Neurological Research (Neurol Res)

Publications in this journal

• Article: Effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia model.

  Dae Young Yoo, Jung Hoon Choi, Woosuk Kim, Sung Min Nam, Hyo Young Jung, Jong Hwi Kim, Moo-Ho Won, Yeo Sung Yoon, In Koo Hwang
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  ABSTRACT: OBJECTIVES: Luteolin, a common flavonoid from many plants, has various pharmacological activities, including a memory-improving effect. In this study, we investigated the effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a rat model of scopolamine (SCO)-induced amnesia. METHODS: Scopolamine was subcutaneously administered for 28 days via an Alzet minipump (44 mg/ml delivered at 2.5 μl/h) along with a daily intraperitoneal administration of vehicle (saline) 10 mg/kg luteolin or 5 mg/kg galantamine (GAL) (a control drug for acetylcholinesterase (AChE) inhibitor) for 28 days. RESULTS: The administration of SCO significantly decreased the spatial alteration percentage in the Y-maze test compared to that in the vehicle (saline)-treated group. The administration of luteolin or GAL significantly improved the spatial alteration percentage compared to that in the SCO-treated group. Similarly, the administration of SCO significantly decreased the cell proliferation (Ki67-positive cells) and neuroblast differentiation (doubleocortin-positive cells) in the dentate gyrus. The administration of luteolin or GAL significantly mitigated the SCO-induced reduction of Ki67- and doublecortin-immunoreactive cells in the dentate gyrus. In addition, the administration of luteolin significantly decreased the lipid peroxidation (malondialdehyde (MDA) levels) and increased the brain-derived neurotrophic factor (BDNF) and AChE levels in the hippocampal homogenates compared to the SCO-treated group. CONCLUSION: These results suggest that the luteolin treatment improves the SCO-induced reduction of cell proliferation and neuroblast differentiation in the dentate gyrus. The mechanism underlying the amelioration of SCO-induced amnesia by luteolin may be associated with the increase in BDNF, acetylcholine, and the decrease in lipid peroxidation.
  Neurological Research 05/2013;
• Article: Reversal of multidrug resistance by magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA in glioblastoma cell line.

  Peng Zhao, Hongyun Wang, Hua Gao, Chuzhong Li, Yazhuo Zhang
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  ABSTRACT: OBJECTIVE: To investigate the reversal effects of MDR1 gene on multidrug resistance in the glioblastoma cell line BT325 by magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA. METHODS: The shRNA expression vector was constructed and the recombinant plasmids were cloned. Magnetic chitosan-Fe3O4 nanoparticles were prepared and the encapsulation rate was determined. After transfection, the BT325 cells were cultured to assay the transfection efficiency. The changing of MDR1 mRNA level and P-gp protein was evaluated. And the sensitivity to different chemotherapeutic drugs was assessed in BT325-siRNA transfected cell and untransfected cell by IC50 values. RESULTS: The MDR1 RNAi plasmid was successfully designed and preparation. The encapsulation efficiency of the magnetic chitosan-Fe3O4 nanoparticle was 98-99%. The transfection efficiency of the siRNA-nanoparticles in BT325 cells was 70-80%. And the MDR1 mRNA levels were downregulated by reverse transcription (RT)-PCR assay. Furthermore, the results of P-gp protein expression decreased on immunocytochemical assay, Western blot and flow cytometry compared with control group. The IC50 values of DOX and VCR were decreased between the transfected cell and normal BT325 cell. CONCLUSION: After targeted transfection of the glioblastoma cell line with magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA, the expression of MDR1 at both the mRNA and protein level decreased, which increased sensitivity to chemotherapy in vitro. It might provide a basis for investigation of the mechanism involved in multidrug resistance in glioma.
  Neurological Research 05/2013;
• Article: Characterization of the anxiolytic and sedative profile of JM-20: a novel benzodiazepine-dihydropyridine hybrid molecule.

  Yanier Nuñez Figueredo, Estael Ochoa Rodríguez, Yamila Verdecia Reyes, Carmen Carrillo Domínguez, Alicia Lagarto Parra, Jeney Ramirez Sánchez, René Delgado Hernández, Marlene Porto Verdecia, Gilberto L Pardo Andreu
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  ABSTRACT: OBJECTIVES: The aim of this study was to investigate the effects of oral administration of a novel benzodiazepine derivative, JM-20, on the neurological behavior of different rodent models, focusing on the GABAergic effect. We have also investigated the acute toxicity of oral administration of JM-20 in mice. METHODS: Mice or rats received oral administration of JM-20 at 2, 4, 8, and 10 mg/kg to evaluate the sedative/hypnotic, anxiolytic, and anticonvulsant effects, as well as the influence on the stereotyped behavior induced by amphetamine. Diazepam (DZP) was used as a positive control. In addition, the mice received a single oral JM-20 dose of 2000 mg/kg to evaluate the acute toxicity. RESULTS: In a dose-dependent manner, JM-20 (i) increased the number of crossings and decreased the number of rearings in the open-field test; (ii) decreased the aggressive behavior of socially-isolated mice; and (iii) increased the latency period for tonic seizure?s onset and the percentage of survival of animals with seizures. Moreover, JM-20 increased the sleeping time induced by barbiturates and the time spent and the number of entries in the open arms of the elevated plus-maze test. In the JM-20 toxicity test, no mortality was observed and only minor signs of toxicity associated with sedation were detected. CONCLUSIONS: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice.
  Neurological Research 05/2013;
• Article: Nitric oxide suppresses L-type calcium currents in basilar artery smooth muscle cells in rabbits.

  Naveen Sharma, Janardhan Prasad Bhattarai, Pyoung Han Hwang, Seong Kyu Han
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  ABSTRACT: Nitric oxide (NO) is well known to be a vasodilator, and NO donor compounds are currently used for treating vasospasm following subarachnoid hemorrhage. However, the action mechanism of cerebral vascular relaxation is not yet clear. L-type calcium channels have been determined to play an essential role in smooth muscle contraction. To investigate the role of L-type calcium channels in NO-induced relaxation of basilar smooth muscle cells, we examined the effect of the NO donor, sodium nitroprusside (SNP) on calcium (Ca(2+)) currents using smooth muscle cells isolated from a rabbit basilar artery. The smooth muscle cells were isolated from rabbit basilar artery by enzyme treatment. To identify L-type Ca(2+) currents, we used cesium chloride, a potassium channel blocker and Bay K8644, an activator of L-type Ca(2+) channel. The L-type calcium currents (91±13·0 pA; n = 11) were significantly reduced by SNP (32±5 pA; n = 11; P<0·05). 1H-[1,2,4] Oxadiazolo [4,3-a] quinoxalin-1-one, a 3',5'-cyclic guanosine monophosphate inhibitor, blocked the effect of SNP on L-type Ca(2+) currents, and similar results were obtained after the application of 7-nitroindazole, a specific NO synthase inhibitor. Furthermore, inward currents were enhanced by Bay K8644 (170±22 pA; n = 5) and were suppressed by SNP (54±13 pA; n = 5; P<0·05). These results demonstrate that NO suppresses the L-type Ca(2+) currents in rabbit basilar smooth muscle cells, and suggest that L-type Ca(2+) channels may play a pivotal role in NO-induced vascular relaxation.
  Neurological Research 05/2013; 35(4):424-8.
• Article: Remote post-conditioning reduces hypoxic damage early after experimental stroke.

  Henrik Hasseldam, Jacob Hansen-Schwartz, Nina Munkholm, Jack Hou, Flemming F Johansen
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  ABSTRACT: Given that reliable markers for early ischemic brain damage are lacking, we set out to test whether pimonidazole can be used as a reliable tool in the quantification of hypoxic insults, at early time points following experimental stroke. We have used semi-quantitative Western blotting detection of pimonidazole adducts in a rat model of reversible middle cerebral artery occlusion (MCAO), treated with remote post-conditioning. First, we demonstrated that a linear relationship exist between pimonidazole binding in the ischemic hemisphere and duration of ischemia, in animals subjected to 5, 15, 30, or 60 minutes of occlusion followed by 120 minutes of reflow. Then we showed a significant reduction in pimonidazole binding in the infarcted hemisphere, when rats with 60 minutes of MCAO, immediately after establishment of cerebral reflow, had 3×15 minutes intermittent hind limb ischemia followed by 24-hour survival. We analysed the middle cerebral arteries from animals with 60 minutes of MCAO and early remote post-conditioning, followed by 30 minutes, 24, or 48 hours of reflow. At 24 hours of reflow increases in phosphorylated protein kinase C-alpha with concomitantly increased levels of p38 phosphorylation were observed. Our investigation demonstrates that pimonidazole can be used for quantifying ischemic impact in stroke, even after very short survival times. It furthermore shows that early remote post-conditioning reduces ischemic damage, probably through hyperpolarization and reduced reflow vasospasm in the conduit middle cerebral arteries.
  Neurological Research 05/2013; 35(4):336-43.
• Article: Comparison between the formula 1/2ABC and 2/3Sh in intracerebral parenchyma hemorrhage.

  Jing Yan, Kaijun Zhao, Jialan Sun, Wanlin Yang, Yulan Qiu, Timothy Kleinig, Yi Fu, Shengdi Chen
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  ABSTRACT: The 1/2ABC formula is the method most commonly used in clinical practice to rapidly estimate intracerebral hemorrhage (ICH) volume. We aimed to compare this method with the alternative '2/3Sh' formula for both regularly and irregularly-shaped hematomas. Computed tomography (CT) images from 344 ICH patients (median volume: 16·66 ml) were retrospectively reviewed. According to the maximum slice, the shape was classified into regular or irregular (multilobular, conical, and other). Volumes as determined by the 1/2ABC and 2/3Sh formulas were compared against the gold standard, computer-assisted planimetry, for various hematoma shapes. With the 1/2ABC method, errors were seen non-significantly more frequently for irregularly-shaped hematomas [OR: 2·85 (95% CI: 0·65-12·50)]. The 1/2ABC method misclassified a greater proportion of hematomas as greater or less than 30 ml in volume: 7·0% (95% CI: 6·0-9·9%). Both the 1/2ABC and 2/3Sh formulas correlated well with gold standard (correlation coefficients >0·9 for each shape). While there was no statistically significant measurement error bias for either method, the 95% confidence intervals of the limit of agreement for 2/3Sh were tighter: -0·22 ml (-4·7-4·25 ml) versus 2·50 ml (-10·35-15·34 ml). Measurement errors were significantly greater with the 1/2ABC method, for both regular and irregular hematomas [1·17 ml (0·48-2·83 ml) versus 0·88 ml (0·42-1·68 ml) and 2·65 ml (1·07-5·88 ml) versus 0·99 ml (0·47-2·28 ml); P<0·05, respectively], although the magnitude of error would only rarely be clinically relevant for regular hematomas. Errors were most evident in assessing multilobular-shaped hematomas [6·49 ml (3·35-13·98 ml) versus 1·86 ml (0·96-9·94 ml); P<0·001]. The 2/3Sh formula leads to fewer clinically-relevant hematoma volume misclassifications than the 1/2ABC formula, and is particularly superior in estimating volumes of irregularly-shaped hematomas.
  Neurological Research 05/2013; 35(4):382-8.
• Article: The role of vein in microvascular decompression for hemifacial spasm: a clinical analysis of 15 cases.

  Xuhui Wang, Parthasarthy D Thirumala, Aalap Shah, Paul Gardner, Miguel Habeych, Donald Crammond, Jeffrey Balzer, Lois Burkhart, Michael Horowitz
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  ABSTRACT: The objective of this study is to investigate the clinical characteristics, intraoperative findings, complications, and outcomes in these patients with hemifacial spasm (HFS) caused by venous compression. We analyzed 15 patients who underwent microvascular decompression (MVD) for HFS caused by venous compression performed at the University of Pittsburgh Medical Center between 1 January 2000 and 31 December 2007. Thirteen of 15 patients underwent repeat MVD, and two patients underwent their first MVD. Clinical data were collected to verify vein as real offending vessel for all of 15 patients with HFS. The mean follow-up period was 4·13 years (range: 1·29-6·76 years). Thirteen patients with repeat MVDs had vein as the offending vessel, such as series of small venule, small veins, and dilated venous stump. The remaining two patients who underwent the first MVD had vein as the only offending vessel. In the first MVD for 13 patients, lateral spread response (LSR) disappeared in five patients (38·5%). In the repeat MVD for these 13 patients, LSR disappeared after the vein was decompressed completely in nine patients (69·2%). An excellent surgical outcome was observed in all the 11 patients with four patients lost during the follow-up period. Post-operative complications were observed in 12 patients included hearing loss, cerebrospinal fluid leakage, worsening facial palsy, difficulty swallowing, dilpopia, and ataxia. Vein can play an important role and can be the offending vessel in MVD for HFS. Women with platysmal involvement and tonus seem to have higher chance of vein as an offending vessel. These patients that have residual LSR at the end of the procedure should undergo exploration for a vein to prevent persistent HFS. Intraoperative monitoring with LSR is an effective tool to evaluate adequate decompression to vein. Although the long-term outcome is excellent for venous compression, the complication rate is much higher. To decrease the complication rate, gentle retraction of the cerebellum and 'low-power' coagulation of the vein might be helpful.
  Neurological Research 05/2013; 35(4):389-94.
• Article: Protective effect of low molecular weight polyethylene glycol on the repair of experimentally damaged neural membranes in rat's spinal cord.

  Sogolie Kouhzaei, Iman Rad, Sara Mousavidoust, Hamid Mobasheri
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  ABSTRACT: Membrane disruption is one of the main factors that cause axonal damage and functional deficits manifested in spinal cord injury (SCI). In this study, we used polyethylene glycol (PEG) to induce immediate membrane sealing and to promote functional recovery after SCI. The effects of PEG (200-2000 Da) on the damaged membrane were monitored by means of spinal cord evoked potentials (SCEPs) in an SCI model in rats. In a parallel study, membranes of neural cells were mechanically damaged in culture by ultrasound waves (20 kHz) and the repairing effects of PEGs were examined afterwards at the single cell level. Analysis of SCEPs showed that the smaller the PEG, the higher was the ultimate recovery of SCEP (i.e. 200 Da caused 49·5% and 2000 Da up to 16·3%). The rate of recovery was maximum with a polynomial trend, when the damaged spinal cord was treated with PEG200 for 25 minutes. The analysis of survival rate of mechanically damaged cells in culture, measured by MTT assay, showed that again smaller PEGs, caused higher membrane sealing rate; 77·8±3·5 for PEG400 (20% w/w) vs 32·1±6·9 for PEG2000 (20% w/w). The large ones (PEG1000 and 2000) that presented minor repair at low concentration, showed no significant sealing effects at high concentrations (>50%). Our studies showed that the application of low molecular weight PEGs, (<50% w/w) can be considered as one of the effective early treatments for SCI.
  Neurological Research 05/2013; 35(4):415-23.
• Article: Caspase-2 and caspase-8 trigger caspase-3 activation following 6-OHDA-induced stress in human dopaminergic neurons differentiated from ReNVM stem cells.

  Zohara L Chaudhry, Bushra Y Ahmed
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  ABSTRACT: The purpose of the study was to establish a suitable model to study Parkinson's disease (PD) pathogenesis in differentiated dopaminergic neurons (dDCN). The specific aim was to demonstrate the involvement of the caspase family and to identify specific caspases which are activated by 6-hydroxydopamine (6OHD) treatment leading to death of dDCN. ReNcell VM cells were differentiated into dDCN and were exposed to 6OHD to induce stress. Western blot (WB) and double immunofluorescent analyses of caspases-2, -3, and -8 were carried out in untreated and 6OHD-treated dDCN. zVADfmk was used to determine if it could inhibit activation of caspases-2, -3, and -8 in dDCN following 6OHD-mediated stress. Our immunofluorescent and WB data showed that 6OHD triggered caspases-2 and -8 activation which in turn activated caspase-3 leading to death of dDCN. Additionally, WB analysis revealed that caspases-2, -3, and -8 activation was reduced by zVADfmk in 6OHD-treated cells. The study showed that 6OHD-induced toxicity triggered caspase mediated death of dDCN. This finding is in support of previous studies using different PD model showing that 6OHD can induce caspases-2 and -3 activation through apoptotic pathway and that both caspases can activate caspase-3 in PD. In addition, our results suggest that caspase-2 cause's cell death might be via an indirect NF kappaB route. This study has established a PD model which can provide better insight to PD pathogenesis on a biochemical and molecular level, leading to a better understanding of PD and potential for new treatments.
  Neurological Research 05/2013; 35(4):435-40.
• Article: Differential nuclear factor-kappa B phosphorylation induced by lipopolysaccharide in the hippocampus of P2X7 receptor knockout mouse.

  Won Il Kim, Hea Jin Ryu, Ji-Eun Kim, Cheong Hoon Seo, Boung Chul Lee, Ihn-Geun Choi, Tae-Cheon Kang
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  ABSTRACT: Lipopolysaccharide (LPS) stimulates the innate immune response in the brain through nuclear factor-kappaB (NF-kappaB) signaling. Since purinergic signals activate NF-kappaB through the P2X7 receptor (P2X7R), we investigated the roles of P2X7R in neuronal NF-kappaB phosphorylation in the mouse hippocampus under basal conditions and P2X7R deletion following LPS treatment in vivo. We performed immunohistochemical studies for neuronal NF-kappaB phosphorylation in the hippocampi of wild type (WT) and P2X7R knockout (KO) mice under basal conditions and LPS treatment. LPS treatment did not induce neuronal damages in both WT and P2X7(-/-) KO mice. In WT animals, LPS treatment increased p65-Ser276 and p65-Ser311 NF-kappaB phosphorylations in hippocampal neurons. However, p52-Ser865, p52-Ser869, p65-Ser468, p65-Ser529, and p65-Ser536 NF-kappaB phosphorylations were unaffected by LPS treatment. In P2X7(-/-) KO mice, neuronal p65-Ser311 NF-kappaB phosphorylation in vehicle-treated animals was higher than that in WT animals. In addition, both p65-Ser276 and p65-Ser311 NF-kappaB phosphorylations were unaffected by LPS treatment in P2X7(-/-) KO mice. These findings indicate that P2X7R may be involved in LPS-induced inflammatory response in neurons, and that p65-Ser311 NF-kappaB phosphorylation may compensate for the loss function of P2X7R by as yet unknown factors.
  Neurological Research 05/2013; 35(4):369-81.
• Article: ACE and ADD1 gene in extra and intracranial atherosclerosis in ischaemic stroke.

  Jayantee Kalita, Usha K Misra, Bishwanath Kumar, Bindu I Somarajan, Sunil Kumar, Balraj Mittal
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  ABSTRACT: Hypertension is closely linked to ischaemic stroke (IS) and atherosclerosis, but there are no studies correlating the candidate hypertensive gene, namely angiotensin converting enzyme (ACE) and adducin 1 (ADD1) with magnetic resonance angiographic (MRA) abnormality, therefore this study was undertaken. Patients with magnetic resonance imaging (MRI) proven IS were included and their demography, stroke risk factors, and clinical findings were noted. Both intracranial (IC) and extracranial (EC) MRA were performed and more than 50% stenosis was considered significant. Angiotensin converting enzyme and ADD1 gene polymorphism was evaluated by polymerase chain reaction (PCR) both in patients and 188 controls. Angiotensin converting enzyme and ADD1 polymorphism were performed in 151 patients whose median age was 60 years and 26·5% were females. Magnetic resonance angiography was abnormal in 77·5%; extracranial magnetic resonance angiography (ECMRA) in 58·3%, and intracranial magnetic resonance angiography (ICMRA) in 66·7%. The conventional risk factors were not different between the IS patients with and without MRA abnormalities. The presence of DD genotype (OR 3·86, 95% CI 0·78-2·28, P = 0·0001) and ADD1 GW genotype (OR 2·05, 95% CI 1·28-3·27, P = 0·003) significantly increased the risk of IS compared to controls. Both genotype and allele frequency of ACE and ADD1 were higher in MRA abnormal IS patients compared to controls; however, these were not significantly different between the patients with and without MRA abnormality. In IS patients, DD genotype and D allele of ACE gene and W allele of ADD1 gene were significantly related to MRA abnormality compared to controls but there was no association of ACE and ADD1 gene polymorphism in IS patients with MRA and without abnormality.
  Neurological Research 05/2013; 35(4):429-34.
• Article: Chronological changes and effects of AMP-activated kinase in the hippocampal CA1 region after transient forebrain ischemia in gerbils.

  Han Ga Wi Nam, Woosuk Kim, Dae Young Yoo, Jung Hoon Choi, Moo-Ho Won, In Koo Hwang, Je Hoon Jeong, Hyung Sik Hwang, Seung-Myung Moon
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  ABSTRACT: Adenosine monophosphate-activated kinase (AMPK) is an energy-specific sensor within the central nervous system. In this study, we observed AMPK and its phosphorylated form (pAMPK) in the hippocampal CA1 region after 5 minutes of transient forebrain ischemia. In addition, we also investigated the effects of Compound C, an AMPK inhibitor, against ischemic damage in gerbils. Adenosine monophosphate-activated kinase and pAMPK immunoreactivity was observed in the hippocampal CA1 region at various time points after ischemia and Compound C was intraperitoneally administered to gerbils immediately after reperfusion and the animals were sacrificed at 5 days after ischemia/reperfusion. Adenosine monophosphate-activated kinase immunoreactivity was transiently increased in the hippocampal CA1 region 1-2 days after ischemia/reperfusion, while AMPK immunoreactivity was almost undetectable in the stratum pyramidale of the CA1 region 4-7 days after ischemia/reperfusion. The administration of Compound C caused a dose-dependent decrease in the ischemia-induced hyperactive behavior, the depletion of ATP, and lactate accumulation in the hippocampal CA1 region within 24 hours after ischemia/reperfusion. In addition, the administration of Compound C decreased reactive gliosis (astrocytes and microglia) and increased the number of cresyl violet-positive neurons when compared to the vehicle-treated group at 5 days post-ischemia/reperfusion. These results suggest that AMPK is transiently phosphorylated following forebrain ischemia in the hippocampal CA1 region and inhibition of AMPK has neuroprotective effects against ischemic damage through the reduction of ATP depletion and lactate accumulation in the hippocampal CA1 region.
  Neurological Research 05/2013; 35(4):395-405.
• Article: Continuous cerebrovascular reactivity monitoring and autoregulation monitoring identify similar lower limits of autoregulation in patients undergoing cardiopulmonary bypass.

  R Blaine Easley, Kathleen K Kibler, Kenneth M Brady, Brijen Joshi, Masahiro Ono, Charles Brown, Charles W Hogue
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  ABSTRACT: Cerebrovascular autoregulation can be monitored with a moving linear correlation of blood pressure to cerebral blood flow velocity (mean velocity index, Mx) during cardiopulmonary bypass (CPB). Vascular reactivity can be monitored with a moving linear correlation of blood pressure to cerebral blood volume trended with near-infrared spectroscopy (hemoglobin volume index, HVx). We hypothesized that the lower limits of autoregulation (LLA) and the optimal blood pressure (ABPopt) associated with the most active autoregulation could be determined by HVx in patients undergoing CPB. Adult patients (n = 109) who underwent CPB for cardiac surgery had monitoring of both autoregulation (Mx) and vascular reactivity (HVx). Individual curves of Mx and HVx were constructed by placing each in 5 mmHg bins. The LLA and ABPopt for each subject were then identified by both methods and compared for agreement by correlation analysis and Bland-Altman. The average LLA defined by Mx compared to HVx were comparable (66±13 and 66±12 mmHg). Correlation between the LLA defined by Mx and HVx was significant (Pearson r = 0·2867; P = 0·0068). The average ABPopt with the most robust autoregulation by Mx was comparable to HVx (75±11 and 74±13 mmHg) with significant correlation (Pearson r = 0·5915; P⩿0·0001). Autoregulation and vascular reactivity monitoring are expected to be distinct, as flow and volume have different phasic relationships to pressure when cerebrovascular autoregulation is active. However, the two metrics have good agreement when identifying the LLA and optimal blood pressure in patients during CPB.
  Neurological Research 05/2013; 35(4):344-54.
• Article: NDRG2 is involved in anti-apoptosis induced by electroacupuncture pretreatment after focal cerebral ischemia in rats.

  Feng Wang, Zijun Gao, Xuying Li, Yan Li, Xin Li, Haixing Zhong, Ning Xu, Feng Cao, Qiang Wang, Lize Xiong
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  ABSTRACT: We first reported that electroacupuncture (EA) pretreatment at the Baihui acupoint (GV20) induces ischemic tolerance. Our recent study demonstrated that N-Myc downstream-regulated gene 2 (NDRG2) expression was up-regulated following transient focal cerebral ischemia. Therefore, we investigated whether NDRG2 was involved in the ischemic tolerance induced by EA pretreatment in rats. Twenty-four hours after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 120 minutes in male Sprague-Dawley rats. The neurobehavioral score, infarction volume, and extent of neuronal apoptosis were evaluated at 24 hours after reperfusion. The expression of NDRG2 in the brain was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR), western blotting, and immunofluorescent staining. Electroacupuncture pretreatment decreased infarction volume and improved neurologic scores at 24 hours after reperfusion. Double immunofluorescence revealed that NDRG2 expression in astrocytes was suppressed in the EA group at 24 hours after reperfusion, and that NDRG2 protein expression was weak in the nucleus and strong in the cytoplasm of the EA group, but strong in the nucleus of the MCAO group. Triple immunofluorescent staining for terminal deoxynucleotidyl transferase nick-end labeling (TUNEL), NDRG2, and 4',6-diamidino-2-phenylindole (DAPI) showed that NDRG2 co-localised with apoptotic cells. Moreover, the number of apoptotic cells decreased with the attenuation of NDRG2 expression in the EA group compared to the MCAO group. Our results indicated that NDRG2 is involved in anti-apoptosis induced by EA pretreatment after focal cerebral ischemia in rats. N-Myc downstream-regulated gene 2 was involved in EA pretreatment-induced cerebral ischemic tolerance. These findings may be important for our understanding of the cellular signaling pathways induced by EA pretreatment.
  Neurological Research 05/2013; 35(4):406-14.
• Article: The protective effect of berberine against neuronal damage by inhibiting matrix metalloproteinase-9 and laminin degradation in experimental autoimmune encephalomyelitis.

  Ying Jiang, Aiming Wu, Cansheng Zhu, Rongbiao Pi, Shaoqiong Chen, Yingying Liu, Lili Ma, Dongliang Zhu, Xiaohong Chen
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  ABSTRACT: This study aims to assess the protective effect of berberine against neuronal damage in the brain parenchyma of mice with experimental autoimmune encephalomyelitis (EAE). EAE was induced in female C57 BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 amino acid peptide. The berberine treatment was initiated on the day of disease onset and administered daily until the mice were sacrificed. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, gelatin gel, and gelatin in situ zymography were analysed in this study. Berberine reduced the TUNEL-positive neuronal cells of EAE mice. Gelatin gel and gelatin in situ zymography showed up-regulation of gelatinase activity, which was mainly located in neurons and colocalized with remarkable laminin degradation in EAE mice. Berberine significantly inhibited gelatinase activity and reduced the laminin degradation in EAE mice. Our data suggest that berberine could provide protection against neuronal damage in EAE by inhibiting gelatinase activity and reducing laminin degradation. These findings provide further support that berberine can be a potential therapeutic agent for multiple sclerosis.
  Neurological Research 05/2013; 35(4):360-8.
• Article: RNA-based blood genomics as an investigative tool and prospective biomarker for ischemic stroke.

  Christopher Cox, Frank R Sharp
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  ABSTRACT: Stroke is a leading cause of death and disability, and considerable effort is being expended to investigation of its pathological mechanisms, as well as the identification of clinically relevant biomarkers that could assist in diagnosis. RNA-based analysis of gene expression in blood represents a new field of study addressing both paradigms. A number of recent animal and human studies using microarray technology demonstrate rapidly-induced, measurable changes in gene expression in response to ischemic trauma, and distinct expression ?profiles? specific to the injury subtype. The incorporation of newer technologies for a more detailed transcriptome analysis holds great promise for further improving our knowledge of stroke at the molecular level, and potentially enhancing standards of diagnosis.
  Neurological Research 04/2013;
• Article: Hyperglycemia in stroke and possible treatments.

  William A Li, Shannon Moore-Langston, Tia Chakraborty, Jose A Rafols, Alana C Conti, Yuchuan Ding
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  ABSTRACT: Hyperglycemia affects approximately one-third of acute ischemic stroke patients and is associated with poor clinical outcomes. In experimental and clinical stroke studies, hyperglycemia has been shown to be detrimental to the penumbral tissue for several reasons. First, hyperglycemia exacerbates both calcium imbalance and the accumulation of reactive oxygen species (ROS) in neurons, leading to increased apoptosis. Second, hyperglycemia fuels anaerobic energy production, causing lactic acidosis, which further stresses neurons in the penumbral regions. Third, hyperglycemia decreases blood perfusion after ischemic stroke by lowering the availability of nitric oxide (NO), which is a crucial mediator of vasodilation. Lastly, hyperglycemia intensifies the inflammatory response after stroke, causing edema, and hemorrhage through disruption of the blood brain barrier and degradation of white matter, which leads to a worsening of functional outcomes. Many neuroprotective treatments addressing hyperglycemia in stroke have been implemented in the past decade. Early clinical use of insulin provided mixed results due to insufficiently controlled glucose levels and heterogeneity of patient population. Recently, however, the latest Stroke Hyperglycemia Insulin Network Effort trial has addressed the shortcomings of insulin therapy. While glucagon-like protein-1 administration, hyperbaric oxygen preconditioning, and ethanol therapy appear promising, these treatments remain in their infancy and more research is needed to better understand the mechanisms underlying hyperglycemia-induced injuries. Elucidation of these mechanistic pathways could lead to the development of rational treatments that reduce hyperglycemia-associated injuries and improve functional outcomes for ischemic stroke patients.
  Neurological Research 04/2013;
• Article: Injection of specific amyloid-beta oligomers (beta1-40:beta1-42=10:1) into rat medial septum impairs memory retention without inducing hippocampal apoptosis.

  Mehmet Bã Lent A-Zdemir, Cagdas Erdogan, Katsunori Iwasaki, Takuya Watanabe, Shin Ishikane, Michihiro Fujiwara
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  ABSTRACT: OBJECTIVES: Because of the well-known neurochemical interactions between the septum and hippocampus during memory processes, we investigated the effect of amyloid-beta (A-beta) injection into the medial septum (MS) on the behavior in Wistar rats. We also assessed whether the observed effects were functional or due to apoptosis. METHODS: Specific A-beta oligomers (beta1-40:beta1-42=10:1) were injected into MS for seven consecutive days. Behavior was assessed with the Morris water maze task. RESULTS: Compared with the control group, rats that received A-beta oligomers exhibited significant memory retention impairment (P<0.05) without apoptosis in the cornu ammonis (CA)1 and CA3 regions of the dorsal hippocampus. DISCUSSION: These data indicate that septal injection of A-beta impairs memory retention, even in the absence of hippocampal apoptosis. This result might bring new insight to spatial memory-related disorders like Alzheimer's disease (AD).
  Neurological Research 04/2013;
• Article: Clinical outcomes of fast MRI-based trombolysis in wake-up strokes compared to superacute ischemic strokes within 12 hours.

  Qingke Bai, Zhenguo Zhao, Paul Fu, Haijing Sui, Xiuhai Xie, Juan Chen, Juan Yang
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  ABSTRACT: BACKGROUND: It is unknown whether thrombolysis is beneficial in patients with Wake-Up Ischemic Strokes (WUIS). This study compares the clinical outcomes of MRI-based intravenous thrombolysis in patients with hyperacute ischemic stroke presenting within 12 hours of symptom onset against WUIS patients receiving the same therapy. METHODS: Patients presenting within 12 hours of acute stroke symptom onset and those with WUIS confirmed by CT, and without intracranial hemorrhage, were encouraged to perform an emergent brain MRI scan to confirm the diagnosis of hyperacute ischemic stroke [hyper-intense in diffusion-weighted imaging (DWI) and no hypo-intense change in T2-weighted imaging (T2WI) or FLAIR]. These patients then received intravenous thrombolytic therapy with tissue-type plasminogen activator (rt-PA). All patients were divided into either stroke presenting within 12 hours or WUIS. The clinical outcomes were assessed by the modified Rankin Scale (mRS) and the Barthal Index (BI) at baseline and at 90 days after the thrombolysis therapy. RESULTS: A total of 427 patients presenting with stroke like symptoms were given a MRI scan. Of these, 240 patients had confirmed diagnosis of hyperacute ischemic stroke (WUIS, n=68, 68/116=58.62% versus within 12 hour, n=172, 172/311=55.3%). Altogether, 186 patients (138 in within 12 hours group, and 48 in WUIS group) received intravenous thrombolytic therapy with rt-PA. No significant differences were found in clinical outcomes between the two groups at the baseline and at 90 days after the thrombolysis therapy. Also, no difference was found in the incidence rate of secondary hemorrhage (including both of asymptomatic and symptomatic) and mortality rate between the two groups. CONCLUSION: Our study suggested that MRI-based intravenous thrombolysis is safe and effective in both of patients' hyperacute stroke within 12 hours of symptom onset and WUIS.
  Neurological Research 04/2013;
• Article: Clinical and imaging characteristics of isolated pontine infarcts: a one-year follow-up study.

  Yi Ju, Mohammed Hussain, Karam Asmaro, Xingquan Zhao, Liping Liu, Jingjing Li, Yongjun Wang
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  ABSTRACT: OBJECTIVE: Although clinically relevant, there is paucity of literature regarding the characteristic findings and outcome in isolated pontine infarction (IPI). In this study, we examined and analyzed the association between neurological findings, imaging features, and outcome at different time periods in patients with acute IPI. METHODS: A total of 101 patients (32 women and 69 men) with IPI were included in this study. The data were prospectively collected within 7 days of stroke onset. A combination of diffusion-weighted imaging (DWI) and magnetic resonance angiography (MRA) was utilized for lesion analysis. Isolated pontine infarcts were categorized into three subtypes: large artery disease (LAD), basilar artery branch disease (BABD), and small artery disease (SAD). Patients were followed for 1 year to assess functional outcome and neurological deficit. RESULTS: The most common type of IPI was BABD (53.5%). The baseline neurologic impairment was significantly more severe in the LAD and BABD groups than the SAD group (P=0.002). Intracranial or extracranial arteriostenosis was dominated by LAD and was found in 44 patients (43.6%). Although 25.7% of patients had a poor outcome at 3 months post-stroke onset, their quality of life improved at the 1-year follow-up period. DISCUSSION: Our study also provided the evidence that unilateral pontine infarction from BABD is the most prevalent subtype of IPI; the incidence of basilar artery stenosis was low; long-term prognosis was favorable.
  Neurological Research 04/2013;