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ABSTRACT: Susceptibility-weighted imaging (SWI) has recently attracted attention for its ability to investigate acute stroke pathophysiology. SWI detects an increased ratio of deoxyhemoglobin to oxyhemoglobin in cerebral venous compartments, which can illustrate cerebral misery perfusion with a compensatory increase of oxygen extraction fraction in the hypoperfused brain. In this study we make the first case report of blunt cervical trauma leading to a stroke, demonstrating the disparity between diffusion-weighted imaging (DWI) and SWI changes, or DWI-SWI mismatch, in the acute ischemic brain. The area of mismatch between a smaller DWI cytotoxic edema and a larger SWI misery perfusion in our patient matured into a complete infarction with time. The DWI-SWI mismatch may signify the presence of an ischemic penumbra, and provide information about viability of the brain tissue at risk of potential infarction if without early reperfusion.
Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 02/2013;
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Masayuki Fujioka,
Takafumi Nakano,
Kazuhide Hayakawa,
Keiichi Irie,
Yoshiharu Akitake,
Yuya Sakamoto,
Kenichi Mishima,
Carl Muroi,
Yasuhiro Yonekawa,
Fumiaki Banno,
Koichi Kokame,
Toshiyuki Miyata,
Kenji Nishio,
Kazuo Okuchi,
Katsunori Iwasaki,
Michihiro Fujiwara, Bo K Siesjö
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ABSTRACT: Highly adhesive glycoprotein von Willebrand factor (VWF) multimer induces platelet aggregation and leukocyte tethering or extravasation on the injured vascular wall, contributing to microvascular plugging and inflammation in brain ischemia-reperfusion. A disintegrin and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) cleaves the VWF multimer strand and reduces its prothrombotic and proinflammatory functions. Although ADAMTS13 deficiency is known to amplify post-ischemic cerebral hypoperfusion, there is no report available on the effect of ADAMTS13 on inflammation after brain ischemia. We investigated if ADAMTS13 deficiency intensifies the increase of extracellular HMGB1, a hallmark of post-stroke inflammation, and exacerbates brain injury after ischemia-reperfusion. ADAMTS13 gene knockout (KO) and wild-type (WT) mice were subjected to 30-min middle cerebral artery occlusion (MCAO) and 23.5-h reperfusion under continuous monitoring of regional cerebral blood flow (rCBF). The infarct volume, plasma high-mobility group box1 (HMGB1) level, and immunoreactivity of the ischemic cerebral cortical tissue (double immunofluorescent labeling) against HMGB1/NeuN (neuron-specific nuclear protein) or HMGB1/MPO (myeloperoxidase) were estimated 24 h after MCAO. ADAMTS13KO mice had larger brain infarcts compared with WT 24 h after MCAO (p < 0.05). The rCBF during reperfusion decreased more in ADAMTS13KO mice. The plasma HMGB1 increased more in ADAMTS13KO mice than in WT after ischemia-reperfusion (p < 0.05). Brain ischemia induced more prominent activation of inflammatory cells co-expressing HMGB1 and MPO and more marked neuronal death in the cortical ischemic penumbra of ADAMTS13KO mice. ADAMTS13 deficiency may enhance systemic and brain inflammation associated with HMGB1 neurotoxicity, and aggravate brain damage in mice after brief focal ischemia. We hypothesize that ADAMTS13 protects brain from ischemia-reperfusion injury by regulating VWF-dependent inflammation as well as microvascular plugging.
Neurological Sciences 01/2012; 33(5):1107-15. · 1.32 Impact Factor
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12/2010; , ISBN: 9780470650714
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Bo K. Siesjö
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ABSTRACT: Siesjö B. K. A method for continuous measurement of the carbon dioxide tension on the cerebral cortex.A method has been developed for direct, continuous measurement of the pCO2 on the surface of the cerebral cortex, using a modification of the tissue pCO2 electrode earlier described (Hertz Siesjö 1959). The modification was made for the purpose of increasing the stability and accuracy of the measurements. The drift of the electrode was thereby reduced to less than 1 mV in five hours and the accuracy was increased to about ± 1.5 per cent. A reduction of the concavity of the pH glass membrane limited the response time of the pCO2 electrode to 25–30 sec following a twofold increase in pCO2. A description is given of the procedures for calibrating, suspending and thermostatting the electrode.The validity and reproducibility of the pCO2 values obtained when the electrode was applied to the cortical surface were investigated in cat experiments during respiratory and circulatory steady states. It was found that within a relatively wide range the pCO2 was independent of the pressure exerted by the electrode on the cortical surface. Provided that the tissue did not present any swelling and that the tissue surface was not damaged or allowed to dry, the pC2 varied very little (coefficient of variation 1.5 per cent) when the electrode was repeatedly applied to the same or to different cortical areas. The influence of superficial cortical vessels was confined to the larger veins (diameter 0.5–1 mm), across which slightly higher (1–5 mm Hg) values were recorded. The findings are discussed in relation to the applicability of the method in studies of the acid-base metabolism of the tissue.
Acta Physiologica Scandinavica 12/2008; 51(4):297 - 313. · 2.55 Impact Factor
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ABSTRACT: The objective of the present study was to assess the capacity of nonsynaptic brain mitochondria to accumulate Ca2+ when subjected to repeated Ca2+ loads, and to explore under what conditions a mitochondrial permeability transition (MPT) pore is assembled. The effects of cyclosporin A (CsA) on Ca2+ accumulation and MPT pore assembly were compared with those obtained with ubiquinone 0 (Ub0), a quinone that is a stronger MPT blocker than CsA, when tested on muscle and liver mitochondria. When suspended in a solution containing phosphate (2 mM) and Mg2+ (1 mM), but no ATP or ADP, the brain mitochondria had a limited capacity to accumulate Ca2+ (210 nmol/mg of mitochondrial protein). Furthermore, when repeated Ca2+ pulses (40 nmol/mg of protein each) saturated the uptake system, the mitochondria failed to release the Ca2+ accumulated. However, in each instance, the first Ca2+ pulse was accompanied by a moderate release of Ca2+, a release that was not observed during the subsequent pulses. The initial release was accompanied by a relatively marked depolarization, and by swelling, as assessed by light-scattering measurements. However, as the swelling was <50% of that observed following addition of alamethicin, it is concluded that the first Ca2+ pulse gives rise to an MPT in a subfraction of the mitochondrial population. CsA, an avid blocker of the MPT pore, only marginally increased the Ca2+-sequestrating capacity of the mitochondria. However, CsA eliminated the Ca2+ release accompanying the first Ca2+ pulse. The effects of CsA were shared by Ub0, but when the concentration of Ub0 exceeded 20 μM, it proved toxic. The results thus suggest that brain mitochondria are different from those derived from a variety of other sources. The major difference is that a fraction of the brain mitochondria, studied presently, depolarized and showed signs of an MPT. This fraction, but not the remaining ones, contributed to the chemically and electron microscopically verified mitochondrial swelling.
Journal of Neurochemistry 07/2008; 74(5):1999 - 2009. · 4.06 Impact Factor
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ABSTRACT: Changes of cerebral acid-balance, notably of extracellular pH (pHe), have long attracted the attention of physiologists. This is mainly because both cerebral blood flow (CBF) and pulmonary
ventilation are exquisitely sensitive to alterations in pHe, whether these are caused by changes in pCO2 or by addition of strong acid or base to cerebral extracellular fluids (see reviews by Kuskchinsky and Wahl, 1978; Siesjö and Ingvar, 1983).
02/2008: pages 651-690;
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Annals of the New York Academy of Sciences 12/2006; 568(1):234 - 251. · 3.15 Impact Factor
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Annals of the New York Academy of Sciences 12/2006; 462(1):207 - 223. · 3.15 Impact Factor
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ABSTRACT: Ischemic damage is greatly enhanced by preischemic hyperglycemia or hypercapnia, which affects many intracellular responses including protein kinase C (PKC) translocation. We explored whether hyperglycemic or hypercapnic ischemia affects lipid metabolism, especially ischemia-induced release of free fatty acids (FFAs) and diacylglycerols (DAGs). A change in intraischemic level of acidosis was induced either by injecting glucose (hyperglycemic, HG) or by adding CO(2) (hypercapnic, HC). Complete cerebral ischemia was induced, and the brain was frozen in situ after 3, 5, and 10 min at 37 degrees C. Frontoparietal neocortex was dissected for FFA and DAG lipid analysis by thin-layer chromatography and gas-liquid chromatography. Significant differences were shown between normoglycemic and either hypercapnic or hyperglycemic values for individual and total FFAs. A significant delay in the release of FFA in ischemia with hyperglycemia or hypercapnia was observed. Significant differences were also shown in individual DAG-acyl groups and total DAGs. Hyperglycemic or hypercapnic ischemia resulted in a significant decrease of DAG at 10 min of ischemia. This was unexpected because a previous study showed that PKC translocation was significantly enhanced under similar condition at this time point. Upon cellular depolarization, massive influx of calcium and FFA accumulation may decrease the PKC dependence of DAG for translocation. In addition, PKC activation may lead to a negative feedback inhibition of phospholipase C.
Brain Research 01/2005; 1030(1):133-40. · 2.73 Impact Factor
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ABSTRACT: Hyperglycemia and hypercapnia aggravate intra-ischemic acidosis and subsequent brain damage. However, hyperglycemia causes more extensive post-ischemic damage than hypercapnia, particularly in the cingulate cortex. We investigated the changes in the subcellular distribution of protein kinase Cgamma (PKCgamma) and the Ca2+/calmodulin-dependent protein kinase II (CaMKII), as well as changes in protein tyrosine phosphorylation during and following 10 min normoglycemic, hyperglycemic (plasma glucose approximately 20 mM) and hypercapnic (paCO2) approximately 300 mm Hg) global cerebral ischemia. During reperfusion period, the translocation to cell membranes of PKCgamma, but not CaMKII, was prolonged by intra-ischemic hyperglycemia, while it was only marginally affected by hypercapnia. The tyrosine-phosphorylation of proteins in the synaptosomal membranes, as well as the extracellular signal-regulated kinase (ERK) in the cytosol, markedly increased during reperfusion following hyperglycemic ischemia, but to a lesser degree following hypercapnic ischemia. Our data suggest that PKCgamma, tyrosine kinase and ERK systems are involved in the process of ischemic damage in the cingulate cortex, where hyperglycemia may affect these kinases through an additional mechanism other than exaggerated acidosis.
Brain Research 02/2004; 995(2):218-25. · 2.73 Impact Factor
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Masayuki Fujioka,
Toshiaki Taoka,
Yoshiyuki Matsuo,
Kenichi Mishima,
Kumiko Ogoshi,
Yoichi Kondo,
Masakazu Tsuda,
Michihiro Fujiwara,
Takao Asano,
Toshisuke Sakaki,
Akihiro Miyasaki,
Darren Park, Bo K Siesjö
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ABSTRACT: Brief focal ischemia leading to temporary neurological deficits induces delayed hyperintensity on T1-weighted magnetic resonance imaging (MRI) in the striatum of humans and rats. The T1 hyperintensity may stem from biochemical alterations including manganese (Mn) accumulation after ischemia. To clarify the significance of this MRI modification, we investigated the changes in the dorsolateral striatum of rats from 4 hours through 16 weeks after a 15-minute period of middle cerebral artery occlusion (MCAO), for MRI changes, Mn concentration, neuronal number, reactivities of astrocytes and microglia/macrophages, mitochondrial Mn-superoxide dismutase (Mn-SOD), glutamine synthetase (GS), and amyloid precursor protein. The cognitive and behavioral studies were performed in patients and rats and compared with striatal T1 hyperintensity to show whether alteration in brain function correlated with MRI and histological changes. The T1-weighted MRI signal intensity of the dorsolateral striatum increased from 5 days to 4 weeks after 15-minute MCAO, and subsequently decreased until 16 weeks. The Mn concentration of the dorsolateral striatum increased after ischemia in concert with induction of Mn-SOD and GS in reactive astrocytes. The neuronal survival ratio in the dorsolateral striatum decreased significantly from 4 hours through 16 weeks, accompanied by extracellular amyloid precursor protein accumulation and chronic glial/inflammatory responses. The patients and rats with neuroradiological striatal degeneration had late-onset cognitive and/or behavioral declines after brief focal ischemia. This study suggests that (1) the hyperintensity on T1-weighted MRI after mild ischemia may involve tissue Mn accumulation accompanied by Mn-SOD and GS induction in reactive astrocytes, (2) the MRI changes correspond to striatal neurodegeneration with a chronic inflammatory response and signs of oxidative stress, and (3) the subjects with these MRI changes are at risk for showing a late impairment of brain function even though the transient ischemia is followed by total neurological recovery.
Annals of Neurology 01/2004; 54(6):732-47. · 11.09 Impact Factor
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ABSTRACT: Stroke is the third leading cause of death in the US, with a prevalence of 750,000 patients per year, and a social cost estimated at $50 billion. Current therapeutics are targeted at restoring blood flow rather than on preventing the actual mechanisms associated with neuronal cell death. Here, we show that, following transient (2 h) middle cerebral artery occlusion (tMCAO) in male, Wistar rats, neuronal damage determined using MAP-2 staining increased progressively after the tMCAO. Notably, such neuronal degeneration was first associated with a decrease in p-Akt in both the focus and penumbra of the infarct region and, later with an increase in cytosolic cytochrome C levels in cortical neurons in the infarct area. These findings implicate that Akt alterations and consequent release of cytochrome C are involved in neuronal death. To further address this issue, NXY-059 (disodium 4-[(tert.-butylimino)methyl]benzene-1,3-disulfonate N-oxide) administered i.v. (30 mg/kg bolus, followed by 30 mg/kg/h infusion for up to 24 h), commencing 1 h after reperfusion, not only prevented the increase in infarct area but also attenuated the postreperfusion increase in neuronal cytosolic cytochrome C and the postperfusion decrease in neuronal p-Akt. Thus, NXY-059, by preventing mitochondrial cytochrome C release by maintaining activation of the Akt pathway, appears to protect neurons from damage after ischemia.
Brain Research 09/2002; 947(2):191-8. · 2.73 Impact Factor
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ABSTRACT: Transient global or forebrain ischemia leads to severe brain damage following delayed neuronal cell death. We previously reported that cyclosporin A (CsA) provides near total suppression of brain damage in rat forebrain ischemia when allowed to pass the blood brain barrier, whereas Tacrolimus (FK506) is considerably less effective. We demonstrate herein that when administered prior to ischemic insult, both immunosuppressants equally block calcineurin, a type 2B Ser/Thr phosphatase, and efficiently inhibit dephosphorylation of pro-apoptotic protein Bad. CsA demonstrates more potent anti-ischemic effects than FK506, partially attributable to amelioration of mitochondrial damage as assayed in vivo and in vitro. These results suggest that pathways including calcineurin and cyclophilins, particularly mitochondrial cyclophilin D, play pivotal roles in ischemic brain damage. Since previous results have shown that CsA is efficacious also when administered after focal ischemia, the present findings give hints to clinical applications for new drugs for the treatment of ischemic damage in the brain as well as in the heart and liver.
Neurobiology of Disease 09/2002; 10(3):219-33. · 5.40 Impact Factor
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ABSTRACT: The free radical trapping agents NXY-059 and alpha-phenyl-N-tert.-butylnitrone (PBN) markedly reduce infarct volume, even when given 1 or 3 h after the start of recirculation, following 2 h of middle cerebral artery (MCA) occlusion in rats. Their anti-ischemic effects are shared by the two immunosuppressants cyclosporin A (CsA) and FK506. Interestingly, CsA causes an additional reduction in infarct volume when given after only 5 min of recirculation, possibly reflecting blockade of a mitochondrial permeability transition (MPT) pore. PBN, CsA and FK506 are known to ameliorate the secondary dysfunction of mitochondrial function, as assessed in vitro, which occurs during the first 4-6 h of recirculation. The present experiments were undertaken to assess whether NXY-059 reduces tissue damage by acting directly on mitochondrial membranes, and provided that this is the case, if blockade of an MPT is involved. The results were compared to those of CsA, which thus served as a reference compound. NXY-059 was given i.v. after 5 min and 1 h, and CsA after 5 min of recirculation. Both NXY-059 and CsA reduced infarct volumes to about 30% of control, prevented the secondary decline in mitochondrial respiratory function during recirculation, and reduced the mitochondrial release of cytochrome c after 6 and 24 h of recirculation. However, NXY-059 failed to block the effect of Ca(2+) on mitochondrial swelling in vitro, as CsA did. Furthermore, NXY-059, given after 5 min of recirculation, did not reproduce the effects of CsA. The results thus suggest that NXY-059 exerts its effects on mitochondria by indirect mechanisms.
Brain Research 05/2002; 932(1-2):99-109. · 2.73 Impact Factor
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ABSTRACT: A recent study reported that hyperglycemia of a brief duration worsens, and of long duration reduces, ischemic brain damage. To test whether this is a valid conception, we induced 10 min of transient forebrain ischemia, recorded postischemic seizures, and evaluated brain morphology. The results showed that administration of glucose 2 h before ischemia aggravated brain damage, induced seizures, and caused animal death in the same manner as was previously observed when glucose was given 30 min before ischemia. Thus, the conclusion that the influence of glucose on an ischemic transient is dependent upon the duration of hyperglycemia is unsubstantiated.
Brain Research 10/2001; · 2.73 Impact Factor
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ABSTRACT: The mechanisms underlying the aggravating effect of hyperglycemia on brain damage are still elusive. The present study was designed to test our hypothesis that hyperglycemia-mediated damage is caused by mitochondrial dysfunction with mitochondrial release of cytochrome c (cyt c) to the cytoplasm, which leads to activation of caspase-3, the executioner of cell death. We induced 15 min of forebrain ischemia, followed by 0.5, 1, and 3 h of recirculation in sham, normoglycemic and hyperglycemic rats. Release of cyt c was observed in the neocortex and CA3 in hyperglycemic rats after only 0.5 h of reperfusion, when no obvious neuronal damage was observed. The release of cyt c persisted after 1 and 3 h of reperfusion. Activation of caspase-3 was observed after 1 and 3 h of recovery in hyperglycemic animals. No cyt c release or caspase-3 activation was observed in sham-operated controls while a mild increase of cyt c was observed in normoglycemic ischemic animals after 1 and 3 h of reperfusion. The findings that there is caspase activation and cyt c relocation support a notion that the biochemical changes that constitute programmed cell death occur after ischemia and contribute, at least in part, to hyperglycemia-aggravated ischemic neuronal death.
Brain Research 04/2001; · 2.73 Impact Factor
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ABSTRACT: The present study was undertaken to investigate whether extracellular signal-regulated kinase (ERK) was involved in mediating hyperglycemia-exaggerated cerebral ischemic damage. Phosphorylation of ERK 1/2 was studied by immunocytochemistry and by Western blot analyses. Rats were subjected to 15 min of forebrain ischemia, followed by 0.5, 1, and 3 h of reperfusion under normoglycemic and hyperglycemic conditions. The results showed that in normoglycemic animals, moderate phosphorylation of ERK 1/2 was transiently induced after 0.5 h of recovery in cingulate cortex and in dentate gyrus, returning to control values thereafter. In hyperglycemic animals, phosphorylation of ERK 1/2 was markedly increased in the cingulate cortex and dentate gyrus after 0.5 h of recovery, the increases being sustained for at least 3 h after reperfusion. Hyperglycemia also induced phosphorylation of ERK 1/2 in the hippocampal CA3 sector but not in the CA1 area. Thus, the distribution of phospho-ERK 1/2 coincides with hyperglycemia-recruited damage structures. The results suggest that hyperglycemia may influence the outcome of an ischemic insult by modulating signal transduction pathways involving ERK 1/2.
Neurobiology of Disease 03/2001; · 5.40 Impact Factor
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ABSTRACT: A recent study showed that a single intracarotid arterial injection of cyclosporin A (CsA) can dramatically reduce infarct volume in rats subjected to transient focal ischemia. The present experiments were undertaken to investigate whether intracarotid arterial injection of CsA reduces brain damage after global ischemia. Since hypothermia is also an efficacious factor in preventing ischemic brain damage, in the second part of the experiments we tested whether a combination of hypothermia and CsA would provide additional brain protection. Global ischemia of a 30-min duration was induced in the rat. CsA (10 mg/kg) was injected into the carotid artery immediately after reperfusion. Hypothermia was instituted after ischemia by allowing spontaneous head temperature to fall to 30–32°C, while body temperature was upheld at 37°C. The results demonstrated that vehicle-treated animals could not survive beyond 1–2 days after reperfusion, and the histopathological outcome in a separate group of rats perfusion-fixed after 1 day reperfusion showed 80–100% brain damage in the caudoputamen, and in the hippocampal CA1, CA3, CA4 and dentate gyrus subregions. Microinfarction and grade 3 damage were frequently observed in the cingulate and parietal cortex and in the thalamus. CsA moderately prolonged animal survival to 3 days after reperfusion and reduced brain damage to grade 2 in the cortical areas and the thalamus. Hypothermia further increased animal survival to at least 6 days after reperfusion and reduced brain damage to 30% in the caudoputamen, to close to zero in the CA3, CA4, and dentate gyrus, and to grade 1–2 in the cortical areas and the thalamus. The combination of hypothermia and CsA did not give additional protection.
Brain Research 03/2001; · 2.73 Impact Factor
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ABSTRACT: Transient ischemia is known to lead to a long-lastingdepression of cerebral metabolic rate and blood flow and to an attenuatedmetabolic and circulatory response to physiological stimuli. However, thecorresponding responses to induced seizures are retained, demonstratingpreserved metabolic and circulatory capacity. The objective of the presentstudy was to explore how a preceding period of ischemia (15 min) alters therelease of free fatty acids (FFAs) and diacylglycerides (DAGs), the formationof cyclic nucleotides, and the influx/efflux of Ca2+, followingintense neuronal stimulation. For that purpose, seizure activity was inducedwith bicuculline for 30 s or 5 min at 6 h after the ischemia. ExtracellularCa2+ concentration (Ca2+e) was recorded, andthe tissue was frozen in situ for measurements of levels of FFAs, DAGs, andcyclic nucleotides. Six hours after ischemia, the FFA concentrations werenormalized, but there was a lowering of the content of 20:4 in the DAGfraction. Cyclic AMP levels returned to normal values, but cyclic GMP contentwas reduced. Seizures induced in postischemic animals showed similar changesin Ca2+e, as well as in levels of FFAs, DAGs, and cyclicnucleotides, as did seizures induced in nonischemic control animals, with theexception of an attenuated rise in 20:4 content in the DAG fraction. Weconclude that, at least in the neocortex, seizure-induced phospholipidhydrolysis and cyclic cAMP/cyclic GMP formation are not altered by a precedingperiod of ischemia, nor is there a change in the influx/efflux ofCa2+ during seizure discharge or in associated spreadingdepression.
Journal of Neurochemistry 11/2000; 75(6):2521 - 2527. · 4.06 Impact Factor
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ABSTRACT: Cyclosporin A (CsA) has been shown to be efficacious in protecting against ischemic injury after short periods (5 to 10 min) of forebrain ischemia. The present experiments were undertaken to study if a long period of forebrain ischemia (30 min), induced at a brain temperature of 37°C, is compatible with survival and if the brain damage incurred can be ameliorated by CsA. The results showed that animals subjected to 30 min of forebrain ischemia at a brain temperature of 37°C failed to survive after the first 24 h of recovery and showed extensive neuronal necrosis in all selectively vulnerable regions after 1 day of survival. CsA, when injected in combination with an intracerebral lesion to open the blood–brain barrier, markedly prolonged the survival time. CsA-injected animals also showed amelioration of histological lesions, an effect that was sustained for at least 4 days. Experiments with mitochondria isolated from the neocortex and hippocampus showed that state 3 respiratory rates decreased during ischemia, recovered after 1 and 3 h of recirculation, and then showed a secondary decline at 6 h. Administration of CsA prevented this secondary decline. Measurements of neocortical cerebral blood flow showed that there was no secondary hypoperfusion prior to secondary mitochondrial dysfunction, implying that changes in blood flow may not be responsible for the rapidly developing, secondary brain damage. The results thus demonstrate that if brain temperature is upheld at 37°C, a 30-min period of ischemia is not compatible with survival after the first day of recovery, and gross histopathological damage develops within that period. CsA was efficacious in prolonging animal survival, ameliorating brain damage, and preventing the secondary mitochondrial dysfunction. Since CsA blocks the mitochondrial permeability transition pore its action may, at least in part, be on mitochondrial integrity and function.
Experimental Neurology 10/2000; · 4.70 Impact Factor
