Hirosaki Stroke Center

Hirosaki, Japan

Hirosaki Stroke Center

Hirosaki, Japan
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Yoshida H.,Hirosaki University | Metoki N.,Hirosaki Stroke Center | Ishikawa A.,Hirosaki University | Imaizumi T.,Hirosaki University | And 5 more authors.
Neuroscience Research | Year: 2010

Edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is known to ameliorate postischemic neuronal dysfunction. Nerve growth factor (NGF) is essential for neuronal growth and survival. We have addressed the effect of edaravone on the NGF expression in astrocytes exposed to hypoxia/reoxygenation. Normal human astrocytes in culture were incubated under hypoxia for 3. h and then treated with edaravone under normal culture condition for up to 72. h. The levels of NGF mRNA were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) or real-time quantitative PCR and NGF protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Edaravone enhanced, in time- and concentration-dependent manners, the expressions of NGF mRNA and protein in astrocytes under reoxygenation condition. After the treatment for 72. h, 1. mmol/L edaravone enhanced the levels of NGF protein in astrocyte-conditioned media by 1.7-fold of the control. An inhibitor of c-Jun N-terminal kinase (JNK) suppressed the effect of edaravone on the NGF expression, and cellular levels of phospho-JNK were increased in response to edaravone. We conclude that edaravone enhances, via the JNK pathway, NGF expression in astrocytes. This agent may exert a neurotrophic effect in the therapy of brain injury in ischemia/reperfusion. © 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society.


Naritomi H.,Senri Chuo Hospital | Moriwaki H.,National Cerebral and Cardiovascular Center | Metoki N.,Hirosaki Stroke Center | Nishimura H.,Nishinomiya Kyoritsu Neurosurgical Hospital | And 10 more authors.
Drugs in R and D | Year: 2010

Background and Objective: Stroke patients with severe leg paralysis are often bedridden in the acute and subacute phase, which increases the risk of disuse muscle atrophy in the chronic phase. The evidence to date indicates that oxidative stress plays an important role in the mechanism of disuse muscle atrophy. Therefore, the aim of this study was to determine if long-term radical scavenger treatment with edaravone following an acute stroke prevents the progression of disuse muscle atrophy and improves leg locomotor function in the chronic phase. Methods: This randomized controlled pilot study was conducted at 19 acute stroke and rehabilitation centers across Japan. Forty-seven ischemic stroke patients with at least leg motor weakness admitted within 24 hours of onset were randomly assigned to receive continuous intravenous infusions of edaravone 30mg twice daily for 3 days (short-term group) or 1014 days (long-term group). The primary endpoints of the study included the degree of leg disuse muscle atrophy, as measured by the percentage change from baseline in femoral muscle circumference 15 cm above the knee, and the improvement in leg locomotor function, as assessed by the maximum walking speed over 10 m, 3 months after the onset of stroke. Results: Three-month follow-up was completed by a total of 41 patients (21 in the short-term group and 20 in the long-term group). On admission, there was no significant difference in the severity of stroke or the grade of leg paresis between the two treatment groups. The grade of disuse muscle atrophy and incidence of gait impairment 3 weeks after stroke onset were also similar between the short- and long-term groups. However, disuse muscle atrophy of the paretic and non-paretic legs was significantly less severe in the long-term versus the short-term treatment group (3.6±5.9% and 1.5±6.0% vs 8.3±5.2% and 5.7±6.4%; p<0.01 and p<0.05) 3 months after stroke onset. Additionally, the maximum walking speed over a distance of 10m was significantly greater in the long-term group (98±67 vs 54±55 cm/sec; p< 0.05). Conclusion: Edaravone treatment for up to 14 days suppresses the progression of disuse muscle atrophy and improves leg locomotor function to a greater extent than shorter-term treatment in acute stroke patients. This suggests that the management of stroke may be improved with long-term edaravone therapy by providing myoprotective effects that ameliorate functional outcome in the chronic phase. © 2010 Naritomi et al., publisher and licensee Adis Data Information BV.


Yoshida H.,Hirosaki University | Mimura J.,Hirosaki University | Imaizumi T.,Hirosaki University | Matsumiya T.,Hirosaki University | And 8 more authors.
Neuroscience Research | Year: 2011

Edaravone is a brain-penetrant free radical scavenger that is known to ameliorate postischemic neuronal dysfunction. The transcription factor Nrf2 plays an important role in the coordinated expression of stress-inducible genes. Here we examined the effects of edaravone and carnosic acid (CA), an Nrf2-inducer, on the expression of nerve growth factor (NGF) in human astrocytes exposed to hypoxia/reoxygenation. Cultured astrocytes were exposed to hypoxia for up to 4.5. h and then treated with edaravone and/or CA under normoxia (reoxygenation) for up to 72. h. Edaravone (~1. mM) and CA (~50μM) treatment synergistically enhanced NGF expression. Nrf2 knockdown by siRNA and the inhibition of JNK (c-Jun N-terminal kinase) by SP600125 decreased both CA-induced NGF expression and Nrf2 nuclear accumulation and suppressed their synergistic effect on NGF expression. In contrast, the MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase) inhibitor U0126 suppressed the synergism without inhibiting CA-induced NGF expression. These results suggest that the synergistic effects of CA and edaravone depend, at least partially, on JNK-dependent Nrf2 accumulation (induced by CA) and on MEK-dependent pathways (induced by edaravone). We conclude that the use of edaravone and CA in combination may have therapeutic potential in the treatment of brain damage, particularly ischemia/reperfusion injury. © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society.


Yoshida T.,Inabe General Hospital | Kato K.,Gifu Prefectural Tajimi Hospital | Yokoi K.,Gifu Prefectural Tajimi Hospital | Oguri M.,Red Cross | And 7 more authors.
International Journal of Molecular Medicine | Year: 2010

Dyslipidemia is an important risk factor for myocardial infarction (MI). We previously showed that gene polymorphisms associated with MI differed among individuals with different lipid profiles. We further examined whether genetic variants that confer susceptibility to MI might differ among individuals with low or high serum concentrations of triglycerides, high density lipoprotein (HDL)-cholesterol, or low density lipoprotein (LDL)-cholesterol. The study population comprised 5270 Japanese individuals, including 1188 subjects with MI and 4082 controls. The 150 polymorphisms examined in the present study were selected by genome-wide association studies of MI and ischemic stroke with the use of the Affymetrix GeneChip Human Mapping 500K Array Set. The initial Chi-square test revealed that the A→G polymorphism (rs12632110) of SEMA3F was significantly (false discovery rate <0.05) associated with MI among individuals with high serum HDL-cholesterol or among those with low serum LDL-cholesterol. Subsequent multivariable logistic regression analysis with adjustment for covariates revealed that rs12632110 was significantly (P<0.01) associated with MI in individuals with high serum HDL-cholesterol or with low serum LDL-cholesterol. The genetic variants that confer susceptibility to MI differ among individuals with different lipid profiles, and the genetic component for the development of MI is more apparent in individuals at low-risk (high HDL- and low LDL-cholesterol levels) compared to those at high-risk. Stratification of subjects according to lipid profiles may thus be important for personalized prevention of MI based on genetic information.


Oguri M.,Red Cross | Kato K.,Gifu Prefectural Tajimi Hospital | Yokoi K.,Gifu Prefectural Tajimi Hospital | Yoshida T.,Inabe General Hospital | And 7 more authors.
American Journal of Hypertension | Year: 2010

Background Hypertension is a major risk factor for cardiovascular disease. Although genetic studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. The purpose of the present study was to identify genetic variants that confer susceptibility to hypertension in Japanese individuals. Methods A total of 5,734 Japanese individuals from two independent populations were examined: Subject panel A comprised 2,066 hypertensive individuals and 824 controls; and subject panel B comprised 834 hypertensive individuals and 2,010 controls. The 150 polymorphisms examined in the present study were selected by genome-wide association studies of myocardial infarction and ischemic stroke with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results The χ2-test revealed that 10 polymorphisms were significantly (P <0.05) related to the prevalence of hypertension in subject panel A. To validate the relations, these polymorphisms were examined in subject panel B. The A→G polymorphism (rs645106) of SDK1 and the C→G polymorphism (rs12078839) of RABGAP1L were significantly associated with hypertension in subject panel B. Multivariable logistic regression analysis with djustment for covariates, as well as a stepwise forward selection procedure revealed that the A→G polymorphism of SDK1 was significantly associated with hypertension in both subject panels A and B, with the G allele protecting against this condition. Conclusions SDK1 may be a susceptibility gene for hypertension in Japanese individuals, although the functional relevance of the identified polymorphism was not determined. © 2010 American Journal of Hypertension, Ltd.


Yoshida T.,Inabe General Hospital | Kato K.,Gifu Prefectural Tajimi Hospital | Yokoi K.,Gifu Prefectural Tajimi Hospital | Oguri M.,Red Cross | And 7 more authors.
International Journal of Molecular Medicine | Year: 2010

Although genetic epidemiological studies have implicated several genetic variants as risk factors for hemorrhagic stroke, the genetic determinants of this condition remain largely unknown. We examined an association of genetic variants with intracerebral or subarachnoid hemorrhage among Japanese individuals. The study population comprised 4,304 unrelated Japanese individuals, including 377 subjects with intracerebral hemorrhage, 205 subjects with subarachnoid hemorrhage, and 3,722 controls. The 150 polymorphisms examined in the present study were selected by genome-wide association studies of ischemic stroke and myocardial infarction with the use of the GeneChip Human Mapping 500K Array Set. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that the C→T polymorphism (rs1324694) of ERLIN1, the C→T polymorphism (rs12679196) of TRAPPC9, and the G→T polymorphism (rs16936752) of WNK2 were significantly (P<0.05) associated with the prevalence of intracerebral hemorrhage, and that the A→G polymorphism (rs3111754) of ITM2C and the A→G polymorphism (rs10986769) of MAPKAP1 were significantly associated with the prevalence of subarachnoid hemorrhage. Genotypes for ERLIN1, TRAPPC9, and WNK2 may prove informative for assessment of the genetic risk for intracerebral hemorrhage, and those for ITM2C and MAPKAP1 may be beneficial in assessment of the genetic risk for subarachnoid hemorrhage in Japanese individuals.


Yoshida T.,Inabe General Hospital | Kato K.,Gifu Prefectural Tajimi Hospital | Yokoi K.,Gifu Prefectural Tajimi Hospital | Oguri M.,Red Cross | And 7 more authors.
International Journal of Molecular Medicine | Year: 2010

Although metabolic syndrome has been recognized as a risk factor for ischemic stroke, genetic factors associated with ischemic stroke in individuals with metabolic syndrome remain unknown. We examined an association of genetic variants with ischemic stroke among individuals with or without metabolic syndrome. The study population comprised 4,387 unrelated Japanese individuals, including 1,884 individuals with metabolic syndrome (240 subjects with ischemic stroke and 1,644 controls) and 2,503 individuals without metabolic syndrome (280 subjects with ischemic stroke and 2,223 controls). The 150 polymorphisms examined in the present study were selected by genome-wide association studies of ischemic stroke and myocardial infarction with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). The initial chi-square test revealed that the C→T polymorphism (rs9925481) of CLEC16A and the A→G polymorphism (rs4923918) of SPTBN5 were significantly (P<0.005) associated with ischemic stroke among individuals with metabolic syndrome. No polymorphism was significantly associated with ischemic stroke among individuals without metabolic syndrome. Multivariable logistic regression analysis with adjustment for covariates and a stepwise forward selection procedure revealed that the A→G polymorphism (rs4923918) of SPTBN5 was significantly (P<0.005), and the C→T polymorphism (rs9925481) of CLEC16A was almost significantly, associated with ischemic stroke in individuals with metabolic syndrome. Genetic variants that confer susceptibility to ischemic stroke may differ among individuals with or without metabolic syndrome. Stratification of subjects according to the presence or absence of metabolic syndrome may thus be important for personalized prevention of ischemic stroke based on genetic information.


Fujimaki T.,Gifu Prefectural Tajimi Hospital | Kato K.,Gifu Prefectural Tajimi Hospital | Yokoi K.,Gifu Prefectural Tajimi Hospital | Oguri M.,Red Cross | And 9 more authors.
Atherosclerosis | Year: 2010

Objective: The purpose of the present study was to identify genetic variants that confer susceptibility to myocardial infarction (MI) in Japanese individuals. Methods: The study population comprised 5014 Japanese individuals, including 1444 subjects with MI and 3570 controls. The 150 polymorphisms examined in the present study were selected by a genome-wide association study for ischemic stroke with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix), and were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Results: An initial screen by the chi-square test revealed that the A→G polymorphism of SEMA3F (rs12632110), the C→T polymorphism of CLEC16A (rs9925481), the A→G polymorphism of LAMA3 (rs12373237), and the C→G polymorphism of PCSK2 (rs6080699) were significantly (false discovery rate for allele frequencies of <0.05) associated with MI. Subsequent multivariable logistic regression analysis with adjustment for covariates and a stepwise forward selection procedure revealed that the A→G polymorphism of SEMA3F (dominant model; P= 0.0014; odds ratio, 0.76), the C→T polymorphism of CLEC16A (dominant model; P= 0.0009; odds ratio, 0.75), the A→G polymorphism of LAMA3 (recessive model; P= 0.0099; odds ratio, 0.80), and the C→G polymorphism of PCSK2 (recessive model; P= 0.0155; odds ratio, 1.19) were significantly (P<. 0.05) associated with the prevalence of MI. Conclusion: Determination of these genotypes may prove informative for assessment of the genetic risk for MI in Japanese individuals. © 2009 Elsevier Ireland Ltd.


Fukumoto Y.,Kyoto University | Fukumoto Y.,Japan Society for the Promotion of Science | Ikezoe T.,Kyoto University | Yamada Y.,Kyoto Prefectural University of Medicine | And 7 more authors.
European Journal of Applied Physiology | Year: 2012

Enhanced echo intensity (EI) on an ultrasound image of skeletal muscle indicates changes in muscle quality, including increases in intramuscular fibrous and adipose tissues. However, it is not known whether muscle quality assessed from the EI of computer-aided gray-scale analysis of an ultrasound image is associated with the muscle strength or body composition of a subject. The objectives of this study were to investigate whether muscle quality assessed from EI measured using gray-scale analysis is associated with muscle strength independently of age or muscle thickness (MT), and to examine the relationship between muscle EI and body composition. Ninetytwo healthy women with a mean age of 70.4 ± 5.5 years (range, 51-87 years) dwelling in Kyoto, Japan, participated in the study. The MT, subcutaneous fat thickness (FT), and EI of the quadriceps femoris on the right extremity were assessed from transverse ultrasound images. Knee extensor isometric strength was used as a measure of the quadriceps femoris muscle strength. EI was significantly correlated with quadriceps strength independently of age or MT, and stepwise regression analysis revealed that MT and EI were independently associated with quadriceps strength. Importantly, EI showed no significant correlations with FT, percentage of body fat (%BF), or body mass index (BMI), while FT, BMI, and %BF did not significantly influence muscle strength. These data suggest that muscle quantity (i.e., MT) and muscle quality assessed from EI measured using computer-aided gray-scale analysis independently contribute to muscle strength in middle-aged and elderly persons. © Springer-Verlag 2011.


Osanai T.,Hirosaki University | Fujiwara N.,Reimeikyo Rehabilitation Hospital | Sasaki S.,Hirosaki Stroke Center | Metoki N.,Hirosaki Stroke Center | And 8 more authors.
Annals of Medicine | Year: 2010

Background and purpose. Homocysteine (Hcy) is an independent predictor of stroke. Coupling factor 6 (CF6) is regulated by nuclear factor kappa B (NF-κB) signaling which is activated by Hcy. We tested the hypothesis that CF6 is elevated with Hcy in stroke. We also examined the effect of vitamin treatment on CF6 and Hcy levels. Methods and results. The 59 Japanese patients with a recent history of stroke were randomly assigned to a group without vitamin treatment (Group 1, n 29) and to a group with treatment with both folic acid and vitamin B12 for 2 months (Group 2, n 30). The CF6 level was elevated in the patients with stroke compared with that in controls (n 64) at admission. In a multiple regression model, the plasma CF6 level was weakly correlated to the total Hcy (tHcy) level. In Group 1, the plasma tHcy and CF6 levels were unchanged. In Group 2, however, they were both decreased, and there was a weak positive correlation between the decreases in plasma levels of CF6 and tHcy. Conclusion. CF6 is elevated in patients with stroke independently of risk factors. Since Hcy and vitamin treatment affect CF6 levels in stroke, CF6 appears to be a novel molecule for the pathogenesis and treatment of stroke. © Informa UK Ltd.

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