Faculty Profiles - YAMASHITA Toru

Papers - YAMASHITA Toru

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Anti-oxidative nutrient-rich diet protects against acute ischemic brain damage in rats. Reviewed International journal

Taijun Yunoki, Kentaro Deguchi, Yoshio Omote, Ning Liu, Wentao Liu, Nozomi Hishikawa, Toru Yamashita, Koji Abe

Brain research 1587 33 - 9 2014.10

Language：English Publishing type：Research paper (scientific journal)

We evaluated the neuroprotective effects of an anti-oxidative nutrient rich enteral diet (AO diet) that contained rich polyphenols (catechins and proanthocyanidins) and many other anti-oxidative ingredients. Wistar rats were treated with either vehicle, normal AO diet (containing 100kcal/100mL, catechin 38.75mg/100mL and proanthocyanidin 19mg/100mL, 1mL/day), or high AO diet (containing 10 times the polyphenols of the normal AO diet) for 14 days, and were subjected to 90min of transient middle cerebral artery occlusion. The AO diet improved motor function, reduced cerebral infarction volume, and decreased both peroxidative markers such as 4-hydroxynonenal, advanced glycation end products, 8-hydroxy-2-deoxyguanosine and inflammatory markers such as monocyte chemotactic protein-1, ionized calcium-binding adapter molecule-1, and tumor necrosis factor-α. Our study has shown that an AO diet has neuroprotective effects through both anti-oxidative and anti-inflammatory mechanisms, indicating that nutritional control with polyphenols could be useful for patients with acute ischemic stroke.

DOI： 10.1016/j.brainres.2014.08.056

Strong improvement of apolipoprotein E/low-density lipoprotein receptor signals by telmisartan in poststroke spontaneously hypertensive stroke resistant. Reviewed International journal

Toru Yamashita, Yun Zhai, Tomoko Kurata, Nozomi Hishikawa, Nobutoshi Morimoto, Yasuyuki Ohta, Kentaro Deguchi, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 23 ( 9 ) 2240 - 9 2014.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Telmisartan, an angiotensin receptor blocker also called metabosartan, is a promising solution for preventing cognitive decline or the incidence of dementia. METHODS: We examined the effects of telmisartan on cholesterol transport-related proteins (apolipoprotein E [ApoE]/low-density lipoprotein receptor [LDL-R]) and microtubule-associated protein 2 (MAP2) in the brain of spontaneously hypertensive stroke resistant (SHR-SR). SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes at 12 weeks of age and then was divided into 3 experiment groups including a vehicle, low-dose telmisartan (.3 mg/kg/day), and high-dose telmisartan (3 mg/kg/day). RESULTS: The low dose served to improve the metabolic syndrome of SHR-SR without lowering the blood pressure (BP) whereas the high dose was used to improve metabolic syndrome while lowering BP. Immunohistologic analysis showed that ApoE expression of cortical neurons was strong in the vehicle group at 6, 12, and 18 months of age, and that this ApoE expression pattern was very similar between the ipsilateral and contralateral sides of cerebral ischemia. On the other hand, LDL-R expression of cortical neurons was transiently increased at 6 months of age only on the ipsilateral side. Telmisartan dramatically suppressed the expression of ApoE/LDL-R at both doses. There was no remarkable difference in neuronal MAP2 staining between the 3 groups. CONCLUSIONS: These findings suggest that both low and high doses of telmisartan prevented the activation of ApoE/LDL-R in SHR-SR after tMCAO, and that the antimetabolic effect was regarded as the most important mechanism with few additional benefits by lowering BP in this transient stroke model.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.04.010

Ketogenic diet therapy is effective in encephalitis with refractory seizures. Reviewed International journal

Kosuke Matsuzono, Tomoko Kurata, Shoko Deguchi, Toru Yamashita, Kentaro Deguchi, Koji Abe

Neurological research 36 ( 10 ) 906 - 10 2014.10

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE AND IMPORTANCE: Although ketogenic diet therapy is effective in refractory seizures in childhood, its effect on adult encephalitis with similar refractory seizures and prolonged encephalopathy has not been well reported. CLINICAL PRESENTATION: We report here a case of a 22-year-old man with acute encephalitis with refractory repetitive partial seizures (AERRPS). INTERVENTION: Partial seizures of the face developed to repeated generalized convulsions, which were refractory against anti-epileptic drugs and a high dose of propofol. After struggling for 9 months, he dramatically recovered after ketogenic diet therapy. CONCLUSION: Ketogenic diet therapy may be an important tool to help cure AERRPS.

DOI： 10.1179/1743132814Y.0000000371

Strong reduction of low-density lipoprotein receptor/apolipoprotein E expressions by telmisartan in cerebral cortex and hippocampus of stroke resistant spontaneously hypertensive rats. Reviewed International journal

Yun Zhai, Toru Yamashita, Tomoko Kurata, Yusuke Fukui, Kota Sato, Syoichiro Kono, Wentao Liu, Yoshio Omote, Nozomi Hishikawa, Kentaro Deguchi, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 23 ( 9 ) 2350 - 61 2014.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Telmisartan is a unique angiotensin II type 1 receptor blocker with a partial peroxisome proliferator-activated receptor-γ (PPARγ) agonistic property to exert not only antihypertensive effect but also antimetabolic syndrome effect. METHODS: We examined the long-term effect of telmisartan on cholesterol transport-related proteins (low-density lipoprotein receptor [LDL-R]/apolipoprotein E [ApoE]) and microtubule-associated proteins 2 (MAP2) in the brains of stroke resistant spontaneously hypertensive rats (SHR-SRs), which were divided into 3 experiment groups including vehicle group (SHR/Ve), low-dose telmisartan group (SHR/Low, .3 mg/kg/day), and high-dose telmisartan group (SHR/High, 3 mg/kg/day). RESULTS: The numbers of LDL-R- and immuno-ApoE-positive neurons increased in both cerebral cortex and hippocampus of SHR/Ve throughout 6, 12, and 18 months of age, compared with age-matched normotensive Wistar rats. On the other hand, telmisartan significantly reduced the numbers of LDL-R- and ApoE immuno-positive neurons in both cerebral cortex and hippocampus, with similar effectiveness in the SHR/Low group without blood pressure (BP) lowering to BP lowering (SHR/High). The decrease of MAP2-positive neuron in SHR/Ve was recovered by telmisartan in both cerebral cortex and hippocampus. CONCLUSIONS: These findings suggest that a long-term treatment with telmisartan directly improved neuronal lipid metabolism in the cerebral cortex and hippocampus of SHR-SR, mainly improving LDL-R and ApoE metabolism (SHR/Low) with a small additive benefit by BP lowering (SHR/High), which could provide a preventative approach in patients with hypertension at risk of Alzheimer disease.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.05.033

Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats. Reviewed International journal

Yoshio Omote, Kentaro Deguchi, Syoichiro Kono, Wentao Liu, Tomoko Kurata, Nozomi Hishikawa, Toru Yamashita, Yoshio Ikeda, Koji Abe

Journal of neuroscience research 92 ( 10 ) 1330 - 7 2014.10

Language：English Publishing type：Research paper (scientific journal)

An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.

DOI： 10.1002/jnr.23406

ICU・CCU あんな症例、こんな症例(第30回) 卵巣奇形腫摘出術後に痙攣重積状態をきたした抗NMDA受容体脳炎の1例

出口健太郎, 柚木太淳, 表芳夫, 角田慶一郎, 菱川望, 山下徹, 阿部康二, 高橋幸利

ICUとCCU 38 ( 9 ) 648 - 651 2014.9

Rivaroxaban and apixaban reduce hemorrhagic transformation after thrombolysis by protection of neurovascular unit in rat. Reviewed International journal

Syoichiro Kono, Toru Yamashita, Kentaro Deguchi, Yoshio Omote, Taijun Yunoki, Kota Sato, Tomoko Kurata, Nozomi Hishikawa, Koji Abe

Stroke 45 ( 8 ) 2404 - 10 2014.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND PURPOSE: This study aimed to assess the risk and benefit of tissue-type plasminogen activator treatment after oral anticoagulation with rivaroxaban or apixaban compared with warfarin or placebo. METHODS: Pretreatment with warfarin (0.2 mg/kg per day), rivaroxaban (2 mg/kg per day), apixaban (10 mg/kg per day), or vehicle (0.5% carboxymethyl cellulose sodium salt) was performed for 7 days. Transient middle cerebral artery occlusion was then induced for 120 minutes, followed by reperfusion with tissue-type plasminogen activator (10 mg/kg per 10 mL). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. Twenty-four hours after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and matrix metalloproteinase-9 activity was measured by zymography. RESULTS: The paraparesis score was significantly improved in the rivaroxaban-pretreated group compared with the warfarin-pretreated group. Intracerebral hemorrhage was observed in the warfarin-pretreated group, and this was reduced in the rivaroxaban and apixaban-pretreated groups compared with the vehicle group. Marked dissociation of astrocyte foot processes and the basal lamina or pericytes was observed in the warfarin-pretreated group, and this was improved in the rivaroxaban and apixaban-pretreated groups. Furthermore, activation of matrix metalloproteinase-9 in the ipsilateral warfarin-pretreated brain was greatly reduced in rivaroxaban- and apixaban-pretreated rats. CONCLUSIONS: This study shows a lower risk of intracerebral hemorrhage after tissue-type plasminogen activator treatment in rats with ischemic stroke that are pretreated with rivaroxaban and apixaban compared with pretreatment with warfarin. Reducing neurovascular dissociation by rivaroxaban and apixaban compared with warfarin could partly explain a reduction in hemorrhagic complications reported in clinical studies.

DOI： 10.1161/STROKEAHA.114.005316

Protective effect of telmisartan against progressive oxidative brain damage and synuclein phosphorylation in stroke-resistant spontaneously hypertensive rats. Reviewed International journal

Yusuke Fukui, Toru Yamashita, Tomoko Kurata, Kota Sato, Violeta Lukic, Nozomi Hishikawa, Kentaro Deguchi, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 23 ( 6 ) 1545 - 53 2014.7

Language：English Publishing type：Research paper (scientific journal)

Previously, we reported that reactive oxygen species and signaling molecules of angiotensin II produced lipid peroxides, degenerated proteins, and injured DNA after cerebral ischemia in normotensive Wistar rats. Here, we investigated the long-term effect of the angiotensin II type I receptor blocker telmisartan on oxidative stress and hyperphosphorylated α-synuclein accumulation in stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 3 months, SHR-SR were divided into 3 treatment groups: SHR-SR vehicle (SHR/Ve), SHR-SR low-dose telmisartan (.3 mg/kg/day) (SHR/low), and SHR-SR high-dose telmisartan (3 mg/kg/day) (SHR/high). Immunohistologic analyses were conducted in these groups and Wistar rats at the age of 6, 12, and 18 months. The SHR/Ve group demonstrated more progressive increase in advanced glycation end product (AGE)-, 4-hydroxy-2-nonenal (4-HNE)-, and phosphorylated α-synuclein (pSyn)-positive cells in the cerebral cortex and hippocampus compared with the Wistar group at 18 months. These expressions were reduced in the SHR/low group even without lowering blood pressure (BP), and expressions were dramatically suppressed in the SHR/high group with lowering of BP. These data suggest that persistent hypertension in SHR-SR strongly potentiate the markers of oxidative damage (AGEs and 4-HNE) and abnormal accumulation of pSyn, which were greatly suppressed by telmisartan in a dose-dependent manner without and with lowering of BP.

DOI： 10.1016/j.jstrokecerebrovasdis.2013.12.052

Telmisartan reduces progressive oxidative stress and phosphorylated α-synuclein accumulation in stroke-resistant spontaneously hypertensive rats after transient middle cerebral artery occlusion. Reviewed International journal

Kota Sato, Toru Yamashita, Tomoko Kurata, Violeta Lukic, Yusuke Fukui, Nozomi Hishikawa, Kentaro Deguchi, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 23 ( 6 ) 1554 - 63 2014.7

Language：English Publishing type：Research paper (scientific journal)

Telmisartan is an angiotensin receptor blocker with high lipid solubility, also called metabosartan, which exerts a special protective effect on both acute brain damage and chronic neurodegeneration. We examined the effects of telmisartan on oxidative stress by advanced glycation end product (AGE) and 4-hydroxynonenal (4-HNE) assays and the accumulation of phosphorylated α-synuclein (pSyn) in the brain of stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 12 weeks, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups: the vehicle group, the low-dose telmisartan group (.3 mg/kg/day), and the high-dose telmisartan group (3 mg/kg/day, postoperatively). Immunohistologic analysis was performed when rats were 6, 12, and 18 months old. AGE, 4-HNE, and pSyn-positive cells (per square millimeter) increased with age in the cerebral cortex and hippocampus of the vehicle group, in the low-dose telmisartan group, these parameters decreased without lowering blood pressure (BP), and in the high-dose telmisartan group, these parameters increased with lowering BP. The present study suggests that a persistent hypertension after tMCAO caused a progressive oxidative stress with the abnormal accumulation of pSyn, and that telmisartan reduced oxidative stress and the accumulation of pSyn without lowering BP (low dose) or improved these conditions with a reduction in BP (high dose) via its pleiotropic effects through a potential peroxisome proliferator-activated receptor gamma stimulation in the brain of SHR-SR.

DOI： 10.1016/j.jstrokecerebrovasdis.2013.12.051

Neurovascular protection of cilostazol in stroke-prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation. Reviewed International journal

Yoshio Omote, Kentaro Deguchi, Syoichiro Kono, Ning Liu, Wentao Liu, Tomoko Kurata, Toru Yamashita, Yoshio Ikeda, Koji Abe

Journal of neuroscience research 92 ( 3 ) 369 - 74 2014.3

Language：English Publishing type：Research paper (scientific journal)

Stroke is the major cause of death and decrease in the activities of daily living. This study sought to evaluate the effects of commonly used antiplatelet drugs on spontaneous cerebral infarction in relation to neurovascular protection associated with angiogenesis and pericyte proliferation. Stroke-prone spontaneously hypertensive rats (SHR-SP) were treated with vehicle, aspirin, clopidogrel, or cilostazol from 8 to 10 weeks of age. The interaction of neurovascular components among endothelial cells, pericytes, and astrocytic endfeet were immunohistochemically examined in brain sections. Angiogenesis associated with vascular endothelial growth factor receptor 2 (VEGFR2) and pericyte proliferation were also examined immunohistochemically. The expression and activity of matrix metalloproteinase 9 (MMP-9) were assessed immunohistochemically and by gelatin zymography. Among the antiplatelet drugs, cilostazol preserved the neurovascular unit (NVU) by preventing astrocytic endfeet or pericytes from pathological detachment found in the vehicle and aspirin treatment. Cilostazol also inhibited the expression and activity of MMP-9, which led to protection of the NVU. Furthermore, in the periinfarct area, cilostazol increased VEGFR2 expression, promoting angiogenesis through proliferation of pericytes. The present study showed a strong protection of NVU integrity by cilostazol and the promotion of angiogenesis by stimulating both endothelial VEGFR2 expression and pericyte proliferation. In addition to the antioxidative effect, these pleiotropic effects of cilostazol contribute to reduce spontaneous infarct volume and preserve motor and cognitive function in SHR-SP.

DOI： 10.1002/jnr.23327

Acceleration of TDP43 and FUS/TLS protein expressions in the preconditioned hippocampus following repeated transient ischemia. Reviewed International journal

Miao Sun, Toru Yamashita, Jingwei Shang, Ning Liu, Kentaro Deguchi, Wentao Liu, Yoshio Ikeda, Juan Feng, Koji Abe

Journal of neuroscience research 92 ( 1 ) 54 - 63 2014.1

Language：English Publishing type：Research paper (scientific journal)

The 43-kDa transactivation response DNA binding protein (TDP43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), heat shock protein 70 (HSP70), and β-amyloid (Aβ) are induced and involved in cerebral ischemia, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), but their relationships in ischemic tolerance have never been examined, although they could be involved in endogenous neuroprotection under ischemic preconditioning. In the present study, Mongolian gerbils were subjected to one or three incidents of basically nonlethal 2-min transient common carotid arteries occlusion (tCCAO). Hippocampal CA1 neurons were lost only in the 2-min three times group at 3 and 7 days, which then gradually recovered from 1 to 6 months. Inductions of TDP43 and FUS/TLS were accelerated from 3 months to 7 days or from 7 days to 1 day, respectively, after 2-min three times ischemia compared with once. The cytoplasmic stainings of TDP43 and FUS/TLS showed a further acceleration of the peaks from 1 months to 3 days or from 1 months to 7 days, respectively, after 2-min three times ischemia compared with once. In contrast, HSP70 was induced only at 7 days after 2-min tCCAO for three times, with no expression for Aβ. These data show that ischemic preconditioning offers a way to induce endogenous neuroprotection and neurogenesis in gerbils, with TDP43, FUS/TLS, and HSP70 involved in this function.

DOI： 10.1002/jnr.23301

Reducing hemorrhagic complication by dabigatran via neurovascular protection after recanalization with tissue plasminogen activator in ischemic stroke of rat. Reviewed International journal

Syoichiro Kono, Kentaro Deguchi, Yoshio Omote, Taijun Yunoki, Toru Yamashita, Tomoko Kurata, Yoshio Ikeda, Koji Abe

Journal of neuroscience research 92 ( 1 ) 46 - 53 2014.1

Language：English Publishing type：Research paper (scientific journal)

This study assesses the risks and benefits of tissue plasminogen activator (tPA) treatment under oral anticoagulation with dabigatran compared with warfarin or vehicle control in transient middle cerebral artery occlusion (tMCAO). After pretreatment with warfarin (0.2 mg/kg/day), dabigatran (20 mg/kg/day), or vehicle (0.5% carboxymethyl cellulose sodium salt) for 7 days, tMCAO was induced for 120 min, followed by reperfusion and tPA (10 mg/kg/10 ml). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. At 24 hr after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and MMP-9 activity was measured by zymography. Paraparesis and intracerebral hemorrhage volume were significantly improved in the dabigatran-pretreated group compared with the warfarin-pretreated group. A marked dissociation between astrocyte foot processes and the basal lamina or pericyte was observed in the warfarin-pretreated group, which was greatly improved in the dabigatran-pretreated group. Furthermore, a remarkable activation of MMP-9 in the ipsilateral warfarin-pretreated rat brain was greatly reduced in dabigatran-pretreated rats. The present study reveals that the mechanism of intracerebral hemorrhage with warfarin-pretreatment plus tPA in ischemic stroke rats is the dissociation of the neurovascular unit, including the pericyte. Neurovascular protection by dabigatran, which was first shown in this study, could partially explain the reduction in hemorrhagic complication by dabigatran reported from clinical study.

DOI： 10.1002/jnr.23302

[Impact of combined medial temporal atrophy and white matter lesions on the cognitive and emotional functions in Alzheimer's disease patients]. Reviewed

Ryou Tokuchi, Kentaro Deguchi, Toru Yamashita, Koji Abe

Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics 51 ( 4 ) 342 - 9 2014

Language：Japanese Publishing type：Research paper (scientific journal)

AIM: The purpose of this study was to determine the relationship between the combined presence of medial temporal atrophy (MTA) and white matter lesions (WMLs: periventricular hyperintensity (PVH) and deep white matter hyperintensity) and the cognitive/emotional function in Alzheimer's disease (AD) patients. METHODS: The subjects included 193 patients with AD and 30 normal elderly controls. On MRI, MTA was rated using the Voxel-based specific regional analysis system for AD (VSRAD). WMLs was also estimated using the Fazekas scale. The MRI measurements were classified as follows: MTA=VSRAD<2 or ≥2; WML absent (-) 0/1 or present (+) 2/3. A total of five groups were assessed, including four groups with AD and a control group. The cognitive and emotional functions were evaluated with neuropsychological tests (Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Geriatric Depression Scale (GDS) and Apathy scale). RESULTS: Four AD groups showed significant declines in the both the MMSE and FAB scores compared to that observed in the control group ((***)p<0.001, (**)p<0.01, (*)p<0.05). Among these four AD groups, the MMSE and FAB scores of in the VSRAD<2 and WML (-) groups significantly declined to VSRAD≥2 and WML (+), respectively group ((*)p<0.05). VSRAD≥2 and WML (+) groups showed demonstrated significantly higher scores than the control group on the GDS ((*)p<0.05), and the PVH (+) group exhibited significantly higher scores than the control group on the apathy scale ((*)p<0.05). Multiple regression analysis identified a VSRAD score of ≥2 and the presence of WMLs to be most significantly associated with the cognitive and emotional functions. CONCLUSIONS: Combined presence of MTA and WML is associated with lower MMSE and FAB scores. Furthermore, depression is also associated with MTA and WML, while PVH independently affects the degree of apathy.

Long-term amelioration of telmisartan on metabolic syndrome-related molecules in stroke-resistant spontaneously hypertensive rat after transient middle cerebral artery occlusion Reviewed

Kentaro Deguchi, Tomoko Kurata, Yusuke Fukui, Wentao Liu, Zhai Yun, Yoshio Omote, Kota Sato, Syoichiro Kono, Nozomi Hishikawa, Toru Yamashita, Koji Abe

Journal of Stroke and Cerebrovascular Diseases 23 ( 10 ) 2646 - 2653 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：W.B. Saunders

Telmisartan is expected to ameliorate not only hypertension, but also metabolic syndrome as a metabosartan. We examined the effects of telmisartan on metabolic syndrome-related molecules such as insulin receptor (IR), peroxisome proliferatoractivated receptor gamma (PPAR-g), and angiotensin 2 type 1 receptor (AT1R) in stroke-resistant spontaneously hypertensive rat (SHR-SR) after transient middle cerebral artery occlusion (tMCAO), by administering telmisartan at either 0 (vehicle), .3 mg/kg/day (low dose), or 3 mg/kg/day (high dose), postoperatively, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months of age. Compared with the vehicle group, the 2 telmisartan groups dose dependently decreased the number of IR- and AT1R-positive neurons in the cerebral cortex in the ipsilateral cerebral cortex from 6 to 18 months after tMCAO. On the other hand, the number of PPAR-g-positive neurons increased in a dose-dependent manner in the 2 telmisartan groups from 6 to 18 months. The present study suggests that telmisartan dose-dependently ameliorated metabolic syndrome-related changes in the poststroke brain of SHR-SR with a direct protective effect (low dose) and an additive benefit, an antihypertensive effect at a high dose, for long-term protection after tMCAO.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.06.012

Telmisartan ameliorates inflammatory responses in SHR-SR after tMCAO Reviewed

Kota Sato, Toru Yamashita, Tomoko Kurata, Yusuke Fukui, Nozomi Hishikawa, Kentaro Deguchi, Koji Abe

Journal of Stroke and Cerebrovascular Diseases 23 ( 10 ) 2511 - 2519 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：W.B. Saunders

Telmisartan, an angiotensin receptor blocker with high lipid solubility, also called metabo-sartan, not only reduces blood pressure (BP), but also ameliorates inflammation in the cerebral cortex and in adipose tissue. We examined the effects of telmisartan on inflammatory responses of monocyte chemotactic protein-1, tumor necrosis factor-a, and ionized calcium-binding adapter molecule 1 in the brain of spontaneously hypertensive rat stroke-resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO). At 12 weeks of age, SHR-SR received tMCAO for 90 minutes and were divided into 3 groups, that is, the vehicle group, a low-dose telmisartan group (.3 mg/kg/day), and a high-dose telmisartan group (3 mg/kg/ day). Immunohistological analysis was performed when rats became 6, 12 and 18 months old. Monocyte chemotactic protein-1, tumor necrosis factor-a, and ionized calcium-binding adapter molecule 1 cells (/mm2) immunoreactivities increased with age in the cerebral cortex and hippocampus of the vehicle group, suggesting strong and persistent inflammatory changes in SHR-SR after tMCAO up to 18 months of age. On the other hand, a low dose of telmisartan significantly reduced such inflammatory changes without lowering BP, whereas a high dose of telmisartan showed a few additional improvements, including the lowering of BP throughout 6-18 months of age. The present study suggests that persistent hypertension after tMCAO caused a long-lasting inflammatory response in the SHR-SR brain, and that even a low dose of telmisartan reduced continuous inflammation without lowering BP via its pleiotropic effects in the SHR-SR brain. A high dose of telmisartan had a few additional benefits, including lowering BP.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.02.019

Direct reprogrammed neuronal cells as a novel resource for cell transplantation therapy. Reviewed International journal

Toru Yamashita, Koji Abe

Cell transplantation 23 ( 4-5 ) 435 - 9 2014

Language：English Publishing type：Research paper (scientific journal)

Cell transplantation/replacement therapy is attractive as a novel strategy for neurological diseases such as Parkinson's disease, Alzheimer's disease, and stroke. To realize this therapy, safer and more therapeutic effective cell resources are now required. Since induced pluripotent stem cells (iPSCs) can retain high replication competence and pluripotency when they differentiate into various kinds of cells, they are regarded as a promising cell source for cell transplantation therapy. However, high tumorigenesis of iPSCs has to be overcome for clinical applications. Recent progress includes the combination of novel transcriptional factors that can convert somatic cells to various kinds of mature neuronal cells and neural stem cells without requiring iPSC fate. Some evidence indicates that these directly induced neuronal cells have little tumorigenic potential. In this article, we discuss the advantage, issues, and possibility of clinical application of these cells for cell transplantation therapy.

DOI： 10.3727/096368914X678274

Cognitive and affective assessments of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients utilizing computerized touch panel-type screening tests. Reviewed

Yuko Kawahara, Masami Ikeda, Kentaro Deguchi, Nozomi Hishikawa, Syoichiro Kono, Yoshio Omote, Kosuke Matsuzono, Toru Yamashita, Yoshio Ikeda, Koji Abe

Internal medicine (Tokyo, Japan) 53 ( 20 ) 2281 - 90 2014

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Cognitive and affective dysfunctions are important aspects for patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). METHODS: We herein examined the cognitive and affective ability in MS (n=35) and NMO (n=10) patients using computerized touch panel-type screening tests. RESULTS: While MS patients and normal controls (NC1, n=40) did not significantly differ in their scores from the Hasegawa dementia scale-revised (HDS-R) or the frontal assessment battery, MS patients did score significantly lower on the mini-mental state examination (MMSE). In contrast, NMO patients did not differ from the normal control group 2 (NC2, n=15) in any of the three cognitive assessments. We also examined the affective ability and found that MS patients scored significantly higher on the apathy scale (AS) compared with the NC1 group, while NMO patients scored significantly higher on the geriatric depression scale (GDS) compared with the NC2 group. Although the GDS and AS scores did not correlate with any of the cognitive assessments among MS patients, the AS scores did correlate with the MMSE and HDS-R among NMO patients. Compared with normal controls, the times to complete the flipping cards and arranging pictures games were significantly longer for MS patients but not for NMO patients. CONCLUSION: These results indicate differences between some features of cognitive and affective dysfunctions between MS and NMO patients. Computerized touch panel-type screening tests may be a more useful and sensitive tool for the cognitive assessment of MS patients than NMO patients.

In vivo optical imaging correlates with improvement of cerebral ischemia treated by intravenous bone marrow stromal cells (BMSCs) and edaravone. Reviewed International journal

FengFeng Tian, Toru Yamashita, Kentaro Deguchi, Yoshio Omote, Hiromi Kawai, Yasuyuki Ohta, Koji Abe

Neurological research 35 ( 10 ) 1051 - 8 2013.12

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Recent studies show that modern In vivo optical imaging can detect matrix metallopeptidase (MMP) activation in the ischemic brain. In this study, we analyze the protective effects of bone marrow stromal cells (BMSCs) and edaravone (EDA) against tissue plasminogen activator (tPA) risk in the ischemic brain with In vivo optical fluorescence MMP imaging. METHODS: At 48 hours after 60 minutes of transient middle cerebral artery occlusion (tMCAO) with tPA, C57BL/6J mice were subjected to motor function analysis, In vivo and ex vivo optical imaging for MMP activation, gelatin zymography, and double immunofluorescent analyses with or without intravenous BMSC transplantation and the intravenous free radical scavenger EDA. RESULTS: In vivo fluorescent signals for MMP were detected over the heads of living mice 48 hours after tMCAO; the strongest were in the tPA group, which were reduced by BMSC or EDA treatment. These In vivo data were confirmed by ex vivo fluorescence imaging. While massive intracerebral hemorrhages were observed in the ischemic hemispheres of the tPA group, only slight hemorrhages were found in the tPA/BMSC, tPA/EDA, and EDA groups. Gelatin zymography showed the strongest MMP-9 activation in the tPA group after tMCAO, which was reduced by BMSC or EDA treatment. CONCLUSION: The present study provides a correlation between In vivo optical imaging of MMP activation and the improvement of ischemic brain damage caused by tPA after tMCAO and treated by BMSC and EDA.

DOI： 10.1179/1743132813Y.0000000252

Cerebral embolic stroke after disappearing takotsubo cardiomyopathy. Reviewed International journal

Kosuke Matsuzono, Yoshio Ikeda, Shoko Deguchi, Toru Yamashita, Tomoko Kurata, Kentaro Deguchi, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 22 ( 8 ) e682-3 2013.11

Language：English Publishing type：Research paper (scientific journal)

Takotsubo cardiomyopathy can induce cerebral embolic stroke because of intracardiac thrombosis, but the timing of cardiogenic embolism relating to takotsubo cardiomyopathy has not been well described. We evaluated a 71-year-old woman with takotsubo cardiomyopathy, who developed cardiogenic cerebral embolism after recovery of cardiac wall motion. Nevertheless, we treated her with anticoagulation therapy. The present clinical observation suggests that attention should be paid to the timing when takotsubo cardiomyopathy resolves against risk of cardiogenic cerebral embolism.

DOI： 10.1016/j.jstrokecerebrovasdis.2013.07.022

Intravenous thrombolysis with neuroprotective therapy by edaravone for ischemic stroke patients older than 80 years of age. Reviewed International journal

Syoichiro Kono, Kentaro Deguchi, Nobutoshi Morimoto, Tomoko Kurata, Toru Yamashita, Yoshio Ikeda, Hisashi Narai, Yasuhiro Manabe, Yoshiki Takao, Sanami Kawada, Kenichi Kashihara, Yasushi Takehisa, Satoshi Inoue, Hideki Kiriyama, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 22 ( 7 ) 1175 - 83 2013.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Alteplase, a recombinant tissue plasminogen activator (tPA), was approved for patients with acute ischemic stroke within 3 hours of stroke onset in Japan in October 2005 at a dose of 0.6 mg/kg. The aim of this study was to assess the safety and efficacy of alteplase in elderly patients in Japan. METHODS: One hundred twenty-nine consecutive patients who were admitted to our 5 hospital groups and who received intravenous tPA within 3 hours of stroke onset between January 2010 and December 2011 were divided into 2 groups by age (<80 years of age [younger group] and >80 years of age [older group]) and by treatment with or without edaravone. Clinical backgrounds and outcomes were investigated. RESULTS: The National Institutes of Health Stroke Scale score on admission was not different in both groups, but the National Institutes of Health Stroke Scale scores 7 days after stroke onset were significantly higher in the older group (score 8; P < .05) than in the younger group (score 4), and the ratio of patients with a modified Rankin Scale score of 4 to 6 was significantly greater in the older group (41.7%; P < .05) than in the younger group (22.2%). However, there was no difference in asymptomatic and symptomatic intracerebral hemorrhage rates between the younger and older groups (asymptomatic 20.2% v 18.8%; symptomatic 2.6% v 2.1%). Patients with edaravone showed a higher recanalization rate (61.9%; P < .01) and a better modified Rankin Scale score at 3 months poststroke (P < .01) than the nonedaravone group. CONCLUSIONS: These data suggest that intravenous alteplase (0.6 mg/kg) within 3 hours of stroke onset was safe and effective, even for very old patients (≥ 80 years of age), but resulted in poor outcomes relating not to tPA but to aging. In addition, edaravone may be a good partner for combination therapy with tPA to enhance recanalization and reduce hemorrhagic transformation.

DOI： 10.1016/j.jstrokecerebrovasdis.2013.02.010

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