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Brain Ischemia (brain + ischemia)
Kinds of Brain Ischemia Selected AbstractsAssociation of Pretreatment ASPECTS Scores with tPA-Induced Arterial Recanalization in Acute Middle Cerebral Artery OcclusionJOURNAL OF NEUROIMAGING, Issue 1 2008Georgios Tsivgoulis MD ABSTRACT BACKGROUND AND PURPOSE The Alberta Stroke Program Early CT-Score (ASPECTS) assesses early ischemic changes within the middle cerebral artery (MCA) and predicts poor outcome and increased risk for thrombolysis-related symptomatic ICH. We evaluated the potential relationship between pretreatment ASPECTS and tPA-induced recanalization in patients with MCA occlusions. SUBJECTS & METHODS Consecutive patients with acute ischemic stroke due to MCA occlusion were treated with standard IV-tPA and assessed with transcranial Doppler (TCD) for arterial recanalization. Early recanalization was determined with previously validated Thrombolysis in Brain Ischemia (TIBI) flow-grading system at 120 minutes after tPA-bolus. All pretreatment CT-scans were prospectively scored by trained investigators blinded to TCD findings. Functional outcome at 3 months was evaluated using the modified Rankin Scale (mRS). RESULTS IV-tPA was administered in 192 patients (mean age 68 ± 14 years, median NIHSS-score 17). Patients with complete recanalization (n= 51) had higher median pretreatment ASPECTS (10, interquartile range 2) than patients with incomplete or absent recanalization (n= 141; median ASPECTS 9, interquartile range 3, P= .034 Mann-Whitney U-test). An ASPECTS ,6 was documented in 4% and 17% of patients with present and absent recanalization, respectively (P= .019). Pretreatment ASPECTS was associated with complete recanalization (OR per 1-point increase: 1.54; 95% CI 1.06,2.22, P= .023) after adjustment for baseline characteristics, risk factors, NIHSS-score, pretreatment TIBI grades and site of arterial occlusion on baseline TCD. Complete recanalization (OR: 33.97, 95% CI 5.95,185.99, P < .001) and higher ASPECTS (OR per 1-point increase: 1.91; 95% CI 1.17,3.14, P= .010) were independent predictors of good functional outcome (mRS 0,2). CONCLUSIONS Higher pretreatment ASPECT-scores are associated with a greater chance of complete recanalization and favorable long-term outcome in tPA-treated patients with acute MCA occlusion. [source] Selective Neuronal Vulnerability Following Mild Focal Brain Ischemia in the MouseBRAIN PATHOLOGY, Issue 4 2003Juri Katchanov The evolution of cellular damage over time and the selective vulnerability of different neuronal subtypes was characterized in the striatum following 30-minute middle cerebral artery occlusion and reperfusion in the mouse. Using autoradiography we found an increase in the density of [3H]PK11195 binding sites,likely reflecting microglial activation,in the lesion border at 3 days and in the whole striatum from 10 days to 6 weeks. This was accompanied by a distinct loss of [3H]flumazenil and [3H]CGP39653 binding sites from 10 days up to 6 weeks reflecting neuronal loss. Brain ischemia resulted in a substantial loss of medium spiny projection neurons as seen at three days by Nissl staining, TUNEL and immunocytochemistry using antibodies against microtubule-associated protein (MAP2), NeuN, (,-opioid receptors, substance P, Lenkephalin, neurokinin B, choline acetyltransferase, parvalbumin, calretinin and somatostatin. Both patch and matrix compartments were involved in ischemic damage. In contrast, the numbers of cholinergic, GABAergic, and somatostatin-containing interneurons in the ischemic striatum were not different from those in the contralateral hemisphere at 3 and 14 days. A low density of glutamate receptors, the ability to sequester calcium by calcium-binding proteins and other hitherto unidentified factors may explain this relative resistance of interneurons to acute ischemia. [source] Redox-based endoplasmic reticulum dysfunction in neurological diseasesJOURNAL OF NEUROCHEMISTRY, Issue 1 2008Gábor Bánhegyi Abstract The redox homeostasis of the endoplasmic reticulum lumen is characteristically different from that of the other subcellular compartments. The concerted action of membrane transport processes and oxidoreductase enzymes maintain the oxidized state of the thiol-disulfide and the reducing state of the pyridine nucleotide redox systems, which are prerequisites for the normal functions of the organelle. The powerful thiol-oxidizing machinery allows oxidative protein folding but continuously challenges the local antioxidant defense. Alterations of the cellular redox environment either in oxidizing or reducing direction affect protein processing and may induce endoplasmic reticulum stress and unfolded protein response. The activated signaling pathways attempt to restore the balance between protein loading and processing and induce apoptosis if the attempt fails. Recent findings strongly support the involvement of this mechanism in brain ischemia, neuronal degenerative diseases and traumatic injury. The redox changes in the endoplasmic reticulum are integral parts of the pathomechanism of neurological diseases, either as causative agents, or as complications. [source] Involvement of , protein kinase C in estrogen-induced neuroprotection against focal brain ischemia through G protein-coupled estrogen receptorJOURNAL OF NEUROCHEMISTRY, Issue 4 2005Shigeto Hayashi Abstract The neuroprotective effects of estrogen were studied in the ischemic model mice by 90 min transient unilateral middle cerebral artery occlusion (MCAO) followed by 22.5 h reperfusion. The total infarct size in C57BL/6 female mice after MCAO and reperfusion was significantly smaller than that in male mice. Intraperitoneal injection of estrogen after the start of reperfusion significantly reduced the infarct volume in the male mice. However, no significant gender difference was found in total infarct size in , protein kinase C (PKC)-knockout mice, suggesting that the neuroprotective effects of estrogen are due to the activation of a specific subtype of PKC, ,PKC, a neuron-specific PKC subtype, in the brain. We demonstrated that exogenous estrogen-induced neuroprotection was attenuated in ,PKC-knockout mice. Immunocytochemical study showed that ,PKC was translocated to nerve fiber-like structures when observed shortly after MCAO and reperfusion. We also visualized the rapid and reversible translocation of ,PKC-GFP (green fluorescent protein) by estrogen stimulation in living CHO-K1 cells. These results suggest that the activation of ,PKC through the G-protein-coupled estrogen receptors on the plasma membrane is involved in the estrogen-induced neuroprotection against focal brain ischemia. [source] Protein aggregation in postsynaptic density after transient brain ischemiaJOURNAL OF NEUROCHEMISTRY, Issue 2003M. Ber, sewicz Brief cerebral ischemia causes changes in synaptic transmission and in consequence in neuronal function manifested in delayed cell death of CA1 hippocampal region. Postsynaptic density (PSD) is composed by a network of interacting proteins, including scaffolding proteins, neurotransmitter receptors, cytoskeletal proteins and protein kinases. PSD dynamically modulates signal transduction what influence the cell fate. We investigated the composition of the PSD network and effect of ischemia on its complexity. Two experimental procedures were applied. The interaction between PSD-95 and Src, Fyn, Raf-1, paxilin or NMDA receptor subunits were explored using coimmunoprecipitation method. In addition, the effect of ischemia-reperfusion on the density of PSD were evaluated by measurement of is solubility. We find out the decrease in solubility of the PSD-95, NR2A, NR2B and Raf-1. Of interest, the latter was restricted to surviving regions of hippocampus. Acknowledgement:, Financed by PBZ-KBN-002/CD/P05/2000. [source] The study of the creatine kinase in rat brain during ischemia by magnetization transfer and biochemical analysisJOURNAL OF NEUROCHEMISTRY, Issue 2003D. Dobrota Various methods are used to study the biochemical changes in the central nervous system under normal and pathological conditions. The magnetization transfer 31P magnetic resonance technique was used here to measure the creatine kinase (CK) reaction rate constant in vivo in rats with cerebral ischemia. The measurements indicated that the rate constant of the CK reaction was significantly reduced in the case of chronic brain ischemia in aged rats. The similar reduction of the creatine kinase activity was found in the ischemic rat brain homogenate measured by biochemical analysis. At the same time, corresponding conventional phosphorus magnetic resonance spectra showed negligible or no change in signal intensities of compounds containing macroergic phosphates. Acknowledgements: This work was supported by the Grant Category C and Comenius University Grant No. X/2003. [source] Workshop 5: NAAG and NAALADase: Functional Properties in the Central and Peripheral Nervous SystemJOURNAL OF NEUROCHEMISTRY, Issue 2002D. Bacich Glutamate carboxypeptidase II (GCPII, also known as N-acetylated-alpha-linked acidic dipeptidase or NAALADase) knockout (KO) mice were generated by inserting a GCPII targeting cassette containing a PGK-Neo resistance marker and stop codons in exons 1 and 2, and removal of exons 1 and 2 intron/exon boundary sequence. Embryonic stem cells were injected into C57BL6 blastocysts, and chimeric offspring born. Germline transmission was confirmed by mating the chimeras to generate heterozygous KO mice. Crossing heterozygous mice generated F2 generation mice homozygous for the null mutant, as confirmed by loss of GCPII protein. NAAG hydrolyzing activity was minimal (0.07 pmol/mg/min) in KO tissue, with normal levels (4.82 pmol/mg/min) in wild types and intermediate levels (1.73 pmol/mg/min) in heterozygotes. Preliminary neuropathy experiments showed KO mice are less affected by nerve-crush and recover faster from the damage-induced neuropathy, as indicated by EMG recording and nerve morphology. Similarly, GCPII KO mice subjected to high dose vitamin B6 displayed less severe neuropathy than wild types, as indicated by reduced sensory nerve conduction velocity and morphological deficits. Also, in a transient middle cerebral artery occlusion model, GCPII KO mice were significantly more resistant to the effects of cerebral ischemia than their wildtype littermates. Findings support GCPII involvement in stroke and in mediating chronic neuropathic conditions and suggest GCPII inhibitors may be useful in treatment of brain ischemia as well as peripheral neuropathies. [source] Sphingolipids in rat model of transient focal cerebral ischemia: implication for stroke injuryJOURNAL OF NEUROCHEMISTRY, Issue 2002M. Khan Lipids are essential for signal transduction in response to trauma leading to neurodegeneration. Ceramide is an important mediator of apoptosis and cell proliferation. We studied the involvement of ceramide/sphingomyelin pathway in rat brain (stroke model) after 45 min ischemia followed by 24-h reperfusion. Ischemia was performed through occlusion of right middle cerebral artery (MCA). The level of ceramide was found increased (70,100% in ischemic side of brain v/s contralateral side of brain). Sphingomyelin levels were also decreased by 20,25% in ischemic brain v/s contralateral side of brain. Increase in ceramide and decrease in sphingomyelin were in good agreement with observed apoptotic cell loss (TUNEL assay) and decrease in the level of cardiolipin (a mitochondrian specific phospholipids) in affected ischemic brain. N-acetyl cysteine (NAC), a therapeutic agent recognized as potent antioxidant provided protective effect. Pretreatment with NAC before ischemia reduced the infarct volume size, suppressed apoptosis, restored cardiolipin level and decreased the levels of free fatty acids. However, NAC did not normalize the ceramide level. These interesting observations raise a question about the role of ceramide and its relationship with apoptosis and oxidative stress in rat brain ischemia. Acknowledgements:, Supported by NIH grants NS-40144, NS-40810, NS-22576, NS-34741 and NS-37766. [source] Endogenously released DOPA is a causal factor for glutamate release and resultant delayed neuronal cell death by transient ischemia in rat striataJOURNAL OF NEUROCHEMISTRY, Issue 3 2001Nobuya Furukawa Glutamate is implicated in neuronal cell death. Exogenously applied DOPA by itself releases neuronal glutamate and causes neuronal cell death in in vitro striatal systems. Herein, we attempt to clarify whether endogenous DOPA is released by 10 min transient ischemia due to four-vessel occlusion during rat striatal microdialysis and, further, whether DOPA, when released, functions to cause glutamate release and resultant delayed neuronal cell death. Ischemia increased extracellular DOPA, dopamine, and glutamate, and elicited neuronal cell death 96 h after ischemic insult. Inhibition of striatal l -aromatic amino acid decarboxylase 10 min before ischemia increased markedly basal DOPA, tripled glutamate release with a tendency of decrease in dopamine release by ischemia, and exaggerated neuronal cell death. Intrastriatal perfusion of 10,30 nm DOPA cyclohexyl ester, a competitive DOPA antagonist, 10 min before ischemia, concentration-dependently decreased glutamate release without modification of dopamine release by ischemia. At 100 nm, the antagonist elicited a slight ceiling effect on decreases in glutamate release by ischemia and protected neurons from cell death. Glutamate was released concentration-dependently by intrastriatal perfusion of 0.3,1 mm DOPA and stereoselectively by 0.6 mm DOPA. The antagonist elicited no hypothermia during and after ischemia. Endogenously released DOPA is an upstream causal factor for glutamate release and resultant delayed neuronal cell death by brain ischemia in rat striata. DOPA antagonist has a neuroprotective action. [source] Residual Flow Signals Predict Complete Recanalization in Stroke Patients Treated With TPAJOURNAL OF NEUROIMAGING, Issue 1 2003Lise A. Labiche MD ABSTRACT Background. Residual blood flow around thrombus prior to treatment predicts success of coronary thrombolysis. The authors aimed to correlate the presence of residual flow signals in the middle cerebral artery (MCA) with completeness of recanalization after intravenous tissue plasminogen activator (TPA). Methods. The authors studied consecutive patients treated with intravenous TPA therapy who had a proximal MCA occlusion on pretreatment transcranial Doppler (TCD). Patients were continuously monitored for 2 hours after TPA bolus. Absent residual flow signals correspond to the thrombolysis in brain ischemia (TIBI) 0 grade, and the presence of residual flow signals was determined as TIBI 1-3 flow grades. Complete recanalization was defined as flow improvement to TIBI grades 4-5. Results. Seventy-five patients with a proximal MCA occlusion had median pre-bolus NIHSS 16 (85% with ,10 points). TPA bolus was given at 141 ± 56 minutes (median 120 minutes). Complete recanalization was observed in 25 (33%), partial in 23 (31%), and no early recanalization was seen in 27 (36%) patients within 2 hours after TPA bolus. Only 19% with absent residual flow signals (TIBI grade 0, n= 26) on pretreatment TCD had complete early recanalization. If pretreatment TCD showed the presence of any residual flow (TIBI 1-3, n= 49), 41% had complete recanalization within 2 hours of TPA bolus (P = .03). Conclusions. Patients with detectable residual flow signals before IV TPA bolus are twice as likely to have early complete recanalization. Those with no detectable residual flow signals have less than 20% chance for complete early recanalization with intravenous TPA and may be candidates for intra-arterial therapies. [source] Ophthalmic Artery Flow Direction on Color Flow Duplex Imaging Is Highly Specific for Severe Carotid StenosisJOURNAL OF NEUROIMAGING, Issue 1 2002Patrick S. Reynolds MD Background/Purpose. Collateral flow patterns are important risk factors for brain ischemia in the presence of internal carotid artery (ICA) stenosis or occlusion. Ophthalmic artery (OA) flow reversal, routinely studied by transcranial Doppler sonography, is an important marker for high-grade ICA stenosis or occlusion. The authors sought to define the value of assessing OA flow direction with color flow duplex ultrasonography (CDUS) in the setting of significant ICA disease. Methods. Of all patients having routine carotid ultrasound in the neurosonology laboratory between July 1995 and November 2000, 152 had both carotid and orbital (OA flow direction by reduced power orbital CDUS) examinations as well as angiographic confirmation of stenosis to which North American Symptomatic Carotid Endarterectomy Trial criteria could be applied. Degree of angiographic stenosis in these 152 patients (304 arteries) was correlated with OA flow direction. Results. Of 304 arteries, 101 had greater than 80% stenosis by angiogram. In 56 of these 101 arteries with high-grade stenosis or occlusion, the ipsilateral OA was reversed; however, OA flow direction was never reversed ipsilateral to arteries with less than 80% stenosis (sensitivity 55%, specificity 100%, negative predictive value 82%, and positive predictive value 100% for OA flow reversal as a marker of high-grade carotid lesions). Discussion/Conclusions. OA flow direction is easily studied with CDUS. Reversed OA flow direction is highly specific (100%) for severe ipsilateral ICA stenosis or occlusion, with excellent positive predictive value, moderate negative predictive value, and limited sensitivity. OA flow reversal is not only quite specific for severe ICA disease, which may be helpful if the carotid CDUS is difficult or inadequate, but may also provide additional hemodynamic insights (ie, the inadequacy of other collateral channels such as the anterior communicating artery). OA evaluation can provide important hemodynamic information and should be included as part of carotid CDUS if there is any evidence of ICA stenosis or occlusion. [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] Enhanced proliferation of progenitor cells in the subventricular zone and limited neuronal production in the striatum and neocortex of adult macaque monkeys after global cerebral ischemia,JOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2005Anton B. Tonchev Abstract Cerebral ischemia in adult rodent models increases the proliferation of endogenous neural progenitor cells residing in the subventricular zone along the anterior horn of the lateral ventricle (SVZa) and induces neurogenesis in the postischemic striatum and cortex. Whether the adult primate brain preserves a similar ability in response to an ischemic insult is uncertain. We used the DNA synthesis indicator bromodeoxyuridine (BrdU) to label newly generated cells in adult macaque monkeys and show here that the proliferation of cells with a progenitor phenotype (double positive for BrdU and the markers Musashi1, Nestin, and ,III-tubulin) in SVZa increased during the second week after a 20-min transient global brain ischemia. Subsequent progenitor migration seemed restricted to the rostral migratory stream toward the olfactory bulb and ischemia increased the proportion of adult-generated cells retaining their location in SVZa with a progenitor phenotype. Despite the lack of evidence for progenitor cell migration toward the postischemic striatum or prefrontal neocortex, a small but sustained proportion of BrdU-labeled cells expressed features of postmitotic neurons (positive for the protein NeuN and the transcription factors Tbr1 and Islet1) in these two regions for at least 79 days after ischemia. Taken together, our data suggest an enhanced neurogenic response in the adult primate telencephalon after a cerebral ischemic insult. © 2005 Wiley-Liss, Inc. [source] Spatiotemporal changes of apolipoprotein E immunoreactivity and apolipoprotein E mRNA expression after transient middle cerebral artery occlusion in rat brainJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2003Hiroshi Kamada Abstract Apolipoprotein E (ApoE) is a constituent of lipoprotein and plays an important role in the maintenance of neural networks. However, spatiotemporal differences in ApoE expression and its long-term role in neural process after brain ischemia have not been studied. We investigated changes of ApoE immunoreactivity and ApoE mRNA expression both in the core and in the periischemic area at 1, 7, 21, or 56 days after 90 min of transient middle cerebral artery occlusion. Double stainings for ApoE plus NeuN or plus ED1 were performed in order to identify cell type of ApoE-positive stainings. The maximal increase of ApoE expression was observed at 7 days in the core and at 7 and 21 days in the periischemic area. In the core, ApoE plus NeuN double-positive cells increased at 1 and 7 days, without ApoE mRNA expression, whereas they increased in the periischemic area, with a peak at 21 days, with ApoE mRNA expression in glial cells but not in neurons. On the other hand, ApoE plus ED1 double-positive cells increased only in the core, with a peak in number at 7 and 21 days and marked ApoE mRNA expression in macrophages. The present study suggests that ApoE plays various important roles in different type of cells, reflecting spatiotemporal dissociation between degenerative and regenerative processes after brain ischemia, and that ApoE is profoundly involved in pathological conditions, such as brain ischemia. © 2003 Wiley-Liss, Inc. [source] Vascular endothelial growth factor gene expression in middle cerebral artery occlusion in the ratACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2005F. Lennmyr Background:, Focal cerebral ischemia induces up-regulation of angiogenic growth factors such as vascular endothelial growth factor (VEGF), which may have both beneficial and harmful effects to the ischemic brain. Vascular endothelial growth factor is up-regulated in models of brain ischemia, but the underlying mechanisms in vivo remain unclear. In the present report we have investigated the concomitant changes in VEGF and glyceraldehyde dehydrogenase (GAPDH) mRNA expression in a model of permanent and transient cerebral ischemia. Methods:, Male Sprague-Dawley rats were exposed to permanent or transient (2 h) middle cerebral artery occlusion (PMCAO, TMCAO). Brain samples were collected at survival times ranging from 6 h to 1 week, and the levels of VEGF164 and GAPDH mRNA were determined using reverse-transcriptase real-time polymerase chain reaction (RT-PCR). Results:, The VEGF mRNA levels decreased gradually over the observation period in a similar manner in both PMCAO and TMCAO. Maximum levels, seen at early observation time points, did not significantly deviate from sham controls. No statistically significant changes in GAPDH mRNA levels were observed, but there was a tendency towards a postischemic decrease with subsequent return to control levels over time. The VEGF/GAPDH ratio followed a pattern of decrease similar to VEGF mRNA alone. Conclusion:, The VEGF mRNA levels at 6 h after MCAO remain near baseline and thereafter decline, regardless of whether the occlusion is permanent or transient (2 h). The findings raise the question of other than transcriptional regulation of VEGF in cerebral ischemia. [source] Severe withdrawal syndrome in three newborns subjected to continuous opioid infusion and seizure activity dependent on brain hypoxia , ischemia.PEDIATRIC ANESTHESIA, Issue 10 2006A possible link Summary Background :,The aim of this investigation was to verify whether brain hypoxia represented a risk factor for the occurrence and severity of opioid abstinence syndrome. Methods :,Three newborns who manifested seizure activity as a result of hypoxia, focal brain ischemia, and hypoxia and sepsis, respectively, were compared with 17 neonates who suffered from hypoxia without developing seizure activity. Results :,The first three neonates suffered a severe withdrawal syndrome (a rating on the neonatal abstinence score >17), the others did not. Conclusions :,It is hypothesized that brain hypoxia facilitated the occurrence and severity of the withdrawal syndrome because some key neurochemical processes (such as N -methyl- d -aspartate activation, protein kinase C activation and nitric oxide production) are common to both phenomena. [source] New England medical center posterior circulation registryANNALS OF NEUROLOGY, Issue 3 2004Louis R. Caplan MD Among 407 New England Medical Center Posterior Circulation registry patients, 59% had strokes without transient ischemic attacks (TIAs), 24% had TIAs then strokes, and 16% had only TIAs. Embolism was the commonest stroke mechanism (40% of patients including 24% cardiac origin, 14% intraarterial, 2% cardiac and arterial sources). In 32% large artery occlusive lesions caused hemodynamic brain ischemia. Infarcts most often included the distal posterior circulation territory (rostral brainstem, superior cerebellum and occipital and temporal lobes); the proximal (medulla and posterior inferior cerebellum) and middle (pons and anterior inferior cerebellum) territories were equally involved. Severe occlusive lesions (>50% stenosis) involved more than one large artery in 148 patients; 134 had one artery site involved unilaterally or bilaterally. The commonest occlusive sites were: extracranial vertebral artery (52 patients, 15 bilateral) intracranial vertebral artery (40 patients, 12 bilateral), basilar artery (46 patients). Intraarterial embolism was the commonest mechanism of brain infarction in patients with vertebral artery occlusive disease. Thirty-day mortality was 3.6%. Embolic mechanism, distal territory location, and basilar artery occlusive disease carried the poorest prognosis. The best outcome was in patients who had multiple arterial occlusive sites; they had position-sensitive TIAs during months to years. Ann Neurol 2004;56:389,398 [source] Liposome-Encapsulated Hemoglobin Reduces the Size of Cerebral Infarction in Rats: Effect of Oxygen AffinityARTIFICIAL ORGANS, Issue 2 2009Dai Fukumoto Abstract Liposome-encapsulated hemoglobin (LEH) with a low oxygen affinity (l-LEH, P50 = 45 mm Hg) was found to be protective in the rodent and primate models of ischemic stroke. This study investigated the role of LEH with a high O2 affinity (h-LEH, P50 = 10 mm Hg) in its protective effect on brain ischemia. The extent of cerebral infarction was determined 24 h after photochemically induced thrombosis of the middle cerebral artery from the integrated area of infarction detected by triphenyltetrazolium chloride staining in rats receiving various doses of h-LEH as well as l-LEH. Both h-LEH and l-LEH significantly reduced the extent of cortical infarction. h-LEH remained protective at a lower concentration (minimal effective dose [MED]: 0.08 mL/kg) than l-LEH (MED: 2 mL/kg) in the cortex. h-LEH reduced the infarction extent in basal ganglia as well (MED: 0.4 mL/kg), whereas l-LEH provided no significant protection. h-LEH provided better protection than l-LEH. The protective effect of both high- and low-affinity LEH may suggest the importance of its small particle size (230 nm) as compared to red blood cells. The superiority of h-LEH over l-LEH supports an optimal O2 delivery to the ischemic penumbra as the mechanism of action in protecting against brain ischemia and reperfusion. [source] S -Nitrosylated Pegylated Hemoglobin Reduces the Size of Cerebral Infarction in RatsARTIFICIAL ORGANS, Issue 2 2009Akira T. Kawaguchi Abstract Cell-free hemoglobin-based oxygen carriers have well-documented safety and efficacy problems such as nitric oxide (NO) scavenging and extravasation that preclude clinical use. To counteract these effects, we developed S -nitrosylated pegylated hemoglobin (SNO-PEG-Hb, P50 = 12 mm Hg) and tested it in a brain ischemia and reperfusion model. Neurological function and extent of cerebral infarction was determined 24 h after photochemically induced thrombosis of the middle cerebral artery in the rat. Infarction extent was determined from the integrated area in the cortex and basal ganglia detected by triphenyltetrazolium chloride staining in rats receiving various doses of SNO-PEG-Hb (2, 0.4, and 0.08 mL/kg) and compared with rats receiving pegylated hemoglobin without S -nitrosylation (PEG-Hb) or saline of the same dosage. Results indicated that successive dilution revealed SNO-PEG-Hb but not PEG-Hb to be effective in reducing the size of cortical infarction but not neurological function at a dose of 0.4 mL/kg. In conclusion, SNO-PEG-Hb in a dose of 0.4 mL/kg (Hb 24 mg/kg) showed to be most effective in reducing the size of cortical infarction, however, without functional improvement. [source] Triflusal: An Antiplatelet Drug with a Neuroprotective Effect?CARDIOVASCULAR THERAPEUTICS, Issue 1 2006José Antonio González-Correa ABSTRACT Triflusal is a derivative of salicylic acid with a well-established platelet aggregation inhibitory profile. Its pharmacokinetic and pharmacodynamic properties differ, however, somewhat from those of acetylsalicylic acid. A number of recent experimental and clinical studies have shown that triflusal is a potentially useful choice in the treatment and prophylaxis of brain ischemia because of its antithrombogenic as well as neuroprotective effects. Its antithrombogenic effect has been demonstrated at the clinical as well as at the experimental level, while its neuroprotective effect has been shown only in experimental models. The drug interferes with thrombogenesis by inhibiting thromboxane synthesis and increasing the levels of cAMP and nitric oxide. Its neuroprotective action is the result of its antioxidant and antiinflammatory effects in brain tissue. From a clinical standpoint triflusal is similar in efficacy to acetylsalicylic acid in preventing stroke, but has less adverse effects, especially it is less likely to cause bleeding. Because of its pharmacodynamic properties and lower rate of adverse reactions, triflusal may be a useful alternative to acetylsalicylic acid in the prevention of stroke. [source] Poly(ADP-Ribose)-Polymerase-Catalyzed Hydrolysis of NAD+: QM/MM Simulation of the Enzyme ReactionCHEMMEDCHEM, Issue 5 2006Daniele Bellocchi Dr. Abstract Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which uses NAD+ as substrate and catalyzes the transfer of multiple units of ADP-ribose to target proteins. PARP is an attractive target for the discovery of novel therapeutic agents and PARP inhibitors are currently evaluated for the treatment of a variety of pathological conditions such as brain ischemia, inflammation, and cancer. Herein, we use the PARP-catalyzed reaction of NAD+ hydrolysis as a model for gaining insight into the molecular details of the catalytic mechanism of PARP. The reaction has been studied in both the gas-phase and in the enzyme environment through a QM/MM approach. Our results indicate that the cleavage reaction of the nicotinamide-ribosyl bond proceeds through an SN2 dissociative mechanism via an oxacarbenium transition structure. These results confirm the importance of the structural water molecule in the active site and may constitute the basis for the design of transition-state-based PARP inhibitors. [source] | |||||||||||||