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Nobutaka Arai

Publications and source records attributed to Nobutaka Arai.

17 recordsLinked to original sources
PubMed2003

Expression of apolipoprotein E in ballooned neurons-comparative immunohistochemical study on neurodegenerative disorders and infarction.

Apolipoprotein E (ApoE) in neurons is suggested to play crucial roles in neuronal degeneration and regeneration. We used antibodies against ApoE and phosphorylated neurofilament (pNF) to investigate the immunohistochemical features of ballooned neurons (BNs) in infarction and in various chronic degenerative disorders, including Pick body disease, corticobasal degeneration/progressive supranuclear palsy, Alzheimer's disease, and frontotemporal dementia. BNs in these chronic degenerative processes were intensely labeled with the anti-pNF as reported, whereas BNs in infarction showed less intense pNF-like immunoreactivity (IR). In addition, BNs in infarction were characterized by an intense ApoE-like IR. This ApoE-like IR was inconsistent or less intense in BNs in the chronic degenerative processes. The rarity of ApoE-positive glial cells in the vicinity of ApoE-positive BNs suggests that accumulated ApoE in BNs is generated in the neurons. Accumulation of ApoE in BNs in infarction may be linked to a regenerative process after acute transection of axons, which seems compromised in chronic degenerative processes.

Aged↗
PubMed2003

Immunoexpression of 14-3-3 proteins in glial cytoplasmic inclusions of multiple system atrophy.

Glial cytoplasmic inclusions (GCIs) are the histological hallmark of multiple system atrophy (MSA). In six postmortem brains of patients with MSA, 14-3-3-protein immunoreactivity was identified in GCIs predominately in the white matter tissue of the basal forebrain and cerebellum. Using double immunohistochemistry, co-localization of 14-3-3-protein and alpha-synuclein immunoreactivities in the GCIs was confirmed. The immunolabeling rate of GCIs with 14-3-3 proteins varied regionally from approximately 40% to 90%. Semiquantitative analysis yielded a significant negative correlation between degree of tissue degeneration and density of 14-3-3-protein-immunoreactive GCIs. The 14-3-3 proteins are active cofactors involved in cellular regulation through binding to phosphorylated motifs in target proteins and alpha-synuclein is a known target of 14-3-3. Our study suggests that 14-3-3 proteins are closely associated with alpha-synuclein in GCIs and 14-3-3 proteins may be candidate cofactors of alpha-synuclein in GCI formation.

14-3-3 Proteins↗
PubMed2003

Motor dysfunction in type 5 adenylyl cyclase-null mice.

Various neurotransmitters, such as dopamine, stimulate adenylyl cyclase to produce cAMP, which regulates neuronal functions. Genetic disruption of the type 5 adenylyl cyclase isoform led to a major loss of adenylyl cyclase activity in a striatum-specific manner with a small increase in the expression of a few other adenylyl cyclase isoforms. D1 dopaminergic agonist-stimulated adenylyl cyclase activity was attenuated, and this was accompanied by a decrease in the expression of the D1 dopaminergic receptor and G(s)alpha. D2 dopaminergic agonist-mediated inhibition of adenylyl cyclase activity was also blunted. Type 5 adenylyl cyclase-null mice exhibited Parkinsonian-like motor dysfunction, i.e. abnormal coordination and bradykinesia detected by Rotarod and pole test, respectively, and to a lesser extent locomotor impairment was detected by open field tests. Selective D1 or D2 dopaminergic stimulation improved some of these disorders in this mouse model, suggesting the partial compensation of each dopaminergic receptor signal through the stimulation of remnant adenylyl cyclase isoforms. These findings extend our knowledge of the role of an effector enzyme isoform in regulating receptor signaling and neuronal functions and imply that this isoform provides a site of convergence of both D1 and D2 dopaminergic signals and balances various motor functions.

Adenylyl Cyclases↗
PubMed2003

Glyceraldehyde 3-phosphate dehydrogenase and endothelin-1 immunoreactivity is associated with cerebral white matter damage in dentatorubral-pallidoluysian atrophy.

DRPLA is a rare neurodegenerative disorder caused by CAG triplet elongation on chromosome 12p. In addition to neurodegeneration of both the dentatorubral and pallidoluysian systems, there is cerebral white matter damage, especially in older cases. Intracellular accumulation of DRPLA protein is widespread in the central nervous system, and DRPLA protein has been shown to immobilize glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which regulates glycolysis and controls mRNA of tissue-type plasminogen activator (tPA) in tissue restoration. However, little is known about the pathogenesis regarding the formation of cerebral white matter damage in DRPLA. Therefore, the pathology of this damage was investigated by examining markers of glycolysis and related processes. Nine clinically and pathologically confirmed DRPLA cases were used in the present study. CAG triplet elongation on chromosome 12p was confirmed in all cases where tissue was available for genotyping (seven cases). PAS and immunohistochemistry with antibodies to GFAP, GAPDH and endothelin-1 were used to demonstrate astrocytosis. The polysaccharides storage state with PAS-positive astrocytes was detected in seven cases. GAPDH- and endothelin-1-positive endothelium and astrocytes were observed in two cases with GFAP-positivity. Based on the biochemical process together with the present results, GAPDH and endothelin-1 immunoreactivity is associated with this damage and the mismetabolism of polysaccharides caused by CAG triplet elongation on chromosome 12p may contribute to the formation of the cerebral white matter damage in DRPLA.

Adolescent↗
PubMed2003

Peculiar form of cerebral microdysgenesis characterized by white matter neurons with perineuronal and perivascular glial satellitosis: A study using a variety of human autopsied brains.

Microdysgenesis (MD) is a neuropathological term that implies a variety of minor developmental abnormalities of the brain. Recently, MD has been used for pathological diagnosis of cerebral tissues surgically resected from epileptic patients. However, criteria or consensus on pathological diagnosis of MD is still vague and controversial because of the lack of control studies. Therefore, this study paid special attention to the presence of white matter neurons with perineuronal glial satellitosis (WMN-GS) and perivascular glial satellitosis (PVGS) in the white matter, which are occasionally observed in epileptic foci, in order to clarify whether they could be handled as definite findings of MD. The materials included 80 autopsied whole brains ranging from normal subjects to patients with cerebrovascular disorder, neurodegenerative diseases and malformations. In each case, the presence of WMN-GS and/or PVGS was searched in 10 gyri in all five lobes (rostral frontal lobe, caudal frontal lobe, parietal lobe, temporal lobe and oc-cipital lobe) and evaluated. Statistically significant, WMN-GS and/or PVGS preferentially appeared in a diseased group consisting of neuronal migration disorder and related conditions, such as polymicrogyria, nodular heterotopia or tuberous sclerosis, leading to a suggestive conclusion that the presence of WMN-GS and/or PVGS could be a peculiar form of MD possibly derived from neuronal migrational arrest or related events, even if they appear alone without any other gross abnormalities.

Adolescent↗
PubMed2003

Histone deacetylase activity is retained in primary neurons expressing mutant huntingtin protein.

Perturbation of histone acetyl-transferase (HAT) activity is implicated in the pathology of polyglutamine diseases, and suppression of the counteracting histone deacetylase (HDAC) proteins has been proposed as a therapeutic candidate for these intractable disorders. Meanwhile, it is not known whether mutant polyglutamine disease protein affects the HDAC activity in declining neurons, though the answer is essential for application of anti-HDAC drugs for polyglutamine diseases. Here, we show the effect of mutant huntingtin (htt) protein on the expression and activity of HDAC proteins in rat primary cortical neurons as well as in human Huntington's disease (HD) brains. Our findings indicate that expression and activity of HDAC proteins are not repressed by mutant htt protein. Furthermore, expression of normal and mutant htt protein slightly increased HDAC activity although the effects of normal and mutant htt were not remarkably different. In human HD cerebral cortex, HDAC5 immunoreactivity was increased in the nucleus of striatal and cortical neurons, suggesting accelerated nuclear import of this class II HDAC. Meanwhile, western blot and immunohistochemical analyses showed no remarkable change in the expression of class I HDAC proteins such as HDAC1 and HDCA8. Collectively, retained activity in affected neurons supports application of anti-HDAC drugs to the therapy of HD.

Animals↗
PubMed2002

Lewy bodies in progressive supranuclear palsy.

Lewy bodies (LBs), whose major component is alpha-synuclein, are a pathological hallmark of Parkinson's disease (PD) but have rarely been reported in progressive supranuclear palsy (PSP). Whether LBs in PSP represent the aging process or the coexistence of PD remains unclear. We found LBs in 5 of 16 patients with PSP. In 4 patients LBs were distributed widely throughout the brain stem and cerebrum in a pattern similar to that in PD. In the remaining patient one LB was found in the pontine reticular formation. Semiquantitative analysis showed that neuronal loss in the locus coeruleus and the dorsal vagal nucleus was more severe in patients with LBs than in patients without LBs. Double-labeling immunohistochemical studies showed co-localization of alpha-synuclein and tau in some neurons. Our study suggests that patients who have PSP with LBs constitute a subset of patients with PSP in whom Lewy body disease is also present.

Aged↗
PubMed2002

Cortical perivascular satellitosis in intractable epilepsy; a form of cortical dysplasia?

This report describes two cases of cortical dysplasia in patients with intractable epilepsy: the first case presents a 12-year-old male with a simple partial seizure of his left arm (case 1), while the second case presents an 8-year-old female with a complex partial seizure (case 2). Magnetic resonance images showed high signal intensity on T2-weighted and fluid attenuated inversion-recovery images in the cerebral cortex of right frontal convexity in case 1 and in the medial temporal lobe and anterior amygdala in case 2. The latter lesion showed focal contrast enhancement. Light microscopy revealed perivascular clustering of small round cells accompanied by dysplastic neurons in the second to sixth layers of the cerebral cortex. The perivascular small cells had uniformly round nuclei and plump, ground-glass-like cytoplasm. These cells closely apposed each other and were adhered to the capillaries. In case 2, a ganglioglioma was also found in the amygdala. Immunohistochemistry revealed that the perivascular small cells were vimentin and focally S-100 protein positive, but were negative for glial fibrillary acid protein, synaptophysin, neurofilament protein, microtubule-associated protein 2, neuronal nuclei antigen, nestin, carbonic anhydrase II, myelin basic protein, CD68, factor VIII, cytokeratin, epithelial membrane antigen, alpha-smooth muscle actin, CD20, CD45 and CD45RO. These data suggest that this is a previously undescribed form of cortical dysplasia comprising dysplastic neurons and immature perivascular cells of possible oligodendroglial or meningothelial lineage. We suggest the term cortical perivascular satellitosis be used to describe this lesion.

Amygdala↗
PubMed2002

Oxidative stress and disturbed glutamate transport in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a hereditary motor neuron disease, and three clinical subtypes of autosomal recessive SMA, including Werdnig Hoffmann disease (type 1), have been shown to be induced by deletion within the same genes. In order to clarify the pathogenesis of motor neuron degeneration in SMA, we immunohistochemically examine the expressions of oxidative stress-related materials (oxidative products) and glutamate transporters, which can prevent glutamate neurotoxicity, in five autopsy cases of SMA type 1. Age-matched controls did not show any deposition of oxidative products in the brain. In contrast, the abnormal deposition of 4-hydroxy-2-nonenal-modified protein, a product of membrane lipid oxidation, was observed in the spinal motor neurons in three cases, although the motor neurons did not show an increase of nitrotyrosine, which was observed in adult-onset amyotrophic lateral sclerosis. In addition, the nuclei of neurons and glial cells in the precentral gyrus, thalamus or cerebellar cortex were immunoreactive for 8-hydroxy-2'-deoxyguanosine in two cases, which was one of the most commonly used markers for oxidative DNA damage. Regarding glial glutamate transporters, three of five cases of SMA type 1 showed a reduction in immunoreactivity for excitatory amino acid transporter-1 (GLAST) in the ventrolateral nucleus of the thalamus, in which there was neither neuronal loss nor gliosis in routine histochemistry. One case, having mechanical ventilation, demonstrated a reduced expression of another glial glutamate transporter (GLT-1) throughout the central nervous system. These data suggest that oxidative stress and disturbed glutamate transport can partly be involved in the motor neuron devastation and/or latent thalamic degeneration in SMA type 1.

Adolescent↗
PubMed2002

Infantile spongiform leukoencephalopathy: clinical and neuropathologic findings.

A 10-month-old male with spongy leukoencephalopathy is presented. Neurologic manifestations included feeding difficulties, horizontal nystagmus, and spasticity at 5 months of age. His head circumference was within the normal range. Radiologic examination demonstrated a diffuse white matter disorder. There was no detectable biochemical abnormality. He followed a neurologically progressive course. Neuropathologic findings revealed characteristic vacuolar changes in the white matter located immediately under the cortex with spongy alterations of the entire subcortical white matter, including intense astrocytic gliosis and marked vascular hyperplasia. Tissue of the matrix was destroyed in the deep white matter to form cystic areas of degeneration. White matter myelin development was severely disturbed compared with that of a normal infant of the same age. Cortical neuronal cells were preserved and did not reveal any specific abnormalities. Electron microscopic examination revealed that each vacuole in the white matter was covered by several layers of myelin structures, and intralamellar splits of white matter myelin were observed. These neuropathologic findings are also observed in some known inherent metabolic disorders. The present patient, however, did not demonstrate any metabolic abnormalities. These findings suggested a new genetic disorder of myelin metabolism.

Brain↗
PubMed2002

Pathological effect of seizures on the hippocampus in cases with temporal lobe epilepsy caused by brain tumors.

The cause of Ammon's horn sclerosis in temporal lobe epilepsy has not yet been clarified. In the present study, the pathological effect of epileptic seizures on the hippocampus was investigated in surgically treated patients with brain tumor-induced temporal lobe epilepsy. Tumors involving the hippocampus were identified as the foci of epilepsy in 13 patients (seven male and six female) and resected after epileptic discharges were found at the hippocampus on intraoperative electrocorticogram. The mean age at operation was 29.8 +/- 11.5 years and the mean age of seizure onset was 19.9 +/- 10.8 years. Because only three of the 13 patients who underwent temporal lobectomy for brain tumors involving the hippocampus had Ammon's horn sclerosis pathologically, it was concluded that it was very unlikely that the Ammon's horn sclerosis was produced by the epileptic seizures. Two of the three patients with pathological signs of Ammon's horn sclerosis had episodes of coma, covulsion, high fever and cyanosis in their past histories that might have portended the appearance of Ammon's horn sclerosis later in their lives.

Adolescent↗
PubMed2002

Neurodegenerative mechanisms in subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis is caused by persistent brain infection of mutated measles virus, showing inflammation, neuronal loss, and demyelination. We neuropathologically examined six autopsy cases of subacute sclerosing panencephalitis, using in situ nick end-labeling and immunohistochemistry. Both the neurons and glial cells in the cerebral cortex showed immunoreactive nuclei in the nick end-labeling in two cases with disease duration within 2 years, whereas they were confined to the glial cells in the demyelinated cerebral white matter in three cases with disease duration ranging from 2 to 10 years. The nuclei and cytoplasm were immunoreactive for 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine, markers of oxidative damage to DNA and ribonucleic acid, respectively, in the cerebral cortex in three cases with disease duration within 9 years. In contrast, 4-hydroxy-2-nonenal-modified proteins, products of lipid peroxidation, were deposited in the demyelinated white matters in four cases with disease duration longer than 9 years. In three cases with long survival, the expression of glial glutamate transporters was reduced in the cerebral cortex. It is speculated in subacute sclerosing panencephalitis that apoptosis and oxidative stress to DNA can contribute to the early neuronal damage, whereas lipid peroxidation and disturbed glutamate transport may be related to the subsequent neurodegeneration.

Adolescent↗
PubMed2002

[A case of intractable epilepsy: diagnosis of tuberous sclerosis based on histopathological findings and immunohistochemical expression of hamartin and tuberin].

We report here a 14-year-old boy suffering from intractable epilepsy since the age of 2. Neuroimaging showed a lesion in the left temporal lobe. He underwent resection of the left temporal lobe and multiple subpial transection of the left frontal lobe at the age of 8. Histopathological findings of surgical specimens were similar to those of tubers of tuberous sclerosis (TSC), although he had no other TSC stigmata. To discriminate from cortical dysplasia grade III, we examined the immunohistochemical expression of hamartin and tuberin, the TSC1 and TSC2 gene products. Based on results, we diagnosed this case as having TSC. He has been seizure free since the operation. Although lower than preoperatively, his intelligence quotient has not been declining progressively.

Adolescent↗
PubMed2002

[Microdysgenesis].

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Cerebral Cortex↗
PubMedDate not supplied

DOPA causes glutamate release and delayed neuron death by brain ischemia in rats.

DOPA seems to be a neuromodulator in striata and hippocampal CA1 and a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS) and baroreflex pathways in the caudal ventrolateral medulla and rostral ventrolateral medulla in the brainstem of rats. DOPA recognition sites differ from dopamine (DA) D(1) and D(2) and ionotropic glutamate receptors. Via DOPA sites, DOPA stereoselectively releases by itself neuronal glutamate from in vitro and in vivo striata. In the cultured neurons, DOPA and DA cause neuron death via autoxidation. In addition, DOPA causes autoxidation-irrelevant neuron death via glutamate release. Furthermore, DOPA released by four-vessel occlusion seems to be an upstream causal factor for glutamate release and resultant delayed neuron death by brain ischemia in striata and hippocampal CA1. Glutamate has been regarded as a neurotransmitter of baroreflex pathways. Herein, we propose a new pathway that DOPA is a neurotransmitter of the primary aortic depressor nerve and glutamate is that of secondary neurons in neuronal microcircuits of depressor sites in the NTS. DOPA seems to release unmeasurable, but functioning, endogenous glutamate from the secondary neurons via DOPA sites. A common following pathway may be ionotropic glutamate receptors-nNOS activation-NO production-baroreflex neurotransmission and delayed neuron death. However, we are concerned that DOPA therapy may accelerate neuronal degeneration process especially at progressive stages of Parkinson's disease.

Animals↗