used for induction of ischemic tolerance after cerebral ischemia. The authors have previously shown that simvastatin is protective after ischemic cerebral injury in normothermic conditions. In this study they further examined whether treatment with simvastatin can reduce ischemic brain injury in a hyperthermic condition. METHODS: Focal ischemic brain injury was induced by embolizing a preformed clot into the middle cerebral artery in rats. The authors initially examined whether treatment with simvastatin could reduce ischemic brain injury without or with hyperthermia. The infarct volume, edema, and neurological deficits were examined. They then studied whether simvastatin could reduce the perfusion deficits, damage to the blood-brain barrier (BBB), and degeneration of neurons in the ischemic injured brain. RESULTS: Simvastatin significantly reduced the infarct volume in both normothermic and hyperthermic conditions, compared with appropriate controls. Concomitantly, this treatment also significantly reduced neurological deficits and brain edema. Administration of simvastatin significantly decreased perfusion deficits, BBB permeability, and degenerated neurons. CONCLUSIONS: These studies suggest that simvastatin is an effective agent for ischemic brain injury not only in normothermic but also in hyperthermic conditions, which may be through the decrease of BBB permeability, degenerated neurons, and perfusion deficits.     

Dynamics of rabbit brain edema in focal lesion and perilesion area after traumatic brain injury: a MRI study

To understand the dynamics of brain edema in different areas after traumatic brain injury (TBI) in rabbit, we used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) to monitor blood-brain barrier (BBB) permeability and cytotoxic brain edema after weight drop-induced TBI in rabbit. The dynamics of BBB permeability and brain edema were quantified using K(trans) and apparent diffusion coefficient (ADC) in the focal and perifocal lesion areas, as well as the area contralateral to the lesion. In the focal lesion area, K(trans) began to increase at 3?h post-TBI, peaked at 3 days, and decreased gradually while remaining higher than sham injury animals at 7 and 30 days. ADC was more variable, increased slightly at 3?h, decreased to its lowest value at 7 days, then increased to a peak at 30 days. In the perifocal lesion area, K(trans) began to increase at 1 day, peaked at 3-7 days, and returned to control level by 30 days. ADC showed a trend to increase at 1 day, followed by a continuous increase thereafter. In the contralateral area, no changes in K(trans) and ADC were observed at any time-point. These data demonstrate that different types of brain edema predominate in the focal and perifocal lesion areas. Specifically cytotoxic edema was predominant in the focal lesion area while vasogenic edema predominated in the perifocal area in acute phase. Furthermore, secondary opening of the BBB after TBI may appear if secondary injury is not controlled. BBB damage may be a driving force for cytotoxic brain edema and could be a new target for TBI intervention.     

The role of the Src family of tyrosine kinases after oxidant-induced lung injury in vivo

BACKGROUND: Patients sustaining major trauma are predisposed to the development of organ dysfunction. We have shown that oxidant stress generated by hemorrhagic shock/resuscitation (S/R) in rodents increases lipopolysaccharide (LPS)-induced lung injury and translocation of nuclear factor kappa B (NF-kappaB) in alveolar macrophages (AMs). In addition, using a cellular model, we have shown that priming with oxidants reprograms LPS signaling through an Src-dependent pathway. In the present studies, we hypothesize that oxidant priming by S/R in vivo involves Src family kinases. METHODS: Rats were bled to a mean arterial pressure of 40 mmHg and maintained for 1 hour, then resuscitated with shed blood and equal volume of Ringer's lactate. In some studies, animals received the antioxidant NAC (0.5 g/kg) or a Src family inhibitor, PP2 (0.1 or 0.2 mg/kg), before resuscitation. LPS was given intratracheally (30 mg/kg) for 4 hours. AMs were lavaged, and total cell counts were determined. AMs were also obtained at end resuscitation and exposed to LPS (0.1 microg/mL) from 0 to 60 minutes. Activation of Hck, an Src family kinase, was analyzed by Western blot using a phosphospecific antibody. Nuclear extracts were obtained to examine NF-kappaB translocation. RESULTS: S/R caused a rise in Src family activity compared with sham animals as shown by the phosphorylation of Hck. This was prevented by treating the animals during resuscitation with NAC. The LPS-induced NF-kappaB translocation in AMs after shock/resuscitation was 3-fold higher than in sham AMs treated with LPS. This augmented translocation was prevented by pretreating the animals with PP2 before resuscitation. In a parallel fashion, PP2 pretreatment reduced the absolute lung neutrophil sequestration. CONCLUSION: Oxidant stress generated during S/R in vivo causes Src family kinase activation in AMs. Inhibition of Src activation by PP2 attenuates AM priming for increased LPS responsiveness after hemorrhagic shock and causes a modest reduction in lung injury. Inhibition of the Src family kinases may be a novel approach for the treatment of lung injury after trauma.     

Inhibition of Src kinase can ameliorate renal interstitial fibrosis in unilateral ureteral obstruction mice

Objective To investigate the effect and mechanism of Src kinase in renal interstitial fibrosis of unilateral ureteral obstruction (UUO) mice. Methods Male C57BL/6J mice were randomly divided into 4 groups, including sham operation group (n=8), sham operation+PP2 group (n=8), UUO operation group (n=8) and UUO operation+PP2 group (n=8). The mice were injected 2 mg/kg PP2 by intraperitoneal everyday after surgery in sham+PP2 group and UUO+PP2 group. PP2 dissolved in 1% DMSO (formulated with normal saline). Sham and UUO group were given equal 1% DMSO. The mice were sacrificed at 7th day. Renal collagen was observed with Sirius red stain. The activities of Src, protein kinase B (PKB, AKT), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and the protein expressions of α-smooth muscle actin (α-SMA) and fibronectin (FN) were detected by Western blotting. The expression of collagen I (COLⅠ) was detected by immunohistochemistry and the expressions of matrix metalloprotein 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), transforming growth factor-β1 (TGF-β1), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6) were measured by ELISA. Results Compared with sham mice, UUO mice on 7th day displayed obvious renal fibrosis. Meanwhile, UUO mice had increased expressions of COLⅠ and FN, and activities of AKT, ERK and p38 MAPK (all P＜0.05). Their renal expressions of α-SMA, TGF-β1, MMP-9, TIMP-1, MCP-1 and IL-6 were also raised (all P＜0.05). Compared with those in UUO group, in UUO+PP2 group the activities of Src, AKT, p38 MAPK and ERK, and expressions of TGF-β1, MCP-1 and IL-6 decreased (all P＜0.05). Additionally, expressions of COLⅠ, FN and α-SMA, collagen deposition and renal fibrosis receded in UUO+PP2 group (all P＜0.05). However, the expressions of MMP-9 and TIMP-1 were not influenced by PP2 treatment. Conclusions Src kinase promotes myofibroblasts accumulation and inflammatory reaction through activating its downstream signaling pathway in the progressing of renal interstitial fibrosis.     

The glutamate AMPA receptor antagonist,YM872, attenuates cortical tissue loss,regional cerebral edema,and neurological motor deficits after experimental brain injury in rats

A massive increase in extracellular glutamate is thought to contribute to brain damage after traumatic brain injury. We examined the neuroprotective effect of the AMPA receptor antagonist YM872 in a rat head injury model using the fluid-percussion procedure. Male Sprague-Dawley rats were subjected to right lateral (parasagittal) fluid-percussion brain injury or sham injury. At 15 min postinjury, they received either YM872 (20 mg/kg/h, 20 mg/3 mL) or normal saline (vehicle) intravenously for 4 h. The administration of YM872 significantly improved the composite neuroscore at 1 and 2 weeks postinjury (p < 0.05), and markedly reduced the volume of tissue loss in the injured cortex (p < 0.05). It also significantly reduced cerebral edema in the ipsilateral parietal cortex at 48 h postinjury (p < 0.01). These results indicate that the posttraumatic administration of YM872 may be neuroprotective by ameliorating cortical tissue loss and regional cerebral edema, and suggest the importance of AMPA receptors in traumatic brain damage involving secondary injury processes.     

Soluble fibronectin induces chemokine gene expression in renal tubular epithelial cells

BACKGROUND: Increasing proteinuria in kidney disease is associated with an increased risk of renal failure. Urinary proteins such as albumin induce inflammatory signaling and gene expression in tubular epithelial cells (TECs). Fibronectin is an extracellular matrix protein that can exist in soluble form and is excreted in the urine of patients with glomerular disease. METHODS: To explore the impact of soluble fibronectin on tubular epithelium, murine TECs were stimulated with soluble fibronectin and chemokine mRNA was determined by RNase protection assay. RESULTS: Fibronectin induced the expression of inflammatory chemokine genes, including monocyte chemoattractant protein-1 (MCP-1) (CCL2) and macrophage inflammatory protein-2 (MIP-2) within 2 hours in a dose-dependent manner. Phosphorylation of Src family tyrosine kinases was also increased in TECs following exposure to fibronectin. Src tyrosine kinases were involved in the fibronectin activation of MCP-1 since the Src inhibitors SU6656 and PP2 effectively reduced the induction of this chemokine. Fibronectin also induced the phosphorylation of extracellular signal-regulated protein kinase (ERK1/2) within minutes in TECs. The ERK kinase (MEK1/2) inhibitor U0126 inhibited the fibronectin induction of MCP-1 mRNA suggesting that ERK1/2 was also involved in this inflammatory pathway. Furthermore, fibronectin also induced phosphorylation of IkappaBalpha within 20 minutes in TECs. The nuclear factor-kappaB (NF-kappaB) inhibitors N-acetyl-L-cysteine (NAC) and pyrrolidinecarbodithioic acid (PDTC) effectively blocked fibronectin induction of MCP-1 mRNA. CONCLUSION: Soluble fibronectin activates MCP-1 gene expression in TECs via Src tyrosine kinases, ERK1/2 and NF-kappaB. These data provide further support to the concept that proteinuria per se contributes to the tubulointerstitial injury observed in glomerular disease.     

Severity profile of penetrating ballistic-like brain injury on neurofunctional outcome, blood-brain barrier permeability, and brain edema formation

This study evaluated the injury severity profile of unilateral, frontal penetrating ballistic-like brain injury (PBBI) on neurofunctional outcome, blood-brain barrier (BBB) permeability, and brain edema formation. The degree of injury severity was determined by the delivery of a water-pressure pulse designed to produce a temporary cavity by rapid (<40?ms) expansion of the probe's elastic balloon calibrated to equal 5%, 10%, 12.5%, or 15% of total rat brain volume (control groups consisted of sham surgery or insertion of the probe only). Neurofunctional assessments revealed motor and cognitive deficits related to the degree of injury severity, with the most clear-cut profile of PBBI injury severity depicted by the Morris water maze (MWM) results. A biphasic pattern of BBB leakage was detected in the injured hemisphere at all injury severity levels at 4?h post-injury, and again at 48-72?h post-injury, which remained evident out to 7 days post-PBBI in the 10% and 12.5% PBBI groups. Likewise, significant brain edema was detected in the injured hemisphere by 4?h post-injury and remained elevated out to 7 days post-injury in the 10% and 12.5% PBBI groups. However, following 5% PBBI, significant levels of edema were only detected from 24?h to 48h post-injury. These results identify an injury severity profile of BBB permeability, brain edema, and neurofunctional impairment that provides sensitive and clinically relevant outcome metrics for studying potential therapeutics.     

Contribution of Src tyrosine kinase to cerebral vasospasm after subarachnoid hemorrhage

OBJECT: Mitogen-activated protein kinase (MAPK) has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to investigate whether Src tyrosine kinase, an upstream regulator of MAPK, is involved in cerebral vasospasm. METHODS: An established canine double-hemorrhage model was used. Twenty-four dogs were divided into four groups: control, vehicle-treated, Src inhibitor PP2-treated, and Src inhibitor damnacanthal-treated groups. Vehicle (dimethyl sulfoxide), PP2, or damnacanthal was injected daily into the cisterna magna of 18 dogs at 3 to 6 days after induction of SAH. Angiography was performed on Day 0 (the day on which the first blood injection was administered to induce SAH) and on Day 7. Western blot analysis of Src and MAPK activation in basilar arteries (BAs) collected on Day 7 post-SAH was performed. Severe vasospasm was observed in the BAs of vehicle-treated dogs. Mild vasospasm was observed in all dogs treated with Src inhibitors. Phosphorylated Src and MAPK were increased after SAH and activation of these kinases in the BAs was abolished by PP2 and damnacanthal. CONCLUSIONS: The tyrosine kinase Src is an important upstream regulator of MAPK, and inhibition of Src might offer a new therapy in the management of cerebral vasospasm.     

Src family kinase inhibitor PP1 reduces secondary damage after spinal cord compression in rats

The synthetic pyrazolopyrimidine, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) is a novel, potent, and selective inhibitor of Src family tyrosine kinases. Vascular permeability appears to be mediated by vascular endothelial growth factor (VEGF), which requires the activation of downstream Src family kinases to exert its function. This study investigates the effects of PP1 on vascular permeability and inflammatory response in a rat spinal cord compression model. Ten minutes after compression, PP1 (PP1 group) or the vehicle only (control group) was administered. On days 1, 3, and 7 after compression, the spinal cords were removed and examined histopathologically to determine the expression of VEGF and the extent of edema and inflammation. The dryweight method was used to measure the water content of the spinal cords. The mRNA levels of tumor necrosis factor a (TNFalpha) and interleukin 1beta (IL-1beta), which is related to inflammatory responses, were measured with a real-time polymerase chain reaction (RT-PCR) system 6 h after compression. Although VEGF expression was similar in both groups, the extent of contusional lesion in the PP1 group was reduced by approximately 35% on day 3. Moreover, the water content on days 1, 3, and 7 was significantly reduced and macrophage infiltration on days 3 and 7 was dramatically reduced in the PP1 group. TNF and IL-1beta mRNA expression in the PP1 group were also significantly reduced. These results indicate that PP1 reduces secondary damage after spinal cord injury.     

Effects of ganglioside GM1 on reduction of brain edema and amelioration of cerebral metabolism after traumatic brain injury

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Kffects of ganglioside GM1 on kreduction of brain edema and amelioration of metabolism after traumatic brain injury

OBJECTIVE: To observe the effects of ganglioside GM1 on reduction of brain edema and amelioration of cerebral metabolism after traumatic brain injury (TBI). METHODS: An acute experimental closed TBI model in rats was induced by a fluid-percussion brain injury model. At five and sixty minutes after TBI, the animals were intraperitoneally injected by ganglioside GM1 (30 mg/kg) or the same volume of saline. At the 6th hour after TBI, effects of ganglioside GM1 or saline on changes of mean arterial pressure (MAP), contents of water, lactic acid (LA) and lipid peroxidation (LPO) in the injured cerebral tissues were observed. RESULTS: After TBI, MAP decreased and contents of water, LA and LPO increased in brain injury group; however, MAP was back to normal levels and contents of water, LA and LPO decreased in ganglioside GM1 treated group, compared with those in brain injury group (P < 0.05). No significant difference between the saline treated group and the brain injury group (P > 0.05) was observed. CONCLUSIONS: Ganglioside GM1 does have obvious neuroprotective effect on early TBI.     

Free-radical scavenger edaravone treatment confers neuroprotection against traumatic brain injury in rats

Traumatic brain injury (TBI) is one of the leading causes of neurological disability in young adults. Edaravone, a novel synthetic small-molecule free-radical scavenger, has been shown to have a neuroprotective effect in both animal models of cerebral ischemia and stroke patients; however, the underlying mechanism is poorly understood. In this report, we investigated the potential mechanisms of edaravone treatment in a rat model of TBI. TBI was induced in the right cerebral cortex of male adult rats using Feeney's weight-drop method. Edaravone (0.75, 1.5, or 3?mg/kg) or vehicle (normal saline) was intravenously administered at 2 and 12?h after TBI. Edaravone treatment significantly decreased hippocampal CA3 neuron loss, reduced oxidative stress, and decreased neuronal programmed cell death compared to vehicle treatment. The protective effects of edaravone treatment were also related to the pathology of TBI on non-neuronal cells, as edaravone decreased astrocyte and glial activation. Lastly, edaravone treatment significantly reduced the presence of inflammatory cytokines, cerebral edema, blood-brain barrier (BBB) permeability, and, importantly, neurological deficits following TBI. Our results suggest that edaravone exerts a neuroprotective effect in the rat model of TBI. The likely mechanism is via inhibiting oxidative stress, leading to a decreased inflammatory response and glial activation, and thereby reducing neuronal death and improving neurological function.     

Diffusion-weighted imaging of edema following traumatic brain injury in rats: effects of secondary hypoxia

Hypoxia and edema are frequent and serious complications of traumatic brain injury (TBI). Therefore, we examined the effects of hypoxia on edema formation after moderate lateral fluid percussion (LFP) injury using NMR diffusion-weighted imaging (DWI). Adult Sprague-Dawley rats were separated into four groups: sham uninjured (S), hypoxia alone (H), trauma alone (T), and trauma and hypoxia (TH). Animals in Groups T and TH received LFP brain injury, with Groups H and TH undergoing 30 min of moderately severe hypoxia (FiO2 = 0.11) immediately after surgery or TBI (respectively). DWIs were obtained at 2, 4, and 24 h and at 1 week post injury, and apparent diffusion coefficient (ADC) maps were constructed. Animals in Groups T and TH showed an early decrease (p < 0.001) in ADC values in the cortex ipsilateral to TBI 4 hr post injury, followed by elevated ADCs 1 week later (p < 0.05). No significant differences in ADC values were seen between T and TH groups in the ipsilateral cortex. In contrast, the ipsilateral hippocampus for Group TH showed only increasing ADC values. This hyperintensity in the ADC map began at 2 h after TBI, was significant by 24 h (p < 0.05), and reached a maximum at 1 week. This hyperintensity was not observed in Group T. Histopathology seen in TBI animals corresponded well with the pathology observed with MRI. Midline shifts reflecting edema were only observed in TBI animals with little difference between normoxic (T) and hypoxic animals (TH). In sum, this study demonstrates that the development and extent of brain edema following TBI can be examined in vivo in rats using DWI technology. TBI resulted in an early decrease in ADC values indicating cytotoxic edema in the cortex that was followed at 1 week by an increase in the ADC that was associated with decreased tissue cellularity. Histopathology corresponded well to the regions of brain injury and edema visualized by T2 and DWI procedures. Overall, the addition of hypoxia to brain injury resulted in a small increase in the magnitude of edema in hippocampus and cortex over that seen with trauma alone.     

Protective effect of erythropoietin on renal ischemia and reperfusion injury

BACKGROUND: Multiple protective effects of erythropoietin (EPO), such as antiapoptotic, antioxidant, angiogenic and neuroprotective effects, against ischemia have been demonstrated in cell culture and animal models. Genistein is also a potent tyrosine kinase inhibitor. The aims of the present study were to evaluate the effects of EPO on renal ischemia/reperfusion injury and to determine the role of the tyrosine kinase pathway on this process. METHODS: Sprague-Dawley rats were assigned to five groups: (i) sham (Group I); (ii) control with renal ischemia (right nephrectomy and clamping on the left renal pedicle for 45 min and reperfusion; Group II); (iii) EPO + ischemia (Group III); (iv) genistein (an inhibitor of tyrosine kinase) + ischemia (Group IV); and (v) EPO + genistein + ischemia (Group V). Recombinant human EPO (1000 IU/kg) and genistein (10 mg/kg) were given 2 hours before ischemia. Blood samples and the left kidney were obtained after 45 min of reperfusion from half of the rats and after 24 h from the other half. RESULTS: The blood urea nitrogen, creatinine, tumour necrosis factor-alpha (P < 0.05) and interleukin-2 (P < 0.01) levels, and renal tissue lipid peroxidation (P < 0.05) were significantly lower in Group III than in Group II at 45 min of reperfusion. Following 24 h of reperfusion, EPO decreased tissue peroxidation and histopathological injury, whereas genistein reversed it. The most prominent ischemic injury was observed in Group IV in which genistein was administered. There was no significant difference between Groups II and V. CONCLUSIONS: These results suggest that EPO is effective in attenuating renal ischemia/reperfusion injury, and this effect may be related to tyrosine kinase activity.     

氯胺酮对脑冷冻伤后自由基和脑水肿的影响

目的 探讨N-甲基-D-天门冬氨酸(N—methyl—D-aspartate，NMDA)受体非竞争性拮抗药氯胺酮对鼠脑冷冻伤后脑内超氧化物歧化酶(superoxide dismutase，SOD)、丙二醛(malondialdehyde，MDA)和脑水肿的影响。方法 49只SD大鼠随机分为假手术组、未治疗组和氯胺酮治疗组。采用液氮局部冷冻左侧鼠脑30s制作冷冻伤模型，分别于2、6、24h处死动物后，用分光光度法测10％脑组织匀浆中SOD活性和MDA产量。结果 脑组织含水量在冷冻伤后显著升高，并随时间延长而加重。氯胺酮治疗后脑组织含水量没有明显减少；脑组织SOD活性在2、6h高于未治疗组，但24h后SOD活性无显著差异。MDA含量比未治疗组在相应时段显著减少。结论 自由基是脑水肿形成的重要因素，氯胺酮能减轻冻伤脑组织中SOD活性的抑制，减少MDA生成，但对脑水肿无明显治疗作用。