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Ichiro Kanazawa

Publications and source records attributed to Ichiro Kanazawa.

At least 37 records · Page 2Linked to original sources
PubMed2004

Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling.

Basic fibroblast growth factor (FGF2)-responsive definitive neural stem cells first appear in embryonic day 8.5 (E8.5) mouse embryos, but not in earlier embryos, although neural tissue exists at E7.5. Here, we demonstrate that leukemia inhibitory factor-dependent (but not FGF2-dependent) sphere-forming cells are present in the earlier (E5.5-E7.5) mouse embryo. The resultant clonal sphere cells possess self-renewal capacity and neural multipotentiality, cardinal features of the neural stem cell. However, they also retain some nonneural properties, suggesting that they are the in vivo cells' equivalent of the primitive neural stem cells that form in vitro from embryonic stem cells. The generation of the in vivo primitive neural stem cell was independent of Notch signaling, but the activation of the Notch pathway was important for the transition from the primitive to full definitive neural stem cell properties and for the maintenance of the definitive neural stem cell state.

Animals↗
PubMed2004

Facilitatory effect on the motor cortex by electrical stimulation over the cerebellum in humans.

Electrical stimulation over the cerebellum is known to transiently suppress the contralateral motor cortex in humans. However, projections from the cerebellar nuclei to the primary motor cortex are disynaptic excitatory pathways through the ventral thalamus. In the present investigation we studied facilitatory effects on the motor cortical excitability elicited by electrical stimulation over the cerebellum by recording surface electromyographic (EMG) responses from the first dorsal interosseous (FDI) muscle in nine normal volunteers. For primary motor cortical activation magnetic stimuli were given over the contralateral hand motor area with a figure-of-eight shaped coil with a current to preferentially elicit I3-waves (test stimulus). For cerebellar stimulation high-voltage electric stimuli were given with an anode on the ipsilateral mastoid process and a cathode over the contralateral process as previously described (conditioning stimulus). The effect of conditioning-test interstimulus intervals was investigated. Anodal cerebellar stimuli increased the size of EMG responses to magnetic cortical stimulation at an interstimulus interval of 3 ms. Reversing the current of conditioning stimulus abolished the facilitation. The same (anodal) conditioning stimuli did not affect electrically evoked cortical responses. Based on the effective polarity of the conditioning stimulus and the time course of facilitation we consider that this effect is due to motor cortical facilitation elicited by activation of the excitatory dentatothalamocortical pathway at the deep cerebellar nuclei or superior cerebellar peduncle. We conclude that the motor cortical facilitation is evoked by cerebellar stimulation in humans.

Adult↗
PubMed2004

Glutamate receptors: RNA editing and death of motor neurons.

The aetiology of sporadic amyotrophic lateral sclerosis (ALS), a fatal paralytic disease, is largely unknown. Here we show that there is a defect in the editing of the messenger RNA encoding the GluR2 subunit of glutamate AMPA receptors in the spinal motor neurons of individuals affected by ALS. This failure to swap an arginine for a glutamine residue at a crucial site in the subunit, which occurs normally in the affected brain areas of patients with other neurodegenerative diseases, will interfere with the correct functioning of the glutamate receptors and may be a contributory cause of neuronal death in ALS patients.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Regulation of glutamate receptor RNA editing and ADAR mRNA expression in developing human normal and Down's syndrome brains.

In human brain, developmental up-regulation in RNA editing at the Q/R site was evident in GluR5 and GluR6, but GluR2 editing in the white matter was down-regulated. Each ADAR mRNA expression was up-regulated in the gray matter, whereas differently regulated in the white matter. ADAR2 mRNA was not overexpressed in the brains of Down's syndrome subjects, nor was there any evidence of changes in the RNA editing efficiency of their GluRs.

Adenosine Deaminase↗
PubMed2004

The primary motor area for voluntary diaphragmatic motion identified by high field fMRI.

In order to identify the precise location of the primary motor area for the diaphragm with respect to the classical motor homunculus, functional magnetic resonance imaging (fMRI) experiments were performed utilizing independent component-cross correlation- sequential epoch (ICS) analysis on a high-field (3.0 Tesla) system. Activations which correlated with voluntary diaphragmatic motion mapped onto the area anterolateral to that for voluntary hand motion (internal control in ICS analysis). Multiple subject analysis yielded the primary motor cortex for the diaphragm to be (+/-48, -4, 47) in the Talairach and Tournoux coordinates. The results were highly consistent with the previously reported cortical area for the diaphragm determined by transcranial electrical/magnetic stimulation.

Adult↗
PubMed2003

Identification of a novel amino-terminal fragment of amyloid precursor protein in mouse neuroblastoma Neuro2a cell.

The amyloid precursor protein (APP) can be catabolized mainly via either an amyloidogenic or non-amyloidogenic pathway, leading to the production of amyloid beta (Abeta) or the secreted form of APP (sAPP), respectively. Abeta is a major component of deposits found in Alzheimer's disease brains and plays an important role in the pathogenesis of this disease, whereas sAPP (though it might have some neurotropic function) has a largely unknown function and metabolism. In this study, a novel 11-kDa APP amino-terminal fragment from Neuro2a cells (but also present in primary cultured neurons, glias, and mouse cerebral cortex) was characterized using mass spectrometric and amino acid sequence analyzes. We could not detect the fragment extracellularly, and suggest that it was generated in a non-secretory, acidic degradation pathway. As this is a fragment of sAPP, it is possible that inhibition of this pathway increases amount of sAPP and results in neuroprotection.

Amino Acid Sequence↗
PubMed2003

Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies.

Accumulation of insoluble alpha-synuclein aggregates in the brain is characteristic of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Although numerous studies on the aggregation properties of alpha-synuclein have been reported, little is known about its degradation so far. In view of proteolytic degradation, we have found that the serine protease neurosin (kallikrein-6) degrades alpha-synuclein and co-localizes with pathological inclusions such as Lewy bodies and glial cytoplasmic inclusions. In vitro study showed that neurosin prevented alpha-synuclein polymerization by reducing the amount of monomer and also by generating fragmented alpha-synucleins that themselves inhibited the polymerization. Upon cellular stress, neurosin was released from mitochondria to the cytosol, which resulted in the increase of degraded alpha-synuclein species. Down-regulation of neurosin caused accumulation of alpha-synuclein within cultured cells. Thus we concluded that neurosin plays a significant role in physiological alpha-synuclein degradation and also in the pathogenesis of synucleinopathies.

Animals↗
PubMed2003

Further evidence to support different mechanisms underlying intracortical inhibition of the motor cortex.

Paired-pulse magnetic stimulation has been widely used to study intracortical inhibition of the motor cortex. Inhibition at interstimulus intervals (ISIs) of 1-5 ms is ascribed to a GABAergic inhibitory system in the motor cortex. However, Fisher et al. have proposed that different mechanisms are operating at an ISI of 1 ms and 2.5 ms. In order to confirm their concept and clarify whether inhibition at all these intervals is produced by a single mechanism, we compared effects of paired-pulse stimulation at ISIs of 1 ms, 2 ms, and 3-5 ms. We evaluated how intracortical inhibition affected the I3-wave, I1-wave, magnetic D-wave, and anodal D-wave components of electromyographic (EMG) responses using previously reported methods. The data suggest that three separate effects occur within these ISIs. At ISIs of 3-5 ms, inhibition was evoked only in responses to I3-waves, whereas no inhibition was elicited in responses to I1-waves or magnetic D-waves. In contrast, at an ISI of 1 ms, responses to I3-waves and I1-waves were moderately suppressed. Moreover, even magnetic D-waves were slightly suppressed, whereas anodal D-waves were unaffected. At an ISI of 2 ms, none of the descending volleys were inhibited. We propose that we should use ISIs of 3-5 ms for estimating function of the GABAergic inhibitory system of the motor cortex by paired-pulse transcranial magnetic stimulation (TMS). Our results support the idea of Fisher et al. that the mechanism responsible for the inhibition at an ISI of 1 ms is not the same as that responsible for suppression at ISIs of 3-5 ms (GABAergic inhibitory circuits in the motor cortex). At an ISI of 2 ms, we suggest that the inhibitory influence evoked by the first stimulus (S1) should collide with or be occluded by the second stimulus (S2), which leads to the lack of inhibition when the subjects make a voluntary contraction of the target muscle.

Adult↗
PubMed2003

PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype.

A body of experimental evidence indicates that transcription and/or mRNA processing factors interacting with the polyglutamine disease gene products play crucial roles in the pathology. PQBP-1 is one of these factors and it has been shown to interact with the spinocerebellar ataxia type-1 (SCA1) disease gene product, ataxin-1. Our previous data suggested that relatively high expression of PQBP-1 in the cerebellum might explain the selective neuronal degeneration of SCA1. To further test whether PQBP-1 expression level regulates neuronal death, we generated transgenic mice of human PQBP-1 driven by a regulatory element for ubiquitous gene expression. The mice showed a late-onset and gradually progressive motor neuron disease-like phenotype, which might be related to neurogenic muscular atrophy observed in SCA1 patients. Ataxia could not be discriminated from predominant progressive weakness. Pathological examinations of the transgenic mice revealed loss of Purkinje and granular cells in the cerebellum as well as that of spinal motor neurons, corresponding to the pathology of human SCA1. These findings show that excessive action of PQBP-1 causes neuronal dysfunction and support PQBP-1 being involved in the pathology of SCA1.

Animals↗
PubMed2003

Histone H3 is aberrantly phosphorylated in glutamine-repeat diseases.

Double-labeling immunohistochemical studies staining with anti-ubiquitin and anti-phosphoserine antibodies and application of an enzymatic dephosphorylation technique reveal neuronal inclusions and affected nuclei to be aberrantly phosphorylated in brain tissues with patients with glutamine-repeat diseases. Regional distribution of the phosphorylated nuclei in neurons correlates with the pathology. To identify the target nuclear protein, transient expression of Huntington's disease exon 1 gene containing an expanded glutamine repeat was generated in a cell culture and nuclear inclusions were isolated with a fluorescence-activated cell sorting system. Immunoblotting studies of the aggregated nuclear proteins using anti-phosphoserine antibody demonstrate the protein of the aberrant phosphorylation as histone H3. The immunoblots of control and diseased brain tissues demonstrate that the phosphorylation of histone H3 is commonly increased in the diseased brains. Aberrant phosphorylation of histone H3 is surmised to be a shared pathological process in glutamine-repeat diseases.

Adult↗
PubMed2003

0.2-Hz repetitive transcranial magnetic stimulation has no add-on effects as compared to a realistic sham stimulation in Parkinson's disease.

To study the efficacy of 0.2-Hz repetitive transcranial magnetic stimulation (rTMS) on Parkinson's disease (PD), 85 patients with PD were enrolled into three groups: 1). motor cortical, 2). occipital, and 3). sham stimulation. A round coil was centered over the vertex in motor cortical stimulation, and over the inion in occipital stimulation. In one session, 100 stimuli of 0.2-Hz rTMS at an intensity of 1.1 times active motor threshold (AMT) were given. In sham stimulation, electric currents were given with electrodes fixed on the head to mimic the sensation in real stimulation. Each session was carried out once a week for the first 8 weeks. The Unified Parkinson Disease Rating Scale (UPDRS), Hamilton Rating Scale for Depression (HRSD) and subjective score (visual analogue scale) were assessed. There were no significant differences in clinical features among the three groups. Total and motor score of UPDRS were improved to the same extent by rTMS over Cz, inion, and sham stimulation. HRSD was improved by rTMS over Cz and sham stimulation in the same manner. Subjective score was not significantly improved by any methods of stimulation. 0.2-Hz rTMS at an intensity of 1.1 x AMT has only a placebo effect on PD. Our realistic sham stimulation maneuver must produce powerful placebo effects as a real stimulation.

Aged↗
PubMed2003

Binding of immunoglobulin G antibodies in Guillain-Barré syndrome sera to a mixture of GM1 and a phospholipid: possible clinical implications.

Anti-GM1 immunoglobulin G (IgG) antibodies are frequently present in sera from patients with Guillain-Barré syndrome (GBS). A previous report on a patient who had a neuropathy with immunoglobulin M (IgM) M-protein binding to a conformational epitope formed by phosphatidic acid (PA) and gangliosides prompted us to investigate the binding of IgG antibodies in GBS sera to a mixture of GM1 and PA (GM1/PA). Of 121 GBS patients, 32 had anti-GM1 IgG antibodies. All 32 also had antibody activity against GM1/PA. Twenty-five (78%) of 32 patients had greater activity against GM1/PA than against GM1 alone. Twelve patients who had no anti-GM1 IgG antibodies had IgG antibody activity against GM1/PA. No GBS patient had IgG antibody against PA alone. In contrast, two rabbit anti-GM1 antisera had greater activity against GM1 alone than against GM1/PA. IgG antibody with greater binding activity against a mixture of GM1 and a phospholipid than against GM1 alone may have an important role in the pathogenesis of GBS and has implications for diagnosis.

Acute Disease↗
PubMed2003

Physical map and haplotype analysis of 16q-linked autosomal dominant cerebellar ataxia (ADCA) type III in Japan.

Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. We previously mapped a gene locus for ADCA with pure cerebellar syndrome (ADCA type III) to a 3-cM region in chromosome 16q, and found a common haplotype among affected individuals. This region was exactly within the locus for another ADCA, spinocerebellar ataxia type 4 (SCA4). To identify the gene causing 16q-linked ADCA type III, we constructed a contig with 38 bacterial artificial chromosome clones between D16S3043 and D16S3095. The size of this contig was estimated to be 4.8 Mb. We found more than 500 nucleotide tandem repeats, including 9 CAG/CTG repeats in this candidate region, although none of the 94 tandem repeats analyzed were expanded in affected individuals. However, we found 11 new polymorphic markers, giving 22 markers spanning the candidate region. By typing these markers on eight Japanese families with ADCA type III, including two new families, we found that a common "founder" haplotype is seen in a more restricted 3.8-Mb region, spanning markers GGAA05 and D16S3095. We present here a newly refined critical interval of 16q-ADCA type III/SCA4. Data of 11 new DNA markers on 16q22.1 would also be useful for other research of genes mapped to this region.

Cerebellar Ataxia↗
PubMed2003

Human skeletal muscle calcium channel alpha1S is expressed in the basal ganglia: distinctive expression pattern among L-type Ca2+ channels.

Voltage-gated calcium channels (VGCCs) are essential molecules for neuronal function. VGCCs consist of five subunits, alpha1, alpha2, beta, gamma, and delta. Among the ten subtypes of the alpha1 subunit (alpha1A-I and S), expression of alpha1S was previously believed to be restricted to the skeletal muscle. We report here, however, that alpha1S is also expressed in human and rat central nervous system. First, we performed PCR screening for VGCC alpha1 subunits in human nervous system using degenerate primers, and identified alpha1S as well as all the eight alpha1 subunits with previously described expression. Intriguingly, alpha1S was selectively localized to the basal ganglia, particularly the caudate nucleus. In situ hybridization showed that alpha1S was expressed in medium-sized caudate neurons. Quantitative analysis using real time RT-PCR revealed a distinct pattern of alpha1S expression among L-type calcium channels. Furthermore, RT-PCR using laser-mediated manipulation of single cells suggested that human alpha1S was coexpressed with ryanodine receptors (RYRs) in GABAergic neurons. Our results suggest the potential relevance of alpha1S to dopaminergic signal transduction and calcium-induced calcium release in caudate neurons.

Animals↗
PubMed2003

Recovery function of and effects of hyperventilation on somatosensory evoked high-frequency oscillation in Parkinson's disease and myoclonus epilepsy.

To evaluate recovery function of and effects of hyperventilation (HV) on high-frequency oscillations (HFOs) of median nerve somatosensory evoked potential (SEP), we recorded SEPs in 8 Parkinson's disease (PD) patients with enlarged HFOs, 4 myoclonus epilepsy (ME) patients and 10 healthy volunteers (N). SEP was recorded from the hand sensory area contralateral to the median nerve stimulated at the wrist. Responses were amplified with filters set at 0.5 and 3000 Hz. HFOs were obtained by digitally filtering raw SEPs from 500 to 1000 Hz. We measured amplitudes of the N20 onset-peak (N20o-p), N20 peak-P25 peak (N20p-P25p), P25 peak-N33 peak (P25p-N33p), the early (1st-2nd) and late (3rd) HFOs. For the recovery function study, paired-pulse stimuli at various interstimulus intervals (20, 50, 100, 150, 200 and 300 ms) were given. To investigate effects of HV, amplitudes of several components of SEPs recorded after HV were compared with those before HV. In PD and ME, the N20o-p recovery curve showed significantly less suppression as compared with those of N. The P25p-N33p recovery curve of ME showed longer suppression than those of N and PD. There were no significant differences in the early or late HFOs recovery curves among three groups. At the dysinhibited state after HV, the late HFO was reduced in association with a significant enlargement of the N20p-P25p amplitude in normal subjects. This suggests that the late HFOs should reflect bursts of inhibitory interneurons. In the ME patients, the early HFOs significantly decreased by HV. The pattern in ME patients may be explained by a kind of compensation for already enhanced SEPs (giant SEP) in the dysinhibited situation. We conclude that (1) Giant HFOs are normally regulated by inhibitory neuronal systems involving in paired stimulation SEP. (2) The late HFOs must reflect bursts of GABAergic inhibitory interneurons.

Adult↗
PubMed2003

A collaborative study on the malignant syndrome in Parkinson's disease and related disorders.

We report the results of a collaborative study on malignant syndrome (MS) that developed in patients being treated with levodopa and other anti-parkinsonian drugs. We analyzed clinical features, laboratory findings, precipitating events, and risk factors for poor outcome. The study was conducted in five centers in Japan. Patients who developed MS between January 1991 and December 1997 were included. The enrollment criteria used were the same as those for neuroleptic MS proposed by Levenson et al. (1985).A total of 99 episodes were encountered in 93 patients (72 with Parkinson's disease and 21 with secondary parkinsonism); one patient had four recurrences of MS and three patients had two recurrences. High fever was the most frequent clinical manifestation of MS followed by worsening of parkinsonism, and then altered levels of consciousness. Serum creatine kinase was abnormally elevated in all the patients studied. Life-threatening complications were rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. The most frequent precipitating event was discontinuation or dose reduction of anti-parkinsonian drugs, particularly levodopa. No drug was the exception in the precipitation of MS. Intercurrent infection was the next most common precipitating event. MS developed without drug withdrawal or infection in some patients. In five patients, severe "wearing off" phenomenon was the only event preceding the onset of MS. Hot weather and dehydration appeared to be the cause in three patients. Among the total of 99 episodes, patients recovered to the pre-MS state following 68 episodes (68.7%); in the remaining 31.3%, patients failed to recover to their previous state. Older age, higher Hoehn and Yahr stage during the symptomatic phase of MS, higher akinesia score, and the absence of wearing off phenomenon prior to developing MS were associated with poor outcome. The most frequently used treatments of MS were intravenous fluid, levodopa, dantrolene sodium, and intragastric bromocriptine. Early introduction of treatment is important. Any elevation of body temperature during the course of anti-parkinsonian drug treatment should be considered as MS until proved otherwise.

Aged↗
PubMed2003

Prevention and treatment of malignant syndrome in Parkinson's disease: a consensus statement of the malignant syndrome research group.

We report a consensus statement of the collaborative research group on the prevention and treatment of malignant syndrome (MS) in Parkinson's disease. The syndrome is quite similar to neuroleptic MS. Although sudden withdrawal of levodopa was the most frequent cause, many other precipitating events were found such as intercurrent infections, dehydration, hot weather, discontinuation of other anti-parkinsonian drugs, and "wearing off" phenomenon. Awareness of this syndrome is most important for its early detection and the prompt commencement of treatment. MS should be suspected whenever the body temperature rises above 38 degrees C without an apparent cause. Treatment consists of ample intravenous fluid, cooling the body, anti-parkinsonian drugs (particularly levodopa and bromocriptine), dantrolene sodium, and antibiotics if infection is present. Rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure constitute serious complications.

Antiparkinson Agents↗