Biomedical subjects

M Asanuma

Publications and source records attributed to M Asanuma.

At least 55 records · Page 3Linked to original sources

PubMed1997

Evidence of brain ischemia in early neonatal sudden death syndrome.

Ten early neonatal sudden death victims (ENSD) were selected for neuropathological and immunohistochemical examinations. The gestational ages of the victims ranged from 36 to 42 weeks, and the postnatal ages from 8 hours to 10 days of life. In 6 of 10 patients, softening with rarefaction was observed in the subcortical or intermediate white matter, which was associated with minimal astrogliosis in the whole white matter. In 7 of the 10 ENSD victims, the number of GFAP-positive glia was significantly greater in both the deep and subcortical white matter than in controls. The brainstem showed mild gliosis in the reticular formation and vagal nuclei of the medulla oblongata in 8 of the 10 ENSD victims. In 8 of the 10 ENSD victims, the number of GFAP-positive astrocytes was greater in both the dorsal vagal nucleus and the reticular formation of the medulla oblongata than in controls. The high incidence of leukomalacia and astrogliosis in the cerebral white matter and brainstem suggests the presence of brain ischemic insults before death, which may be prenatal in some cases.

Astrocytes↗

PubMed1997

Effects of lecithinized superoxide dismutase on traumatic brain injury in rats.

Only small amounts of superoxide dismutase (SOD) are present in the extracellular space to scavenge excess amounts of superoxide anions (02-) released after traumatic brain injury (TBI). Experiments were performed in rats with cerebral contusion produced by weight-drop technique. We investigated the effects of exogenous lecithinized SOD (PC-SOD) on accumulation of 02- produced in our model, by measuring the level of SOD activity (using the NBT-reducing method) and the expression of copper, zinc-SOD (Cu, Zn-SOD) mRNA (by Northern blot analysis). As determined by tissue-specific gravity, administration of PC-SOD reduced brain edema in the periphery of the lesion 6 h after contusion. SOD activity increased in the peripheral region at 30 min after contusion, but returned to normal levels at 6 h after TBI. Administration of PC-SOD increased SOD activity up to 6 h after TBI. The expression of Cu, Zn-SOD mRNA increased in the core region, peripheral portion, and contralateral hemisphere up to 6 h after TBI, then was suppressed in all three regions by PC-SOD. Our results confirm the important role of 02- in the development of brain edema after TBI and indicate that PC-SOD diminishes brain edema through a protective effect against 02-.

Animals↗

PubMed1997

Dantrolene sodium reverses the increase in cAMP response element and TPA responsive element DNA-binding activity in the rabbit brain following haloperidol administration and heat stress.

Using electrophoretic mobility-shift assay (EMSA), we examined DNA-binding activity of cAMP response element (CRE), onto its responsive element CRE, as well as TPA responsive element (TRE) in the medial hypothalamus and striatum of the experimental rabbits administered with haloperidol under heat stress exposure and studied the effects of dantrolene sodium to the transcriptional factor. In EMSA with nuclear extracts from the rabbit brain, the DNA-binding activities of CRE and TRE in medial hypothalamus and striatum increased following haloperidol and heat stress. These increases were maintained by coadministration with atropine. The treatment with dantrolene sodium markedly reversed such increases. The alterations of activities of these transcriptional factors may reflect the therapeutic effect of dantrolene sodium.

Animals↗

PubMed1996

Alterations of cAMP response element-binding activity in the aged rat brain in response to administration of rolipram, a cAMP-specific phosphodiesterase inhibitor.

Transcription factor, cAMP response element-binding protein (CREB), which is phosphorylated by cAMP-dependent kinase via an increase in cAMP, and regulates gene transcription by binding to the cAMP response element (CRE) on target genes. We examined age-dependent alterations in the DNA-binding activity of CREB in rat brain regions, and the effects of rolipram, a cAMP-specific phosphodiesterase (PDE) inhibitor on the CRE-binding activity by electrophoretic mobility-shift assay (EMSA). A marked age-dependent decrease in the CRE-binding activity was shown in all brain regions examined, especially in the basal forebrain, the striatum and the hippocampus. Furthermore, CRE-binding activities in the basal forebrain of both young-adult and aged rats significantly increased 2 h after rolipram administration (1 mg/kg, i.p.), and the rolipram treatment recovered the decreased CRE-binding activity in the aged rats. The saturation experiment in EMSA also revealed that rolipram reversed the decrease in the maximum CRE-bindings in the basal forebrain with aging. Since the 5' upstream region of the rat choline acetyltransferase (ChAT) gene contains CRE, and ChAT-positive neurons in the basal forebrain project to the frontal cortex and the hippocampus, rolipram may exert its previously reported ameliorating effect on the age-related reductions of ChAT activities in the frontal cortex and the hippocampus by phosphorylating CREB in the basal forebrain with activation of cAMP-dependent protein kinase via inhibition of PDE.

Afferent Pathways↗

PubMed1996

Relationship between cholinergic dysfunction and discrimination learning disabilities in Wistar rats following chronic cerebral hypoperfusion.

The effects of chronic hypoperfusion of cerebral blood flow (CBF) on central cholinergic indices and intellectual functions were investigated in rats. Male Wistar rats, aged 9 weeks, were anesthetized with pentobarbital, and the bilateral common carotid arteries were permanently ligated. Cortical CBF in the hypoperfused rats was markedly decreased at 6 weeks after the operation. In the hypoperfused group, cholinergic indices were changed to consist two phases after the operation, before (acute) and after (chronic) 6 weeks after the operation. At 6 weeks, choline acetyltransferase activity was restored to the sham-operated level compared with the changes in the frontal cortex and thalamus + midbrain at 3 weeks. On the other band, the maximum number of muscarinic acetylcholine receptors was reduced in the frontal cortex, hippocampus and striatum at 6 weeks and thereafter remained at this low level. In discrimination learning task, the percentage of correct responses in the hypoperfused rats was generally reduced in contrast with that of the sham-operated rats, although the number of total responses were not changed. As a consequence, cholinergic dysfunctions correlate with discrimination learning disabilities in the hypoperfused rats. These findings suggest that the hypoperfused rat may be useful for the cerebrovascular type dementia model to clarify pathophysiology.

Analysis of Variance↗

PubMed1996

Long-term time course of regional changes in cholinergic indices following transient ischemia in the spontaneously hypertensive rat brain.

Using an animal model of forebrain ischemia in spontaneously hypertensive rats (SHR) by 3-h bilateral carotid occlusion, and various indices of the cerebral cholinergic system were assessed for periods up to 24 weeks. The lesions observed histologically in the hippocampus of SHR 2 weeks after ischemia were less severe than those in the frontal cortex. Marked elevation of acetylcholine concentration was transiently observed in the frontal cortex, hippocampus and thalamus + midbrain at 2 weeks, and in the striatum at 1-4 weeks after ischemia. Choline acetyltransferase activity remained unchanged in all regions throughout the experimental period except for a minimal decrease in the frontal cortex at 4 weeks. Choline esterase (ChE) activity was slightly decreased in the frontal cortex at 2-4 weeks after ischemia but recovered by 8 weeks. A decrease in the hippocampus was seen at 8 weeks. The B(max) for the M1-receptor was significantly reduced by 2 weeks in the frontal cortex and by 4 weeks in the hippocampus. Low B(max) values in both regions persisted through week 24. These delayed hippocampal changes in the ChE activity and M1-receptor in SHR were similar to those of the very much delayed changes in M1-receptor previously reported in the gerbil model for transient ischemia. In contrast, Wistar-Kyoto rats (WKY), used as normotensive controls, exhibited no histological or biochemical changes for up to 24 weeks. The difference between SHR and WKY may depend on the more severe cerebral blood flow depletion during carotid ligation in the former. The chronic state of SHR after the transient ischemia may be a useful pathophysiological model for human cerebral infarctions with hypertension.

Acetylcholine↗

PubMed1996

Preventive effects of bifemelane hydrochloride on decreased levels of muscarinic acetylcholine receptor and its mRNA in a rat model of chronic cerebral hypoperfusion.

Changes in muscarinic acetylcholine receptor (mACh-R) binding and muscarinic cholinergic m1 receptor (m1-R) mRNA levels were determined in a rat model of cerebral hypoperfusion in which hypoperfusion was induced by permanent bilateral occlusion of the common carotid arteries. After 6 weeks of hypoperfusion, mACh-R binding activity was significantly reduced in the frontal cortex (79.0 percent, P <0.01), striatum (74.2 percent, P < 0.01) and hippocampus (78.6 percent, P < 0.01), and the m1-R mRNA levels in the frontal cortex (86.6 percent, P < 0.05) and striatum (89.4 percent, P < 0.05) compared with sham-operated control. Repeated administration of bifemelane hydrochloride (15 mg/kg/day, p.o., once a day from the day of operation for 6 weeks) prevented the hypoperfusion-induced loss of mACh-R binding and m1-R mRNA levels above described. Since the central cholinergic systems play an important role in learning and memory, these findings suggest that bifemelane hydrochloride is useful to treat and/or prevent vascular dementia which is closely related to cerebral hypoperfusion.

Animals↗

PubMed1996

Relationship of substance P and gliosis in medulla oblongata in neonatal sudden infant death syndrome.

Substance P and glial fibrillary acidic protein (GFAP) immunohistochemistry was applied to the medulla of neonatal infants who died of sudden infant death syndrome (SIDS). A quantitative analysis of cells demonstrating immunoreactivity to GFAP and substance P in 15 neonatal SIDS cases revealed increased GFAP immunoreactivity in the reticular formation, the dorsal vagal nucleus, and the solitary nucleus and an increase in substance P immunoreactivity in the spinal trigeminal nucleus and the solitary nucleus as compared with that in age-matched controls. GFAP immunopositivity suggests astrogliosis which implies a pathologic insult to neurons in the area of astrogliosis. The failure of neurons in these sites to show enhanced substance P immunopositivity may indirectly indicate altered neurons. Further study of prenatal events may be of importance in clarifying the pathogenesis of neonatal SIDS.

Chi-Square Distribution↗

PubMed1996

Scavenging effects of dopamine agonists on nitric oxide radicals.

It has recently been considered that free radicals are closely involved in the pathogenesis of Parkinson's disease (PD), and the level of nitric oxide radical (.NO), one of the free radicals, is reported to increase in PD brain. In the present study, we established a direct detection system for .NO in an in vitro .NO-generating system using 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-N-methyl-1-propa namine as an .NO donor and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO) by electron spin resonance (ESR) spectrometry and examined the quenching effects of the dopamine agonists pergolide and bromocriptine on the amount of.NO generated. .NO appeared to be scavenged by pergolide and, to a lesser extent, by bromocriptine. In the competition assay, the 50% inhibitory concentration values for pergolide and bromocriptine were estimated to be approximately 23 and 200 microM, respectively. It was previously reported that in vivo treatment of pergolide and bromocriptine completely protected against the decrease in levels of striatal dopamine and its metabolites in the 6-hydroxydopamine-injected mouse. Considering these findings, pergolide and probably bromocriptine may also protect against dysfunction of dopaminergic neurons because of its multiple effects; not only does it stimulate the presynaptic autoreceptors, but it also directly scavenges .NO radicals and hence protects against .NO-related cytotoxicity. This ESR spectrometry method using carboxy-PTIO may be useful for screening other drugs that can quench .NO.

Benzoates↗

PubMed1996

Expression of mRNA encoding neurotrophic factors and its regulation in a hybrid neuronal cell line.

In a cultured hybrid neuronal cell line (BIM) which was produced between human neuroblastoma cells (IMR32) and thymidine auxotrophs (B3T) of rat nerve-like cells (B103), the mRNAs encoding ciliary neurotrophic factor (CNTF) and neurotrophins were detected by the polymerase chain reaction method. The conditioned medium of BIM cells enhanced choline acetyltransferase (ChAT) activity in septal neurons and survival of ciliary ganglion neurons. The mRNA expression of CNTF and neurotrophins in BIM cells was differently regulated by the stimulation with cAMP, FGF and retinoic acid. These data suggest multiple regulation and collaboration of neurotrophic factors.

Animals↗

PubMed1995

Age-related changes in composition of transcription factor, AP-1 complex in the rat brain.

We examined age-related changes in composition of transcription factor, activator protein-1 (AP-1) which binds to TPA responsive element (TRE) in the non-stimulated rat brain, using electrophoretic mobility-shift assay with immunodepletion/supershift assay. The total TRE-binding activity in the frontal cortex and the hippocampus of the aged rats markedly decreased to 66% and 43%, respectively, and TRE-bindings of AP-1 in both regions also decreased to 82% and 66%, respectively, with aging. Jun-Jun dimers accounted for approximately half of the total TRE-bindings and 80-90% of the AP-1 bindings, while there were fewer Fos-Jun dimers, in both examined regions of the non-stimulated adult. The proportion of active Fos-Jun heterodimers in the frontal cortex increased to up to half of the AP-1 bindings in the aged rats, indicating that cortical AP-1-related transcription may increase with aging even under the non-stimulated condition. In the hippocampus, inactive Jun-Jun homodimers became predominant in AP-1 with aging. This regional diversity of age-related changes in the composition of AP-1 in the brain may be related to changes or dysfunction in neuronal signal transduction in the aged.

Aging↗

PubMed1995

Neuropeptide levels in discrete brain regions in the iminodipropionitrile-induced persistent dyskinesia rat model.

To clarify the role of neuropeptides in dyskinesia induced by iminodipropionitrile (IDPN), the levels of five representative neuropeptides were examined in discrete regions of the rat brain 4 weeks after intraperitoneal injection of IDPN. The five neuropeptides examined were methionine-enkephalin (Met-Enk), substance P (SP) and somatostatin, which are closely related to extrapyramidal function, and thyrotropin-releasing hormone (TRH) and cholecystokinin octapeptide (CCK-8), which are closely related to the neural mechanism of the dopamine system. IDPN pretreatment significantly increased Met-Enk in the basal ganglia but not SP or somatostatin; however, all three neuropeptide levels were increased in the hindbrain. In IDPN-treated rats, TRH and CCK-8 levels were increased in the nucleus accumbens, and the frontal cortical CCK-8 level was extremely increased. These findings, together with previous reports, suggest that neuropeptides in the basal ganglia, hindbrain and cerebral cortex play important roles in the manifestation of dyskinetic symptoms.

Animals↗

PubMed1995

Effects of repeated injection of cyclosporin A on pentylenetetrazol-induced convulsion and cyclophilin mRNA levels in rat brain.

To investigate the relationship between the immune system and convulsions in an animal model, we examined the effects of repeated administration with the immunosuppressant cyclosporin A on pentylenetetrazol (PTZ)-induced convulsions and the changes in the mRNA expression of its binding protein cyclophilin in the rat brain. The consecutive administration of cyclosporin A (5 mg/kg, s.c., 14 days) significantly aggravated the severity of convulsions induced with PTZ 75 mg/kg, i.p. Furthermore, it down-regulated the levels of cyclophilin mRNA in several brain regions and inhibited the PTZ-induced increase of hippocampal cyclophilin mRNA. Compared with the group without PTZ pretreatment or the group treated with chronic vehicle administration after the PTZ-preinjection, chronic cyclosporin A administration after the initial injection of PTZ apparently aggravated convulsions after the second PTZ injection. Interestingly, the increase in hippocampal cyclophilin mRNA observed after a single PTZ injection was not found after the second PTZ injection in the group with PTZ pretreatment. Therefore, these findings suggest that cyclosporin A administered peripherally can affect the central nervous system, and that an immune response associated with the first convulsive episode plays a key role in severity during subsequent attacks.

Amino Acid Isomerases↗

PubMed1995

Cyclosporin A prevents ischemia-induced reduction of muscarinic acetylcholine receptors with suppression of microglial activation in gerbil hippocampus.

We previously reported the late onset reduction of muscarinic acetylcholine receptors (LORMAR) which begins 7 days after a 5-min period of experimentally induced forebrain ischemia in the gerbil hippocampus. This study demonstrated that post-ischemic administration of cyclosporin A (CsA) reduced LORMAR 10 days after 5 min of forebrain ischemia in the gerbil hippocampus, suggesting that immunosuppression by CsA may reduce damage to the cholinergic system after ischemia. Microglia positive for HLA-DR class II antigen which presented in the hippocampal CA1 area, the region most vulnerable to ischemia, were also reduced by CsA. CsA may suppress microglial activation especially with regard to the antigen-presenting function, and LORMAR may be attenuated by this modulation of microglial function.

Animals↗

PubMed1995

Effects of single cyclosporin A pretreatment on pentylenetetrazol-induced convulsion and on TRE-binding activity in the rat brain.

Using electrophoretic mobility-shift assay (EMSA), we examined changes in DNA-binding activities of transcriptional factor-activated protein-1 (AP-1), which is a Fos-Jun protein complex, onto its responsive element TRE in the hippocampus and amygdaloid nucleus of rats stimulated with pentylenetetrazol (PTZ) injection, and also investigated the effects of a single administration of the immunosuppressant cyclosporin A (CsA). In EMSA with nuclear extracts from the rat brain, the TRE-binding activity of AP-1 in the hippocampus and amygdaloid nucleus markedly increased 2 h after the PTZ injection (75 mg/kg, i.p.). These PTZ-induced increases of the TRE-binding protein in these regions were completely suppressed, by pretreatment with CsA (5 mg/kg, s.c.) 1 h before the PTZ injection. In addition, the administration of CsA significantly ameliorated PTZ-induced convulsion. This therapeutic effect of single CsA pretreatment may be based, in part, on the effects on the TRE-binding activity of AP-1 in the brain. Since single pretreatment of CsA in the present study had no effect on the PTZ-induced induction of c-fos mRNA, c-jun mRNA, Fos protein nor Jun protein, the inhibitory effects of single CsA administration on PTZ-induced TRE-binding activity in the brain may be related to the effects of CsA on AP-1 itself. These results suggest that an immune response via activation of transcriptional factor in the brain tissue is involved in the convulsion.

Amygdala↗

PubMed1995

Regional differences in late-onset iron deposition, ferritin, transferrin, astrocyte proliferation, and microglial activation after transient forebrain ischemia in rat brain.

With use of iron histochemistry and immunohistochemistry, regional changes in the appearance of iron, ferritin, transferrin, glial fibrillary acidic protein-positive astrocytes, and activated microglia were examined from 1 to 24 weeks after transient forebrain ischemia (four-vessel occlusion model) in rat brain. Expression of the C3bi receptor and the major histocompatibility complex class II antigen was used to identify microglia. Neuronal death was confirmed by hematoxylin-eosin staining only in pyramidal cells of the hippocampal CA1 region, which is known as the area most vulnerable to ischemia. Perls' reaction with 3,3'-diaminobenzidine intensification revealed iron deposits in the CA1 region after week 4, which gradually increased and formed clusters by week 24. Iron also deposited in layers III-V of the parietal cortex after week 8 and gradually built up as granular deposits in the cytoplasm of pyramidal cells in frontocortical layer V. An increasing astroglial reaction and the appearance of ferritin-immunopositive microglia paralleled the iron accumulation in the hippocampal CA1 region, indicating that iron deposition was probably produced in the process of gliosis. Neither neuronal death nor atrophy was found in the cerebral cortex. Nevertheless, an astroglial and ferritin-immunopositive microglial reaction became evident at week 8 in the parietal cortex. On the other hand, the granular iron deposition in the pyramidal neurons of frontocortical layer V was not accompanied by any glial reaction in the chronic stage of ischemia. Three different types of iron deposition in the chronic phase after transient forebrain ischemia were shown in this study. In view of the neuronal damage caused by iron-catalyzed free radical formation, the late-onset iron deposition may be relevant to the pathogenesis of the chronic brain dysfunction seen at a late stage after cerebral ischemia.

Animals↗

PubMed1995

M1 receptors in blood pressure-controlled ischemic spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: Hypertension is a primary aggravating factor in cerebral infarction. An acute rise in blood pressure (BP) at the time of a stroke may be harmful to the brain in a hypertensive subject because both cerebral vascular structure and function are altered by hypertension. Muscarinic M1 receptors are concerned with memory and learning. We aimed to evaluate the effect of controlling BP in hypertensive subjects at the time of stroke with a biochemical index of brain damage. METHODS: We gave a single dose of either the antihypertensive alpha-blocker phentolamine (2 mg/kg IP) or the calcium antagonist nicardipine (2 mg/kg IP) at the start of bilateral carotid artery occlusion to spontaneously hypertensive rats undergoing 3 hours of transient ischemia; we measured the time course of mean BP (MBP) and changes in the M1 receptor and its mRNA in three brain regions 2 weeks after the transient ischemia. RESULTS: Administration of phentolamine or nicardipine not only significantly suppressed the ischemia-induced rise of MBP, it actually decreased MBP during ischemia. In an ischemic control group, M1 receptor binding decreased in the frontal cortex and M1 receptor mRNA increased in the hippocampus 2 weeks after the ischemia. In contrast, both phentolamine- and nicardipine-treated ischemic rats showed no changes in either index compared with sham-operated controls. CONCLUSIONS: Controlling BP during an ischemic insult attenuates ischemia-induced damage of M1 receptors in the brain of spontaneously hypertensive rats. These results suggest that a rapid intensive increase of BP at the time of a stroke may exacerbate brain damage in hypertensive individuals.

Animals↗

PubMed1995

Cholecystokinin alterations and effects of levodopa administration in the MPTP-treated mouse brain.

To clarify the effects of levodopa administration on MPTP-induced alterations in neuropeptides, we examined the effects of repeated levodopa injections (200 mg/kg i.p.) for 2 weeks starting 4 weeks after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment (30 mg/kg i.p. twice/day for 5 days) on cholecystokinin-octapeptide (CCK-8), substance P (SP) and thyrotropin-releasing hormone (TRH) concentrations at 6 weeks after the MPTP treatment. In the striatum, CCK-8 significantly but slightly decreased in the MPTP-treated mice, coinciding with the MPTP-induced marked reduction of dopamine (DA). This considerable reduction of striatal CCK-8 may result from the selectivity of MPTP since the mesolimbic DA neurons coexisting with CCK-8 are intact with the MPTP treatment. Furthermore, this MPTP-induced decrease in CCK-8 persisted with repeated levodopa administration; therefore, the ineffectiveness of the levodopa treatment may have been be due to the degeneration of the nigrostriatal DA neurons. SP and TRH contents showed little or no change with levodopa treatment in the MPTP-treated mouse brain. The CCK-8 level decreased in the thalamus+midbrain, hippocampus and hindbrain of the MPTP+levodopa-treated group, although there were no changes in the MPTP-treated controls. These results suggest that DAergic neurons, except those in the nigrostriatum, strongly interact with the CCK neurons in these brain regions.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗