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Yasuto Itoyama

Publications and source records attributed to Yasuto Itoyama.

17 recordsLinked to original sources
PubMed2003

Protection of dopaminergic neurons with a novel astrocyte modulating agent (R)-(-)-2-propyloctanoic acid (ONO-2506) in an MPTP-mouse model of Parkinson's disease.

We examined the neuroprotective effects of a novel astrocyte-modulating agent, (R)-(-)-2-propyloctanoic acid (ONO-2506), in a mouse model of Parkinson's disease. Male C57BL/6 mice received four intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (10 mg/kg) at 1-h intervals. Dopamine content in the striatum, measured with HPLC 3 days after MPTP injection, was reduced to 23% of control. But this dopamine depletion was dose-dependently prevented by repeated treatments with ONO-2506 (3, 10 and 30 mg/kg, i.p.) administered 1, 6, 24 and 48 h after MPTP injection (51% of control in 30 mg/kg group, p<0.01). ONO-2506 treatment (30 mg/kg) started after 6 h, followed by treatments at 24 and 48 h, also prevented the reduction of dopamine content (42% of control vs. 11% of control in the saline-treated group, p<0.01). We also performed immunohistochemistry for tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP). The MPTP injection resulted in a loss of TH-positive dopaminergic neurons (42% of control, p<0.01) in the substantia nigra after 7 days, but ONO-2506 treatment prevented this neuronal loss (70% of control, p<0.01). The MPTP injection led to reactive astrocytosis in the striatum after 7 days, but ONO-2506 induced earlier, moderate astrocytic activation after 3-7 days. These findings show that ONO-2506 protects dopaminergic neurons against MPTP neurotoxicity probably through facilitating astrocytic support for neuronal recovery from injury. Pharmacological modulation of astrocytes may offer a novel therapeutic strategy for Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2003

Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice.

Mutations in a Cu, Zn-superoxide dismutase (SOD1) cause motor neuron death in human familial amyotrophic lateral sclerosis (FALS) and its mouse model, suggesting that mutant SOD1 has a toxic effect on motor neurons. However, the question of how the toxic function is gained has not been answered. Here, we report that the mutant SOD1s linked to FALS, but not wild-type SOD1, aggregated in association with the endoplasmic reticulum (ER) and induced ER stress in the cDNA-transfected COS7 cells. These cells showed an aberrant intracellular localization of mitochondria and microtubules, which might lead to a functional disturbance of the cells. Motor neurons of the spinal cord in transgenic mice with a FALS-linked mutant SOD1 also showed a marked increase of GRP78/BiP, an ER-resident chaperone, just before the onset of motor symptoms. These data suggest that ER stress is involved in the pathogenesis of FALS with an SOD1 mutation.

Animals↗
PubMed2003

Survival and death-promoting events after transient spinal cord ischemia in rabbits: induction of Akt and caspase3 in motor neurons.

OBJECTIVE: The mechanism of spinal cord injury has been thought to be related to the vulnerability of spinal motor neuron cells to ischemia. However, the mechanisms of such vulnerability are not fully understood. We previously reported that spinal motor neurons might be lost as a result of programmed cell death and investigated a possible mechanism of neuronal death by means of immunohistochemical analysis for CPP32 (caspase3) and serine-threonine kinase (Akt). METHODS: We used a rabbit spinal cord ischemia model with use of a balloon catheter. The spinal cord was removed at 8 hours or 1, 2, or 7 days after 15 minutes of transient ischemia, and histologic changes were studied with hematoxylin and eosin staining. Western blot analysis for Akt and caspase3, temporal profiles of Akt and caspase3 immunoreactivity, and double-label fluorescence immunocytochemical studies were performed. RESULTS: The majority of motor neurons were preserved until 2 days but were selectively lost at 7 days of reperfusion. Western blot analysis revealed no immunoreactivity for Akt and caspase3 in the sham-operated spinal cords. However, such immunoreactivity became apparent at 8 hours after transient ischemia, decreased at 1 day, and returned to the baseline level at 2 days. A double-label fluorescence immunocytochemical study revealed that both Akt and caspase3 were positive at 8 hours of reperfusion in the same motor neurons, which eventually die. CONCLUSION: These results suggests that transient spinal cord ischemia activates both cell death and survival pathways after ischemia. The activation of Akt protein at the early stage of reperfusion might be one of the factors responsible for the delay in neuronal death after spinal cord ischemia.

Animals↗
PubMed2003

Oxidative damage and reduction of redox factor-1 expression after transient spinal cord ischemia in rabbits.

OBJECTIVE: The mechanism of spinal cord injury has been thought to be related to the vulnerability of spinal motor neuron cells against ischemia. However, the mechanisms of such vulnerability are not fully understood. We previously reported that spinal motor neurons may be lost by programmed cell death and thus now investigate a possible mechanism of neuronal death with immunohistochemical analysis for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and redox factor-1 (Ref-1). METHODS: We used a rabbit spinal cord ischemia model with a balloon catheter. The spinal cord was removed at 8 hours, 1, 2, or 7 days after 15 minutes of transient ischemia, and histologic changes were studied with hematoxylin-eosin staining. Western blot analysis for Ref-1, temporal profiles of 8-OHdG and Ref-1 immunoreactivity, and double-label fluorescence immunocytochemical studies were performed. RESULTS: Most motor neurons were preserved until 2 days but were selectively lost at 7 days of reperfusion. Western blot analysis of a sample from sham control spinal cord showed a characteristic 37-kDa band that was reduced after ischemia. Immunohistochemistry showed the nuclear expression of Ref-1 in motor neurons of control spinal cords, and immunoreactivity was decreased 1 day after ischemia. On the other hand, no nuclear expression was seen of 8-OHdG in motor neurons of control spinal cords, and immunoreactivity was increased 1 day after ischemia. Double-label fluorescence immunocytochemical study revealed that both 8-OHdG and Ref-1 were positive at 8 hours of reperfusion in the same motor neurons, which eventually die. CONCLUSION: These results suggest that Ref-1 decreased in motor neurons after transient spinal cord ischemia and that this reduction preceded oxidative DNA damage. The reduction of Ref-1 protein at the moderately late stage of reperfusion may be one of the factors responsible for the delay in neuronal death after spinal cord ischemia.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

Expression of OX40 in muscles of polymyositis and granulomatous myopathy.

OX40 is selectively expressed on activated autoreactive memory T cells and these OX40+ lymphocytes may play a crucial role in autoimmune diseases. To determine whether OX40+ lymphocytes are involved in the pathomechanism of human inflammatory muscle diseases, we immunohistochemically examined the distribution of OX40+ cells in muscles from patients with polymyositis and granulomatous myopathy, and compared with that of cells bearing other activation markers, such as IL-2 receptor (IL-2R) and HLA-DR. In polymyositis, OX40+ mononuclear cells were found predominantly in the perivascular sites and to a lesser degree in the endomysium. Scanty IL-2R+ mononuclear cells were located only in the endomysium and HLA-DR was expressed on half of the mononuclear cells distributed diffusely in the perivascular sites and in the endomysium. Mononuclear cell infiltration in the perivascular sites was greater in the muscles in which OX40+ cells were present in the perivascular sites than in those without OX40+ cells in the perivascular sites (p<0.05). In granulomatous myopathy, OX40+ cells were detected in the centers of the granulomas. In contrast, IL-2R+ cells were present at the periphery of the granulomas and HLA-DR was detected on mononuclear cells throughout the granulomas. OX40+ mononuclear cells with specific distributions in muscles may be involved in the pathomechanism of polymyositis and granulomatous myopathy, and can be a candidate molecule of selective immunotherapy in these diseases.

Adult↗
PubMed2002

Impaired chemosensitivity to hypoxia is a marker of multiple system atrophy.

Sudden death is common in patients with multiple system atrophy (MSA). In its early stages, the cerebellar presentation MSA-C can be indistinguishable from idiopathic late-onset cerebellar ataxia. We studied the hypoxic ventilatory response in MSA-C and idiopathic late-onset cerebellar ataxia patients. Six patients with idiopathic late-onset cerebellar ataxia that later evolved to MSA had impaired hypoxic ventilatory response when minimal autonomic failure was still present, whereas for patients with unimpaired hypoxic ventilatory response their diagnosis remained idiopathic late-onset cerebellar ataxia. The demonstration of impaired hypoxic ventilatory response appears to be a good marker enabling earlier diagnosis of MSA in patients presenting with idiopathic late-onset cerebellar ataxia.

Aged↗
PubMed2002

Systemic increase of oxidative nucleic acid damage in Parkinson's disease and multiple system atrophy.

8-hydroxy-2'-deoxyguanosine (8-OHdG) or 8-hydroxyguanosine (8-OHG), a product of oxidized DNA or RNA, is a good marker of oxidative cellular damage. In this study, we measured the 8-OHdG/8-OHG levels in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) and multiple system atrophy (MSA). Compared to age-matched controls, the mean levels of serum 8-OHdG/8-OHG were significantly higher in PD (P < 0.0001). Although no gender differences were observed in the controls, the mean values of serum 8-OHdG/8-OHG were significantly higher in female PD cases (P < 0.005) than in male patients. 8-OHdG/8-OHG levels in CSF were also increased significantly in patients with PD and MSA, however, their relative values were generally much lower than those in the serum. Together with previous studies showing increased peripheral 8-OHdG levels in Alzheimer's disease and amyotrophic lateral sclerosis, the data presented here suggest that systemic DNA/RNA oxidation is commonly observed in neurodegenerative diseases. Our results also imply that female patients with PD show higher levels of oxidative stress, which may explain the faster progression of this disease in females.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

Pure optic-spinal form of multiple sclerosis in Japan.

We evaluated the clinical and laboratory features of the optic-spinal form of multiple sclerosis (OSMS) with no brain lesions on repeated MRI--termed pure OSMS. By reviewing the medical records of 118 Japanese clinically definite multiple sclerosis patients seen between 1988-1999, we found 10 patients (8.5%), nine of whom were women, with only relapsing optic neuritis (ON) and myelitis (MY) clinically and consistently normal brain MRI during follow-ups of >or=5 years. Three patients suffered severe ON and MY, but the other seven had mild disease (six were graded 1 in the Disability Status Scale). Despite frequent relapses, mild pure OSMS was characterized by younger onset and mild spinal symptoms as in 'benign' classical multiple sclerosis (CMS). MRI often revealed multiple cervico-thoracic cord lesions of variable lengths. Oligoclonal IgG bands (OB) were negative in all cases. HLA-DPB1*0501, whose association with OSMS has been reported, was positive only in six patients (including three patients with severe pure OSMS). Four patients with DRB1*1501-DQB1*0602, to which CMS is closely linked, had mild disease. Though pure OSMS was heterogeneous with regard to clinical severity and human leukocyte antigen (HLA) class II alleles, this form of multiple sclerosis was characterized by a definite female preponderance and negative OB that distinguished it from CMS.

Adult↗
PubMed2002

Silent cerebral microbleeds on T2*-weighted MRI: correlation with stroke subtype, stroke recurrence, and leukoaraiosis.

BACKGROUND AND PURPOSE: Gradient-echo T2*-weighted MRI is uniquely sensitive to detect silent, old hemosiderin deposits, but the clinical significance of such "microbleeds" remains to be determined. Therefore, we investigated the incidence and the number of microbleeds among different stroke subtypes and the correlation with stroke recurrence and the severity of leukoaraiosis. METHODS: This study consisted of 213 patients (73.5+/-9.1 years old, 104 men and 109 women), who were classified according to stroke subtypes into atherothrombotic infarction (24 patients), cardioembolic infarction (23 patients), lacunar infarction (66 patients), intracerebral hemorrhage (35 patients), and control (65 patients) groups. Gradient-echo T2*-weighted MRI was performed with a 1.5 T system, and asymptomatic microbleeds were located and counted. RESULTS: The incidence and the number of microbleeds were significantly greater in patients with intracerebral hemorrhage (71.4% and 9.1+/-13.8, respectively) and lacunar infarction (62.1% and 7.4+/-16.1) compared with patients with cardioembolic infarction (30.4% and 2.5+/-5.6), atherothrombotic infarction (20.8% and 0.63+/-1.53), and controls (7.7% and 0.09+/-0.34). There was a correlation between the number of microbleeds and the severity of periventricular hyperintensity (r=0.626, P<0.0001). There was also a correlation between the number of microbleeds and the number of intracerebral hemorrhages (r=0.689, P<0.0001) or lacunar infarctions (r=0.514, P<0.0001). The locations of microbleeds were subcortical white matter (31.8%), thalamus (24.8%), basal ganglia (19.8%), brain stem (12.0%), and cerebellum (11.7%). CONCLUSIONS: The findings suggest that microbleeds on T2*-weighted MRI are an indicator of advanced small artery disease of the brain with an increased risk for bleeding. This result should be taken into consideration when treating patients with stroke, and further studies are required.

Aged↗
PubMed2002

Near-infrared spectroscopic topography as a tool to monitor motor reorganization after hemiparetic stroke: a comparison with functional MRI.

BACKGROUND AND PURPOSE: Motor functional recovery from stroke can occur, but the mechanisms underlying this restorative process remain to be elucidated. We used near-infrared spectroscopic (NIRS) topography in comparison with functional MRI (fMRI) to evaluate the compensatory motor activation of cortical regions in patients who recovered from hemiparesis after cortical cerebral infarction. METHODS: We examined 6 right-handed patients who suffered cerebral infarction of the middle cerebral artery territory with minimal or mild residual contralateral hemiparesis (4 men and 2 women, 59 to 79 years old, all had left hemiparesis). Both fMRI and NIRS were studied during a hand movement task at chronic stages. Five right-handed, normal subjects (3 men and 2 women, 44 to 81 years old) served as controls. RESULTS: fMRI and NIRS detected very similar cerebral cortical activation, although NIRS detected only superficial activation. The spatial resolution of NIRS was less than that of fMRI, but NIRS provided a dynamic profile of activation. Normal subjects activated predominantly the contralateral primary sensorimotor cortex and supplementary motor areas during each hand movement. All the stroke patients exhibited the normal activation pattern during normal hand movement. On affected hand movement, the stroke patients showed extended activation not only in the contralateral motor cortex but also in the ipsilateral motor cortex (primary motor cortex and supplementary motor areas). CONCLUSIONS: Both fMRI and NIRS studies provided evidence for the contribution of ipsilateral motor cortical compensation or reorganization to the recovery from poststroke hemiparesis. The result demonstrated that NIRS was a unique tool to monitor poststroke alterations in cortical motor functions.

Adaptation, Physiological↗
PubMed2002

[A case of neuralgic amyotrophy manifesting bilateral anterior interosseous nerve syndrome].

A 49-year-old woman acutely developed severe bilateral shoulder pain followed by weakness of the right shoulder girdle muscles. Within a few days, an inability to flex the terminal phalanges of the bilateral thumbs and index fingers emerged. Neurologic examination 1 month after the onset of symptoms showed atrophy of the right shoulder girdle muscles and mild decreased cutaneous sensation in the distribution of the right axillary nerve. Needle electromyography examination at this time showed fibrillation potentials in the right deltoid and bilateral flexor pollicus longus muscles. Recruitment of the right deltoid, supra- and infraspinatus muscles was reduced. Motor unit potentials in these muscles were of normal configuration. Nerve conduction studies in the upper limb were normal. She was diagnosed as neuralgic amyotrophy with bilateral anterior interosseous nerve syndrome. 4 months later, the muscles innervated by the bilateral anterior interosseous nerve improved in the muscle strength. Clinical features of this case were compatible with a mononeuropathy multiplex form of neuralgic amyotrophy associated with an autoimmune etiology. We think this case is important for speculating the pathogenesis of neuralgic amyotrophy. This case reminds us that patients with neuralgic amyotrophy sometimes demonstrate anterior interosseous nerve syndrome and most patients manifesting anterior interosseous nerve syndrome are patients with neuralgic amyotrophy.

Brachial Plexus Neuritis↗
PubMed2002

[A case of Marchiafava-Bignami disease: serial changes with diffusion-weighted MR imaging].

We report a 34-year-old man who presented with alcohol-withdrawal delirium. In the early phase, diffusion-weighted MR imaging demonstrating a high intensity area in the corpus callosum, indicating Marchiafava-Bignami disease. T2-weighted MR imaging did not clearly show the lesion. He was treated and completely recovered in terms of clinical state and MRI findings. Although historically the most of Marchiafava-Bignami disease was not cured, it seems that the lesion is reversible by management in the early stage. We propose that diffusion-weighted MR imaging is useful for the early detection of Marchiafava-Bignami disease.

Adult↗
PubMed2002

[Late-onset nonketotic hyperglycinemia: a case report].

We report a 66-year-old woman who developed mental deterioration in her school days, and progressive gait disturbance, dysarthria and bradykinesia in her 40 s. Her parents were consanguineous, and the two of her brothers were suspected to have the allied disorder. On physical examination, she was short-statured and high-arched palate was observed. Neurological examination revealed dementia, abnormal eye movement, dysarthria, spastic paraparesis with hyperreflexia, bilateral Babinski signs, cerebellar ataxia and dysuria. Brain MRI showed marked hypoplasia of corpus callosum with dilatation of lateral ventricles and cerebral sulci and significant cerebellar atrophy. Amino acid analyses showed significant elevation of glycine without ketosis in serum, cerebrospinal fluid, and urine, which lead us to the diagnosis of late-onset nonketotic hyperglycinemia(NKH). NKH is known to be a rare autosomal recessive metabolic disorder primarily caused by deficient activity of various components of the mitochondrial glycine cleavage system. Onset of the disease occurs most often in early infancy, however, later-onset variants have been described. Usually, late-onset NKH only manifests mild mental deterioration, character change, seizure, ataxia or spastic paraparesis, which sometimes makes difficulty in differentiating this disease from other hereditary cerebellar ataxia or spastic paraparesis. In addition, many structural brain abnormalities have been reported accompanied with NKH, and especially, agenesis or hypoplasia of corpus callosum is the most characteristic feature in this disease. Therefore, we emphasized that amino acid analyses should be considered in any patients who have cerebellar ataxia or spastic paraparesis of unknown cause with these neuroradiological findings.

Aged↗