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Ischemic Injury (ischemic + injury)
Selected AbstractsArteriolar Remodeling Following Ischemic Injury Extends from Capillary to Large Arteriole in the MicrocirculationMICROCIRCULATION, Issue 5 2008Alexander M. Bailey ABSTRACT Objective: Skeletal muscle vasculature undergoes arteriogenesis to restore tissue perfusion and function following loss of blood flow. This process has been shown to occur in large vessels following ischemia, although recent studies suggest this may occur in the microcirculation as well. We tested the hypothesis that ischemia induces microvascular remodeling in the skeletal muscle microcirculation on the scale of capillary to sub-35 ,m diameter arterioles. Methods: Ligations of a feeding arteriole to the caudal-half of the spinotrapezius muscle were performed on C57BL/6 mice. At 5 days, microvascular remodeling responses were quantified using intravital and whole-mount confocal microscopy. Immunohistochemistry was performed to visualize vessels, incorporated leukocytes, and regions of hypoxia. Results: Ischemic tissue underwent localized microvascular remodeling characteristic of arteriogenesis, including pronounced vessel tortuosity. In patent microvessels (diameters 15,35 ,m), we observed increases in vascular density (38%), branching (90%) and collateral development (36.5%). The formation of new arterioles (diameters 6,35 ,m) increased by 24.3%, while chronic hypoxia was absent from all tissues. Conclusions: Ischemic injury induces arteriogenesis in skeletal muscle microcirculation. Furthermore, this surgical model enables en face analysis of microcirculatory adaptations with single-cell resolution and can provide investigators with morphometric data on a microscale that is difficult to achieve using other models. [source] Microvasculitis In Non-Diabetic Lumbosacral Radiculoplexus Neuropathy (LSRPN): Similarity To The Diabetic Variety (DLSRPN)JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2001Pjb Dyck Diabetic lumbosacral radiculoplexus neuropathy (DLSRPN) has been shown to be due to ischemic injury from microvasculitis. The present study tests whether ischemic injury and microvasculitis are the pathologic cause of non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN), and whether the pathologic alterations are different between LSRPN and DLSRPN. We studied distal cutaneous nerve biopsies of 47 patients with LSRPN and compared findings with those of 14 age-matched healthy controls and 33 DLSRPN patients. In both disease conditions, we found evidence of ischemic injury (multifocal fiber degeneration and loss, perineurial degeneration and scarring, characteristic fiber alterations, neovascularization, and injury neuroma) that we attribute to microvasculitis (mural and perivascular mononuclear inflammation of microvessels, inflammatory separation, fragmentation and destruction of mural smooth muscle, and previous microscopic bleeding [hemosiderin]). Teased nerve fibers in LSRPN showed significantly increased frequencies of axonal degeneration, segmental demyelination, and empty nerve strands. The segmental demyelination appeared to be clustered on fibers with axonal dystrophy. The nerves with abnormal frequencies of demyelination were significantly associated with nerves showing multifocal fiber loss. We reached the following conclusions: 1) LSRPN is a serious condition with much morbidity that mirrors DLSRPN. 2) Ischemic injury from microvasculitis appears to be the cause of LSRPN. 3) Axonal degeneration and segmental demyelination appear to be linked and due to ischemia. 4) The pathologic alterations in LSRPN and DLSRPN are indistinguishable, raising the question whether these 2 conditions have a common underlying mechanism, and whether diabetes mellitus contributes to the pathology or is a risk factor in DLSRPN. 5) Both LSRPN and DLSRPN are potentially treatable conditions. [source] Arteriolar Remodeling Following Ischemic Injury Extends from Capillary to Large Arteriole in the MicrocirculationMICROCIRCULATION, Issue 5 2008Alexander M. Bailey ABSTRACT Objective: Skeletal muscle vasculature undergoes arteriogenesis to restore tissue perfusion and function following loss of blood flow. This process has been shown to occur in large vessels following ischemia, although recent studies suggest this may occur in the microcirculation as well. We tested the hypothesis that ischemia induces microvascular remodeling in the skeletal muscle microcirculation on the scale of capillary to sub-35 ,m diameter arterioles. Methods: Ligations of a feeding arteriole to the caudal-half of the spinotrapezius muscle were performed on C57BL/6 mice. At 5 days, microvascular remodeling responses were quantified using intravital and whole-mount confocal microscopy. Immunohistochemistry was performed to visualize vessels, incorporated leukocytes, and regions of hypoxia. Results: Ischemic tissue underwent localized microvascular remodeling characteristic of arteriogenesis, including pronounced vessel tortuosity. In patent microvessels (diameters 15,35 ,m), we observed increases in vascular density (38%), branching (90%) and collateral development (36.5%). The formation of new arterioles (diameters 6,35 ,m) increased by 24.3%, while chronic hypoxia was absent from all tissues. Conclusions: Ischemic injury induces arteriogenesis in skeletal muscle microcirculation. Furthermore, this surgical model enables en face analysis of microcirculatory adaptations with single-cell resolution and can provide investigators with morphometric data on a microscale that is difficult to achieve using other models. [source] Glutamate receptor-mediated ischemic injury of premyelinated central axons,ANNALS OF NEUROLOGY, Issue 5 2009James J.P. Alix Objective Ischemic injury of axons is a feature of periventricular leukomalacia, a pathological correlate of cerebral palsy. Recent evidence suggests that axons are damaged before they receive the first layer of compact myelin. Here we examine the cellular mechanisms underlying ischemic-type injury of premyelinated central axons. Methods Two-thirds of axons in the postnatal day 10 (P10) rat optic nerve are small premyelinated axons (<0.4,m in diameter), and one-third have undergone radial expansion in preparation for glial contact and the onset of myelination. Compound action potential recording and quantitative electron microscopy were used to examine the effect of modeled ischemia (oxygen-glucose deprivation) upon these two axon populations. Glutamate receptor (GluR) expression was investigated using polymerase chain reaction (PCR) and immunostaining approaches at the confocal light and ultrastructural levels. Results Oxygen-glucose deprivation produced action potential failure and focal breakdown of the axolemma of small premyelinated axons at sites of contact with oligodendrocyte processes, which were also disrupted. The resulting axon loss was Ca2+ -dependent, Na+ - and Cl, -independent, and required activation of N -methyl-D-aspartic acid (NMDA) and non-NMDA GluRs. NMDA receptor expression was localized to oligodendrocyte processes at sites of contact with premyelinated axons, in addition to expression within compact myelin. No periaxonal NMDA receptor expression was observed on oligodendrocyte processes ensheathing large premyelinated axons and no protective effect of GluR block was observed in these axons. Interpretation NMDA receptor-mediated injury to oligodendrocyte processes navigating along small premyelinated axons precedes damage to the underlying axon, a phenomena that is lost following radial expansion and subsequent oligodendrocyte ensheathment. Ann Neurol 2009;66:682,693 [source] A case of massive kidney graft calcification that developed early in a child recipient with hyperparathyroidismCLINICAL TRANSPLANTATION, Issue 2007Yukiko Kanetsuna Abstract:, A boy aged six yr and six months with end-stage renal disease because of focal segmental glomerulosclerosis underwent cadaveric renal transplantation. Ischemic injury during the operation resulted in a severely dysfunctional graft. A renal graft biopsy was performed on post-operative day (POD) 21. The biopsy specimen showed the presence of many intratubular calcium crystals, patchy tubular injury, and focal aggressive tubulointerstitial rejection. Pelvic computed tomography performed on POD 23 also showed prominent calcification in and around up to two-thirds of the graft. After the biopsy, the graft function recovered, and hemodialysis was stopped on POD 22. A second graft biopsy was performed on POD 52. This biopsy specimen showed recovery from rejection, although the nephrocalcinosis remained. It was suggested that secondary hyperparathyroidism and hyperphosphatemia provoked nephrocalcinosis in this patient. [source] Novel MRI and fluorescent probes responsive to the Factor XIII transglutaminase activityCONTRAST MEDIA & MOLECULAR IMAGING, Issue 4 2010Lorenzo Tei Abstract Transglutaminases, including factor XIII and tissue transglutaminase, participate in multiple extracellular processes associated with remodeling of the extracellular matrix during wound repair, blood clotting, tumor progression and fibrosis of ischemic injuries. The aim of this work was to evaluate a novel substrate analog for transglutaminase optimized by molecular modeling calculations (DCCP16), which can serve for molecular imaging of transglutaminase activity by magnetic resonance imaging and by near-infrared imaging. Experimental data showed covalent binding of Gd,DCCP16 and DCCP16-IRIS Blue to human clots, to basement membrane components and to casein in purified systems as well as in three-dimensional multicellular spheroids. In vivo, DCCP16 showed enhancement with a prolonged retention in clots and tumors, demonstrating the ability to detect both factor XIII and tissue transglutaminase mediated covalent binding of the contrast material. Copyright © 2010 John Wiley & Sons, Ltd. [source] Inactivation of astroglial NF-,B promotes survival of retinal neurons following ischemic injuryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2009Galina Dvoriantchikova Abstract Reactive astrocytes have been implicated in neuronal loss following ischemic stroke. However, the molecular mechanisms associated with this process are yet to be fully elucidated. In this work, we tested the hypothesis that astroglial NF-,B, a key regulator of inflammatory responses, is a contributor to neuronal death following ischemic injury. We compared neuronal survival in the ganglion cell layer (GCL) after retinal ischemia-reperfusion in wild-type (WT) and in GFAP-I,B,-dn transgenic mice, where the NF-,B classical pathway is suppressed specifically in astrocytes. The GFAP-I,B,-dn mice showed significantly increased survival of neurons in the GCL following ischemic injury as compared with WT littermates. Neuroprotection was associated with significantly reduced expression of pro-inflammatory genes, encoding Tnf-,, Ccl2 (Mcp1), Cxcl10 (IP10), Icam1, Vcam1, several subunits of NADPH oxidase and NO-synthase in the retinas of GFAP-I,B,-dn mice. These data suggest that certain NF-,B-regulated pro-inflammatory and redox-active pathways are central to glial neurotoxicity induced by ischemic injury. The inhibition of these pathways in astrocytes may represent a feasible neuroprotective strategy for retinal ischemia and stroke. [source] Activation of CysLT receptors induces astrocyte proliferation and death after oxygen,glucose deprivationGLIA, Issue 1 2008Xiao-Jia Huang Abstract We recently found that 5-lipoxygenase (5-LOX) is activated to produce cysteinyl leukotrienes (CysLTs), and CysLTs may cause neuronal injury and astrocytosis through activation of CysLT1 and CysLT2 receptors in the brain after focal cerebral ischemia. However, the property of astrocyte responses to in vitro ischemic injury is not clear; whether 5-LOX, CysLTs, and their receptors are also involved in the responses of ischemic astrocytes remains unknown. In the present study, we performed oxygen-glucose deprivation (OGD) followed by recovery to induce ischemic-like injury in the cultured rat astrocytes. We found that 1-h OGD did not injure astrocytes (sub-lethal OGD) but induced astrocyte proliferation 48 and 72 h after recovery; whereas 4-h OGD moderately injured the cells (moderate OGD) and led to death 24,72 h after recovery. Inhibition of phospholipase A2 and 5-LOX attenuated both the proliferation and death. Sub-lethal and moderate OGD enhanced the production of CysLTs that was inhibited by 5-LOX inhibitors. Sub-lethal OGD increased the expressions of CysLT1 receptor mRNA and protein, while moderate OGD induced the expression of CysLT2 receptor mRNA. Exogenously applied leukotriene D4 (LTD4) induced astrocyte proliferation at 1,10 nM and astrocyte death at 100,1,000 nM. The CysLT1 receptor antagonist montelukast attenuated astrocyte proliferation, the CysLT2 receptor antagonist BAY cysLT2 reversed astrocyte death, and the dual CysLT receptor antagonist BAY u9773 exhibited both effects. In addition, LTD4 (100 nM) increased the expression of CysLT2 receptor mRNA. Thus, in vitro ischemia activates astrocyte 5-LOX to produce CysLTs, and CysLTs result in CysLT1 receptor-mediated proliferation and CysLT2 receptor-mediated death. © 2007 Wiley-Liss, Inc. [source] Fatal outcome from extreme acute gastric dilation after an eating bingeINTERNATIONAL JOURNAL OF EATING DISORDERS, Issue 7 2006Endre Gyurkovics MD Abstract Objective: A 22-year-old woman is presented with acute gastric dilation after an eating binge, who died of complications of acute reperfusion syndrome. Method: A young patient was admitted in our clinic with critical condition without any significant previous medical history. Her initial complaints , diarrhea, vomiting and abdominal pain , began after an enormous food intake. There was no history of medications or toxic substances. Physical examination showed a normally-developed, well-nourished female in severe distress with an extremely distended abdomen. Femoral pulses were absent. The US and CT scan showed a dilated stomach, extended into the pelvis, dislocating the intestinal organs and compressed the aorta and mesenteric veins. Results: Urgent laparotomy was performed. An enormously distended stomach was encountered without volvulus, obstruction or adhesions. About 11 liters of gastric content was removed gastrotomy and nasogastric tube. Following the gastric decompression, the mesenteric and femoral pulses reappeared. During the operation, the cardio-respiratory status was stabilized, but in the following 24 hours irreversible shock developed, possibly due to the reperfusion of the retroperitoneal organs and the lower extremities. In the postoperative period disseminated intravascular coagulopathy developed. In an uncontrollable state of diffuse bleeding, 36 hours post-operation, the patient died. In retrospective investigation, the family confessed that previous psychological treatments which aimed at her bulimic attacks. Conclusion: Acute gastric dilatation is very uncommon and is of various etiologies, two of these being anorexia nervosa and bulimia. Several cases documenting complications of gastric dilatation were published; however, such severe complications, involving gastric infarction and compression of the aorta with ischemic injury of the bowels and lower extremities, are rare. © 2006 by Wiley Periodicals, Inc. Int J Eat Disord 2006 [source] A Simple Technique of Distal Limb Perfusion During Prolonged Femoro-Femoral CannulationJOURNAL OF CARDIAC SURGERY, Issue 2 2006Navid Madershahian M.D. A serious complication of prolonged femoral cannulation remains the ischemic injury of the distal limb. Subjects: To minimize the incidence of ischemia in the cannulated leg, we have begun to provide antegrade femoral blood flow by placing a vascular introducer percutaneously distal to the arterial cannula into the superficial femoral artery and connecting it to the side port of the arterial line. Conclusion: This technique of distal limb perfusion was found to be safe and effective in preventing lower limb ischemia for patients with prolonged femoral cannulation for extracorporeal circulatory support. [source] Hypoxia-induced apoptosis and tube breakdown are regulated by p38 MAPK but not by caspase cascade in an in vitro capillary model composed of human endothelial cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2007Toshiro Ohta In order to improve medical treatment of ischemic injury such as myocardial infarction, it is important to elucidate hypoxia-induced changes to endothelial cells. An in vitro blood vessel model, in which HUVECs are stimulated to form a network of capillary-like tubes, was used to analyze hypoxia-induced morphological and biochemical changes. When exposed to hypoxia, the network of capillary tubes broke down into small clusters. This tube breakdown was accompanied by chromatin condensation and cell nuclear fragmentation, morphological markers of apoptosis, and activation of two apoptotic signals, caspase-3 and p38. We investigated what roles caspase cascade and p38 play in hypoxia-induced apoptosis and tube breakdown by using zVAD-fmk and SB203580, specific inhibitors of these two apoptotic signals, respectively. Chromatin condensation and cell nuclear fragmentation and tube breakdown were effectively inhibited by SB203580, but not by zVAD-fmk. SB203580 caused dephosphorylation of p38, which indicates that p38 was autophosphorylated. Inhibition by zVAD-fmk caused slight MW increase in p17 and emergence of p19, which indicates that the inhibitor caused partial processing of caspase-3. Inhibition of p38 suppressed activation of caspase-3 but not vice versa. In addition, these two inhibitors were shown to differentially inhibit cleavage of so-called caspase substrates. SB203580 inhibited cleavage of PARP and lamin A/C, while zVAD-fmk inhibited cleavage of lamin A/C but not that of PARP. Taken together, these results show that p38 is located upstream of caspase cascade and that, although caspase-3 is activated, a p38-regulated caspase-independent pathway is crucial for the execution of hypoxia-induced apoptosis and tube breakdown. J. Cell. Physiol. 211: 673,681, 2007. © 2007 Wiley-Liss, Inc. [source] Congenital DNA repair deficiency results in protection against renal ischemia reperfusion injury in miceAGING CELL, Issue 2 2009Denis Susa Summary Cockayne syndrome and other segmental progerias with inborn defects in DNA repair mechanisms are thought to be due in part to hypersensitivity to endogenous oxidative DNA damage. The accelerated aging-like symptoms of this disorder include dysmyelination within the central nervous system, progressive sensineuronal hearing loss and retinal degeneration. We tested the effects of congenital nucleotide excision DNA repair deficiency on acute oxidative stress sensitivity in vivo. Surprisingly, we found mouse models of Cockayne syndrome less susceptible than wild type animals to surgically induced renal ischemia reperfusion injury, a multifactorial injury mediated in part by oxidative damage. Renal failure-related mortality was significantly reduced in Csb,/, mice, kidney function was improved and proliferation was significantly higher in the regenerative phase following ischemic injury. Protection from ischemic damage correlated with improved baseline glucose tolerance and insulin sensitivity and a reduced inflammatory response following injury. Protection was further associated with genetic ablation of a different Cockayne syndrome-associated gene, Csa. Our data provide the first functional in vivo evidence that congenital DNA repair deficiency can induce protection from acute stress in at least one organ. This suggests that while specific types of unrepaired endogenous DNA damage may lead to detrimental effects in certain tissues, they may at the same time elicit beneficial adaptive changes in others and thus contribute to the tissue specificity of disease symptoms. [source] Morphological and hemodynamic magnetic resonance assessment of early neonatal brain injury in a piglet modelJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 1 2004Berit H. Munkeby MD Abstract Purpose To investigate the utility of functional and morphological magnetic resonance imaging (MRI) to assess the extent of brain injury in a hypoxia-ischemia (HI) piglet model and further to validate that the desired ischemic injury was successfully induced. Materials and Methods MRI was performed at 1.5 T in anesthetized piglets (N = 10, age = 12-36 hours). Relative cerebral blood flow (rCBF), time-to-peak (TTP) contrast, and apparent diffusion coefficient (ADC) were estimated at different time points pre-, during, and post-HI. The effect following bilateral clamping of the carotid arteries was assessed by contrast-enhanced MR angiography (MRA) and phase contrast MR angiography (PCA) (N = 4). Results A linear correlation was observed between relative cerebral perfusion reduction and cerebral ADC during HI (r2 = 0.85, P < 0.05). There was no correlation between rCBF reduction during 30 minutes of HI and cerebral ADC after 30 or 150 minutes of reperfusion/reoxygenation (RR). Conclusion The combination of morphological and functional (perfusion and diffusion) MRI enabled consistent assessment of both the presence and absence of complete occlusion as well as the functional significance of the occlusion. J. Magn. Reson. Imaging 2004;20:8,15. © 2004 Wiley-Liss, Inc. [source] Anoxia leads to a rapid translocation of human trypsinogen 4 to the plasma membrane of cultured astrocytesJOURNAL OF NEUROCHEMISTRY, Issue 2 2010Krisztián Tárnok J. Neurochem. (2010) 115, 314,324. Abstract Trypsinogen 4 is specifically expressed in the human brain, mainly by astroglial cells. Although its exact role in the nervous tissue is yet unclear, trypsin 4-mediated pathological processes were suggested in Alzheimer's disease, multiple sclerosis and ischemic injury. In the present study, we analyzed the intracellular distribution of fluorescently tagged human trypsinogen 4 isoforms during normal and anoxic conditions in transfected mouse primary astrocytes. Our results show that initiation of anoxic milieu by the combined action of KCN treatment and glucose deprivation rapidly leads to the association of leader peptide containing trypsinogen 4 constructs to the plasma membrane. Using rhodamine 110 bis-(CBZ-L-isoleucyl-L-prolyl-L-arginine amide), a synthetic chromogen peptide substrate of trypsin, we show that anoxia can promote extracellular activation of trypsinogen 4 indicating that extracellular activation of human trypsinogen 4 can be an important component in neuropathological changes of the injured human brain. [source] Dopamine activates Nrf2-regulated neuroprotective pathways in astrocytes and meningeal cellsJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Andy Y. Shih Abstract The transcription factor Nrf2 controls inducible expression of multiple antioxidant/detoxification genes. We previously found that Nrf2 -/- mice have increased sensitivity to in vivo mitochondrial stress and ischemia. Although Nrf2 regulated these forms of neuronal toxicity, it was unclear which injury-triggered signal(s) led to Nrf2 activation in vivo. In this study, we use primary cultures to test the hypothesis that excessive dopamine release can act as an endogenous Nrf2-inducing signal. We cultured two cell types that show increased Nrf2 activity during ischemia in vivo, astrocytes and meningeal cells. Cultures were infected with an adenovirus reporter of Nrf2 transcriptional activity. Dopamine-induced Nrf2 activity in both cell types by generating oxidative stressors, H2O2 and dopamine-quinones. Nrf2 activation in meningeal cells was significantly higher than astrocytes. The effect of dopamine was blocked by antioxidants, and by over-expression of either dominant-negative Nrf2 or Keap1. Nrf2 induction was specific to oxidative stress caused by catecholaminergic neurotransmitters as epinephrine also induced Nrf2, but the monoamine serotonin had no significant effect. These in vitro results suggest Nrf2 activity in astrocytes and meningeal cells link the neurotoxic actions of dopamine to neuroprotective pathways that may potentially modulate ischemic injury and neurodegeneration. [source] Transient forebrain ischemia modulates focal adhesion kinase (FAK)-mediated signal transduction in gerbil hippocampusJOURNAL OF NEUROCHEMISTRY, Issue 2003M. Ziemka-Na Focal adhesion kinase (FAK) is thought to play a major role in conveying survival signals from extracellular matrix (ECM). Phosphorylated FAK may interact with other nonreceptor kinases such as Src, and adaptor molecule Cas, perhaps providing a pathway by which ECM may regulate cell viability. In the present study the expression and tyrosine phosphorylation of FAK, Src and Cas after 5 min of global ischemia were investigated. The primary activation/phosphorylation of FAK, observed during first 6 h after ischemic injury, was followed by its profound down-regulation. At 72 h of reperfusion the level of phosphorylated FAK decrease to about 50% of the control. The decrease of FAK phosphorylation coincides with its proteolytic degradation. Cleavage of FAK coincided temporally with the loss of Src and Cas. Ischemia-induced proteolytic processing of the investigated proteins may lead to the interruption of ECM-derived signals and compromise neuronal survival. Acknowledgements:, Sponsored by SCSR 4P05A 08619 and Med. Res. Ctr. [source] Magnetic Resonance Imaging and Diffusion-Weighted Imaging Changes After Hypoglycemic ComaJOURNAL OF NEUROIMAGING, Issue 2 2005S. L. Jung ABSTRACT The authors report a case of severe hypoglycemic encephalopathy in an elderly patient. The magnetic resonance images showed bilateral cortical signal changes and basal ganglia lesions, which spared the thalami. The lesions were bright on fluid-attenuated inversion recovery and diffusion-weighted images and dark on the apparent diffusion coefficient map, being more conspicuous on the diffusion-weighted images than on the fluid-attenuated inversion recovery images. A literature review of the imaging features and pathophysiological mechanism in comparison with those of hypoxic ischemic injury is discussed. [source] Cerebral Hemodynamics Changes During Retrograde Brain Perfusion in DogsJOURNAL OF NEUROIMAGING, Issue 2 2001Alexander Y. Razumovsky PhD ABSTRACT The objective of this study was to examine cerebral hemodynamics changes during hypothermic circulatory arrest (HCA) with and without retrograde cerebral perfusion (RCP). Thirteen colony-bred hound dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18°C. Five dogs underwent 2 hours of HCA without RCP and 8 with RCP. The animals were then rewarmed on CPB until normothermic and weaned. Cerebral blood flow velocity (CBFV) and Gosling Pulsatility Index (PI) in the middle cerebral artery (MCA) were studied using transcranial Doppler (TCD) ultrasound. At baseline and during pre- and postarrest CPB, there was anterograde direction of blood flow in the MCA. During HCA with RCP, there was retrograde direction of blood flow in the MCA. There was no difference in CBFV between pre-, during, and postarrest CPB in the group with RCP; however, there was significantly increased CBFV during postarrest CPB in the group without RCP compared to the dogs with RCP. Later, at 3 hours after postarrest CPB, there was decreased CBFV in all animals accompanied by increased PI (2.4 ± 0.4 and 2.2 ± 0.6 for animals with RCP and without RCP, respectively) and abnormal TCD waveform changes including decreased diastolic compartment and sharp systolic peak. During hypothermic circulatory arrest, RCP provides CBFV in the MCA comparable to MCA CBFV during CPB. HCA dogs without RCP showed immediate hyperemia on reperfusion. The decreased CBFV and increased PI at 1 hour after postarrest CPB could be an indicator of progressive ischemic injury due to the increased intracranial pressure despite the implementation of RCP. [source] An angiotensin II type 1 receptor blocker can preserve endothelial function and attenuate brain ischemic damage in spontaneously hypertensive ratsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2010Naoki Oyama Abstract Hypertension reduces endothelial nitric oxide synthase (eNOS) expression and leads to endothelial dysfunction. However, few studies have demonstrated the influences of hypertension on eNOS function in the cerebral cortex. The present study investigates the influences of hypertension on endothelial function in the cerebral cortex and the protective effects of antihypertensive agents against brain ischemia through the preservation of endothelial function. Five- and ten-week-old male Wistar rats and spontaneously hypertensive rats (SHR) were used for experiments. Five-week-old SHR received olmesartan, hydralazine, or vehicle for 5 weeks in drinking water. eNOS activation in the cerebral cortex was evaluated by analyzing levels of total and Ser1177 -phosphorylated eNOS protein by Western blot. Blood pressure of 10-week-old SHR without treatment was clearly high, and the ratio of phospho-eNOS/total eNOS protein was significantly low. Five-week treatment with olmesartan or hydralazine suppressed the elevation of blood pressure and the reduction of phosphorylated eNOS-Ser1177 in SHR, and olmesartan was more effective in maintaining phosphorylation of eNOS-Ser1177 than hydralazine. To assess the contribution of eNOS to maintaining cerebral blood flow (CBF), we monitored CBF by laser-Doppler flowmetry after L-N5 -(1-iminoethyl)ornithine (L-NIO) infusion. CBF response to L-NIO was preserved in olmesartan-treated SHR but not in hydralazine-treated SHR. Furthermore, infarct volume 48 hr after transient focal brain ischemia in olmesartan-treated SHR was significantly reduced compared with vehicle-treated SHR. These findings indicate that chronic prehypertensive treatment with olmesartan could attenuate brain ischemic injury through the maintenance of endothelial function in the cerebral cortex in SHR. © 2010 Wiley-Liss, Inc. [source] Endogenous neurogenesis and neovascularization in the neocortex of the rat after focal cerebral ischemiaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2008Hye Young Shin Abstract The present study was designed to examine whether endogenous neurogenesis and neovascularization occur in the neocortex of the ischemic rat brain after unilateral middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were divided into six groups (n = 29): one control group (n = 4) and five groups composed of animals sacrificed at increasing times post-MCAO (2 days and 1, 2, 4, and 8 weeks; n = 5 per group). To determine the presence of neurogenesis and neovascularization in the ischemic brain, nestin, Tuj1, NeuN, GFAP, Tie2, RECA, and 5-bromo-2,-deoxyuridine (BrdU) were analyzed immunohistochemically. In addition, nestin, GFAP, and Tie2 expression was determined by Western blotting. Triple-labeling of nestin, BrdU, and laminin was performed to visualize the interaction between endogenous neurogenesis and neovascularization. The number of BrdU- and nestin-colabeled cells increased markedly in the neocortex and border zone of the ischemic area up to 1 week after MCAO and decreased thereafter. Western blot analysis revealed that the expression of nestin, Tie-2, and GFAP was amplified in the ipsilateral hemisphere 2days after MCAO and peaked 1 week after MCAO, compared with that in the normal brain. After ischemic injury, nestin- and BrdU-colabeled cells were observed in the vicinity of the endothelial cells lining cerebral vessels in the ipsilateral neocortex of the ischemic brain. Endogenous neurogenesis and neovascularization were substantially activated and occurred in close proximity to one other in the ipsilateral neocortex of the ischemic rat brain. © 2007 Wiley-Liss, Inc. [source] Protective effects of sesamin and sesamolin on hypoxic neuronal and PC12 cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2003Rolis Chien-Wei Hou Abstract Reactive oxygen species (ROS) are important mediators of a variety of pathological processes, including inflammation and ischemic injury. The neuroprotective effects of sesame antioxidants, sesamin and sesamolin, against hypoxia or H2O2 -induced cell injury were evaluated by cell viability or lactate dehydrogenase (LDH) activity. Sesamin and sesamolin reduced LDH release of PC12 cells under hypoxia or H2O2 -stress in a dose-dependent manner. Dichlorofluorescein (DCF)-sensitive ROS production was induced in PC12 cells by hypoxia or H2O2 -stress but was diminished in the presence of sesamin and sesamolin. We evaluated further the role of mitogen-activated protein kinases (MAPKs) and caspase-3 in hypoxia-induced PC12 cell death. Extracellular signal-regulated protein kinase (ERK) 1, c-jun N-terminal kinase (JNK), and p38 MAPKs of signaling pathways were activated during hypoxia. We found that the inhibition of MAPKs and caspase-3 by sesamin and sesamolin correlated well with the reduction in LDH release under hypoxia. Furthermore, the hypoxia-induced apoptotic-like cell death in cultured cortical cells as detected by a fluorescent DNA binding dye was reduced significantly by sesamin and sesamolin. Taken together, these results suggest that the protective effect of sesamin and sesamolin on hypoxic neuronal and PC12 cells might be related to suppression of ROS generation and MAPK activation. © 2003 Wiley-Liss, Inc. [source] Activation of adenosine triphosphate-sensitive potassium channels confers protection against rotenone-induced cell death: Therapeutic implications for Parkinson's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2002Kwok-Keung Tai Abstract It is anticipated that further understanding of the protective mechanism induced by ischemic preconditioning will improve prognosis for patients of ischemic injury. It is not known whether preconditioning exerts beneficial actions in neurodegenerative diseases, in which ischemic injury plays a causative role. Here we show that transient activation of ATP-sensitive potassium channels, a trigger in ischemic preconditioning signaling, confers protection in PC12 cells and SH-SY5Y cells against neurotoxic effect of rotenone and MPTP, mitochondrial complex I inhibitors that have been implicated in the pathogenesis of Parkinson's disease. The degree of protection is in proportion to the bouts of exposure to an ATP-sensitive potassium channel opener, a feature reminiscent of ischemic tolerance in vivo. Protection is sensitive to a protein synthesis inhibitor, indicating the involvement of de novo protein synthesis in the protective processes. Pretreatment of PC12 cells with preconditioning stimuli FeSO4 or xanthine/xanthine oxidase also confers protection against rotenone-induced cell death. Our results demonstrate for the first time the protective role of ATP-sensitive potassium channels in a dopaminergic neuronal cell line against rotenone-induced neurotoxicity and conceptually support the view that ischemic preconditioning-derived therapeutic strategies may have potential and feasibility in therapy for Parkinson's disease. © 2002 Wiley-Liss, Inc. [source] Brain damage following severe acute normovolemic hemodilution in combination with controlled hypotension in ratsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 10 2007Y. L. Ge Background and aim:, The reduced oxygen content and perfusion pressure during acute normovolemic hemodilution (ANH) and controlled hypotension (CH) raise concerns about hypoperfusion and ischemic injury to the brain. In this study on rats, we examined the brain damage following four different degrees of ANH combined with CH. Methods:, Forty rats were randomly assigned to receive a sham operation or CH and ANH [with a hematocrit (Hct) of 30, 25, 20 or 15%]. ANH was performed after baseline physiological parameters had been monitored for 20 min; 30 min later, CH was induced using sodium nitroprusside, and the mean arterial blood pressure was maintained at 50,60 mmHg for 1 h. Rats were killed 3.5 h after hemodilution. Ultrastructural alterations in the CA1 region of the rat hippocampus were observed, and serum concentrations of S100B and neuron-specific enolase (NSE) were measured before and after ANH. Results:, The serum S100B concentration increased significantly in the Hct 20% + CH and Hct 15% + CH groups. However, there were no significant differences in the serum levels of NSE between the groups. In the CA1 region of the rat hippocampus, marked ultrastructural alterations, such as mitochondrial denaturalization and nucleus distortion, were observed in the Hct 20% + CH and Hct 15% + CH groups. Conclusion:, Severe ANH (Hct , 20%) combined with CH may induce cerebral damage, as confirmed by marked ultrastructural alterations in the CA1 region of the rat hippocampus and significantly increased serum levels of S100B, and should be avoided. [source] Dexmedetomidine during coronary artery bypass grafting surgery: is it neuroprotective?ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2007A preliminary study Background:, In the present study, we aimed to determine whether during coronary artery bypass grafting (CABG) surgery, dexmedetomidine has protective effects against cerebral ischemic injury. Method:, Twenty-four patients, aged 50,70 years, undergoing CABG surgery were randomized into two groups of 12 patients each: those receiving dexmedetomidine (group D) and those not receiving it (group C). As basal blood samples from arterial and jugular bulb catheters were drawn, dexmedetomidine (1 ,g/kg bolus and infusion at a rate of 0.7 ,g/kg/h) was administered to patients in group D. Arterial and jugular venous blood gas analyses, serum S-100B protein (S-100B), neuron-specific enolase (NSE) and lactate measurements were performed after induction, 10 min after the initiation of cardiopulmonary bypass (CPB), 1 min after declamping, at the end of CPB, at the end of the operation and 24 h after surgery. Mann,Whitney U - and Wilcoxon's tests were used for statistical analyses. Results:, No significant between-group differences were found regarding arterial and jugular venous pH, PO2, PCO2 and O2 saturations. S-100B, NSE and lactate levels were also similar between groups D and C. During the post-operative period, there were no clinically overt neurological complications in any patient. Conclusion:, Cerebral ischemia marker (S-100B, NSE, lactate) patterns were as expected during CPB; however, there were no differences between the groups, which led us to believe that during CABG surgery dexmedetomidine has no neuroprotective effects. Future studies with larger populations are recommended to further establish the effects of this drug. [source] Response Characteristics Of Cutaneous Mechanoreceptors In Neuropathic RatsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 3 2002A Bulka The activity of single myelinated afferents was recorded from dorsal roots L4-5 in normal Sprague-Dawley rats and animals that developed mechanical hypersensitivity following ischemic injury to the sciatic nerve. The mechanical response properties and conduction velocity of afferents conducting through the injury site (about 50% of units) were similar to controls. However, the majority of afferents not conducting through the injury site exhibited ongoing activity. The results suggest that mechanical allodynia may be at least partly due to the central integration of activity arising from these two populations of afferents in neuropathic rats. [source] Microvasculitis In Non-Diabetic Lumbosacral Radiculoplexus Neuropathy (LSRPN): Similarity To The Diabetic Variety (DLSRPN)JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2001Pjb Dyck Diabetic lumbosacral radiculoplexus neuropathy (DLSRPN) has been shown to be due to ischemic injury from microvasculitis. The present study tests whether ischemic injury and microvasculitis are the pathologic cause of non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN), and whether the pathologic alterations are different between LSRPN and DLSRPN. We studied distal cutaneous nerve biopsies of 47 patients with LSRPN and compared findings with those of 14 age-matched healthy controls and 33 DLSRPN patients. In both disease conditions, we found evidence of ischemic injury (multifocal fiber degeneration and loss, perineurial degeneration and scarring, characteristic fiber alterations, neovascularization, and injury neuroma) that we attribute to microvasculitis (mural and perivascular mononuclear inflammation of microvessels, inflammatory separation, fragmentation and destruction of mural smooth muscle, and previous microscopic bleeding [hemosiderin]). Teased nerve fibers in LSRPN showed significantly increased frequencies of axonal degeneration, segmental demyelination, and empty nerve strands. The segmental demyelination appeared to be clustered on fibers with axonal dystrophy. The nerves with abnormal frequencies of demyelination were significantly associated with nerves showing multifocal fiber loss. We reached the following conclusions: 1) LSRPN is a serious condition with much morbidity that mirrors DLSRPN. 2) Ischemic injury from microvasculitis appears to be the cause of LSRPN. 3) Axonal degeneration and segmental demyelination appear to be linked and due to ischemia. 4) The pathologic alterations in LSRPN and DLSRPN are indistinguishable, raising the question whether these 2 conditions have a common underlying mechanism, and whether diabetes mellitus contributes to the pathology or is a risk factor in DLSRPN. 5) Both LSRPN and DLSRPN are potentially treatable conditions. [source] Non-heart-beating donor porcine livers: The adverse effect of coolingLIVER TRANSPLANTATION, Issue 1 2005Srikanth Reddy Normothermic preservation has been shown to be advantageous in an experimental model of preservation of non-heart-beating donor (NHBD) livers, which have undergone significant warm ischemic injury. The logistics of clinical organ retrieval might dictate a period of cold preservation prior to warm perfusion. We have investigated the effects of a brief period of cold preservation on NHBD livers prior to normothermic preservation. Porcine livers were subjected to 60 minutes of warm ischaemia and then assigned to following groups: Group W (n = 5), normothermic preservation for 24 hours; and Group C (n = 6), cold preservation in University of Wisconsin solution for 1 hour followed by normothermic preservation for 23 hours (total preservation time, 24 hours). Synthetic function (bile production and factor V production) and cellular damage were compared on the ex vivo circuit during preservation. There was no significant difference in the synthetic function of the livers (bile production and factor V production). Markers of hepatocellular damage (alanine aminotransferase and aspartate aminotransferase release), sinusoidal endothelial cell dysfunction (hyaluronic acid), and Kupffer cell injury (,-galactosidase) were significantly higher in Group C. The histology of the livers at the end of perfusion was similar. In conclusion, a brief-period cold preservation prior to normothermic perfusion maintains the synthetic function and metabolic activity but results in significant hepatocellular damage, sinusoidal endothelial cell dysfunction, and Kupffer cell injury. Transplant studies are required to establish whether livers treated in this way are viable for transplantation. (Liver Transpl 2005;11:35,38.) [source] Ischemic preconditioning and intermittent clamping improve murine hepatic microcirculation and Kupffer cell function after ischemic injuryLIVER TRANSPLANTATION, Issue 4 2004Katarína Vajdová The aim of this study was to evaluate whether the protective effect of intermittent clamping and ischemic preconditioning is related to an improved hepatic microcirculation after ischemia/reperfusion injury. Male C57BL/6 mice were subjected to 75 or 120 min of hepatic ischemia and 1 or 3 hours of reperfusion. The effects of continuous ischemia, intermittent clamping, and ischemic preconditioning before prolonged ischemia on sinusoidal perfusion, leukocyte-endothelial interactions, and Kupffer cell phagocytic activity were analyzed by intravital fluorescence microscopy. Kupffer cell activation was measured by tissue levels of tumor necrosis factor (TNF)-,, and the integrity of sinusoidal endothelial cells and Kupffer cells were evaluated by electron microscopy. Continuous ischemia resulted in decreased sinusoidal perfusion rate and phagocytic activity of Kupffer cell, increased leukocyte-endothelial interactions and TNF-, levels. Both protective strategies improved sinusoidal perfusion, leukocyte-endothelial interactions and phagocytic activity of Kupffer cells after 75-minutes of ischemia, and intermittent clamping also after 120 minutes ischemia. TNF-, release was significantly reduced and sinusoidal wall integrity was preserved by both protective procedures. In conclusion, both strategies are protective against ischemia/reperfusion injury by maintaining hepatic microcirculation and decreasing Kupffer cell activation for clinically relevant ischemic periods, and intermittent clamping appears superior for prolonged ischemia. (Liver Transpl 2004;10:520,528.) [source] Simultaneous diffusion MRI measurements from multiple perfused rat hippocampal slicesMAGNETIC RESONANCE IN MEDICINE, Issue 3 2002Timothy M. Shepherd Abstract Rat brain slices provide a controllable tissue model in which to investigate the biophysical basis of diffusion-weighted magnetic resonance (MR) signal changes observed clinically in nervous tissue after ischemic injury. This study describes a new multislice perfusion chamber that allows for the simultaneous acquisition of diffusion-weighted MR images from multiple perfused rat hippocampal slices (eight slices in the present study). These images had a signal-to-noise ratio (SNR) of 48 ± 3 at b = 8080 s/mm2, which was sufficient to analyze the multicomponent diffusion properties of water in rat hippocampal slices. The tissue water diffusion parameters (ffast = 0.527 ± 0.041, Dfast = 1.268 ± 0.087 × 10,3 mm2/s, and Dslow = 0.060 ± 0.003 × 10,3 mm2/s) were stable for at least 8 hr after slice procurement (ANOVA, P > 0.05), suggesting that it may be possible to study the acute temporal evolution of diffusion changes in multiple brain slices following experimental perturbation. Magn Reson Med 48:565,569, 2002. © 2002 Wiley-Liss, Inc. [source] Effects of Estrogen on Postischemic Pial Artery Reactivity to ADPMICROCIRCULATION, Issue 5 2009MIN LI ABSTRACT Objective: The aims of this work were to determine if 1) ischemia alters pial artery responsiveness to the partially nitric oxide (NO)-dependent dilator, ADP, 2) the alteration depends on 17,-estradial (E2), and 3) NO contributes to E2 protective effects. Materials and Methods: Response to ADP and the non-NO-dependent dilator, PGE2, were examined through closed cranial windows. Ovariectomized (OVX) and E2-replaced (E25, 0.025 mg; or E50, 0.05 mg) rats were subjected to 15-minute forebrain ischemia and one-hour reperfusion. Endothelial NO synthase (eNOS) expression was determined in pre- and postischemic isolated cortical microvessels. Results: In OVX rats, ischemia depressed pial responses to ADP, but not to PGE2. Both doses of E2 maintained responses to ADP and had no effect on the response to PGE2. eNOS inhibition decreased the ADP response by 60% in the E25 rats and 50% in the E50 rats, but had no effect in the OVX rats. Compared to the OVX group, microvessel expression of eNOS was increased by E2, but postischemic eNOS was unchanged in both groups. Conclusions: The nearly complete loss of postischemic dilation to ADP suggests that normal non-NO-mediated dilatory mechanisms may be acutely impaired after ischemic injury. Estrogen's protective action on ADP dilation may involve both NO- and non-NO-mediated mechanisms. 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