Biomedical subjects

M Asanuma

Publications and source records attributed to M Asanuma.

At least 37 records · Page 2Linked to original sources

PubMed1998

Chronic cerebral hypoperfusion disrupts discriminative behavior in acquired-learning rats.

We describe an 'acquired-learning' rat model that was used to investigate the effects of chronic cerebral hypoperfusion on the maintenance of previously acquired discriminative behavior using the discriminating learning task. Male Wistar rats, aged 11 weeks, were trained to discriminate between lamp-on and lamp-off states under an operant-type learning procedure. After 30 sessions, we selected 'acquired-learning' rats with an average discrimination ratio higher than 75% recorded during the last three sessions. Chronic hypoperfusion was then induced by permanent ligation of both common carotid arteries under pentobarbital anesthesia. The rats were tested after surgery over a period of 12 weeks and brain tissue was analyzed for muscarinic acetylcholine receptor (mACh-R) binding. Cerebral hypoperfusion resulted in a significant reduction in the discrimination ratio throughout the observation period, compared with sham-operated rats. However, chronic hypoperfusion would not affect on motor function. The maximum number of mACh-R examined 12 weeks after the operation was significantly reduced in the frontal cortex and hippocampus in the hypoperfusion group. Impaired discrimination learning was associated with a reduction in mACh-R. Our findings suggest that chronic cerebral hypoperfusion in acquired-learning rats is a useful model for investigating the pathophysiology of dementia and that cortical and/or hippocampal cholinergic systems contributes to learning impairment, at least, in our learning task.

Analysis of Variance↗

PubMed1998

Methamphetamine-induced increase in striatal NF-kappaB DNA-binding activity is attenuated in superoxide dismutase transgenic mice.

Methamphetamine injection (x4 with 2-h interval) caused dose-dependent activation of striatal NF-kappaB activity. Striatal NF-kappaB binding increased significantly at 1-3 h after the last injection of methamphetamine (10 mg/kg, i.p. x4). This induction of striatal NF-kappaB activity was significantly attenuated in Cu, Zn-superoxide dismutase transgenic mice in a gene dosage-dependent fashion. The present results suggest that reactive oxygen species generated by methamphetamine injections can activate striatal NF-kappaB DNA-binding during this drug-induced toxic process.

Animals↗

PubMed1998

Protective effects of nicergoline against hydrogen peroxide toxicity in rat neuronal cell line.

We examined the effects of nicergoline on hydrogen peroxide (H2O2)-induced neurotoxicity in cultured rat neuronal cell line (B50). H2O2 induced death of B50 cells in a dose-dependent manner. The H2O2-induced neuronal cell death was significantly decreased in B50 cells maintained in the presence of nicergoline. We compared the levels of antioxidants (glutathione, catalase and superoxide dismutase) in nicergoline-treated and untreated B50 cells. Lipid peroxidation products (thiobarbituric acid reactive substances, TBARS) levels were also measured. Cultures treated with nicergoline had higher levels of catalase activity. TBARS level was significantly lower in nicergoline-treated cells than in untreated cells. Our results suggest that nicergoline may induce the up-regulation of intracellular antioxidant defences and protect the neuronal cells against oxidative stress.

Animals↗

PubMed1998

Superoxide radicals are mediators of the effects of methamphetamine on Zif268 (Egr-1, NGFI-A) in the brain: evidence from using CuZn superoxide dismutase transgenic mice.

Administration of methamphetamine (METH) to mammals is known to cause deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. Acute administration of METH causes activation of immediate-early genes (IEGs) such as c-fos and Zif268 mRNA in rodent brains. However, the exact mechanisms involved in these changes have not been completely clarified. As a first step towards assessing a possible role for free radicals in METH-induced changes in IEGs, we have used CuZn superoxide dismutase (SOD) transgenic (Tg) mice and have quantified the effects of METH on c-fos and Zif268 mRNAs by in situ hybridization techniques. Mice were injected with 25 mg/kg of METH and sacrificed at various time points afterwards. There were significant METH-induced increases in both c-fos and Zif268 mRNAs in the frontal cortex and striatum of both strains of animals. Interestingly, the increases in Zif268 were markedly attenuated in the CuZn SOD-Tg mice; the increases in c-fos were also attenuated, but to a significantly lesser degree. These results indicate that superoxide radicals might play an important role in the activation of Zif268 after METH administration. Because IEGs are modulators of gene expression, these results also raise the possibility that oxidative mechanisms might be important factors in neuroadaptive changes caused by stimulant drugs.

Animals↗

PubMed1998

Pergolide scavenges both hydroxyl and nitric oxide free radicals in vitro and inhibits lipid peroxidation in different regions of the rat brain.

The free radical hypothesis for the pathogenesis and/or progression of Parkinson's disease (PD) has gained wide acceptance in recent years. Although it is clear that dopamine (DA) agonists cannot completely replace levodopa therapy, they can be beneficial early in the course of PD by reducing the accumulation of DA which undergoes auto-oxidation and generates cytotoxic free radicals. In the present study we demonstrate that pergolide, a widely used DA agonist, has free radical scavenging and antioxidant activities. Using a direct detection system for nitric oxide radical (NO.) by electron spin resonance (ESR) spectrometry in an in vitro .NO-generating system, we examined the quenching effects of pergolide on the amount of NO. generated. Pergolide dose-dependently scavenged NO.. In the competition assay, the IC50 value for pergolide was estimated to be about 30 microM. Pergolide also dose-dependently attenuated the hydroxyl radical (.OH) signal in an in vitro FeSO4-H2O2 ESR system with an approximate IC50 value of 300 microM. Furthermore, this agent significantly inhibited phospholipid peroxidation of rat brain homogenates in in vitro experiments and after repeated administration (0.5 mg/kg/24 h, i.p. for 7 days). Our findings suggest a neuroprotective role for pergolide on dopaminergic neurons due to its free radical scavenging and antioxidant properties.

Animals↗

PubMed1998

Melatonin attenuates methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain.

Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. The pineal hormone, melatonin, has been shown to have neuroprotective effects against toxic quinones and oxidative stress produced by catecholamines. The present study was thus undertaken to assess possible protective effects of melatonin against METH-induced neurotoxic effects on the striatum and the nucleus accumbens by using autoradiographic techniques. Four dosages (5, 20, 40, 80 mg/kg) of melatonin were administered to mice intraperitoneally 30 minutes prior to the injections of METH (4 x 5 mg/kg) given at 2-hour intervals. The lowest doses of melatonin (5 mg/kg) had no significant effects against METH-induced toxicity. However, the higher doses (40 or 80 mg/kg) of melatonin significantly attenuated METH-induced toxic effects on both dopamine and serotonin systems. These data provide further evidence for a possible role of oxidative stress in METH-induced toxicity.

Animals↗

PubMed1998

Effects of lecithinized SOD on sequential change in SOD activity after cerebral contusion in rats.

To analyze the effect of lecithinized superoxide dismutase (SOD) on superoxide accumulation after traumatic brain injury (TBI) in rats, we studied the SOD activity by NBT-reducing method and the expression of Cu,Zn-SOD mRNA by Northern blot analysis. As determined by the specific gravity method, the administration of lecithinized SOD decreased brain edema in the periphery of the lesion at 6 hr after contusion. SOD activity, without lecithinized SOD administration, increased at the peripheral portion at 30 min after contusion, but decreased to normal level at 6 hr after TBI. By administration of lecithinized SOD, the increase of SOD activity was preserved until 6 hr after TBI. The expression of Cu,Zn-SOD mRNA increased in the core lesion, peripheral portion, and contralateral hemisphere until 6 hr after TBI, then was suppressed in all three areas by lecithinized SOD. These results support the hypothesis that superoxide anions may play an important role in the development of brain edema after TBI, and that leciyhinized SOD appears to prevent brain edema through a protective effect against superoxide anions.

Animals↗

PubMed1998

Effects of repeated cyclosporin A administration on iminodipropionitrile-induced dyskinesia and TRE-/CRE-binding activities in rat brain.

To clarify the involvement of immunophilin ligands in the pathogenesis and pathophysiology of dyskinesia, we examined the effects of repeated administration of cyclosporin A (CsA) on rat dyskinesia induced by repeated injection of iminodipropionitrile (IDPN 100 mg/kg, i.p., for 7 days). The addition of CsA treatment (5 mg/kg, s.c., 1 h before each IDPN injection) exacerbated IDPN-induced dyskinesia. In the group treated with both CsA and IDPN, the concentration of dopamine was significantly increased in the striatum and nucleus accumbens compared with the group treated with IDPN alone. Furthermore, in the electrophoretic mobility shift assay, the injection of CsA + IDPN increased binding activities of transcription factors to the TPA (12-O-tetradecanoylphorbol-13-acetate)-responsive element (TRE) and to the cAMP response element (CRE) in the striatum and nucleus accumbens, compared with those in rats treated with IDPN alone. The levels of D1-receptor mRNA in the striatum were significantly decreased in the IDPN-treated rats but were at the control level in the rats given CsA + IDPN. These findings suggest that the behavioral aggravation of the IDPN-induced dyskinesia caused by CsA administration may be due to the acceleration of the pre- and post-synaptic dopaminegic systems via activation of transcription factors which bind upstream to tyrosine hydroxylase and D1-receptor genes, and that the immunophilin binding agents such as CsA are involved in this aggravated dyskinesia.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice.

6-Hydroxydopamine is a neurotoxin that produces degeneration of the nigrostriatal dopaminergic pathway in rodents. Its toxicity is thought to involve the generation of superoxide anion secondary to its autoxidation. To examine the effects of the overexpression of Cu,Zn-superoxide dismutase activity on 6-hydroxydopamine-induced dopaminergic neuronal damage, we have measured the effects of 6-hydroxydopamine on striatal and nigral dopamine transporters and nigral tyrosine hydroxylase-immunoreactive neurons in Cu,Zn-superoxide dismutase transgenic mice. Intracerebroventricular injection of 6-hydroxydopamine (50 microg) in non-transgenic mice produced reductions in the size of striatal area and an enlargement of the cerebral ventricle on both sides of the brains of mice killed two weeks after the injection. In addition, 6-hydroxydopamine caused marked decreases in striatal and nigral [125I]RTI-121-labelled dopamine transporters not only on the injected side but also on the non-injected side of non-transgenic mice; this was associated with decreased cell number and size of tyrosine hydroxylase-immunoreactive dopamine neurons in the substantia nigra pars compacta on both sides in these mice. In contrast, superoxide dismutase transgenic mice were protected against these neurotoxic effects of 6-hydroxydopamine, with the homozygous transgenic mice showing almost complete protection. These results provide further support for a role of superoxide anion in the toxic effects of 6-hydroxydopamine. They also provide further evidence that reactive oxygen species may be the main determining factors in the neurodegenerative effects of catecholamines.

Animals↗

PubMed1998

Manda, a fermented natural food, suppresses lipid peroxidation in the senescent rat brain.

The level of lipid peroxidation reflects the degree of free radical-induced oxidative damage in brain tissue of the elderly. We examined the effects of Manda, a product prepared by yeast fermentation of several fruits and black sugar, on lipid peroxidation in the senescent rat brain as model of aging. Senescent rats were provided with a diet containing 50 g/100 g Manda for 8 days, supplemented on day 8 with an intragastric administration of Manda (6.0 g/kg body wt.) twice daily. The hydroxyl radical scavenging activity was generated by the FeSO4-H2O2 system and analyzed by electron spin resonance spectrometry. Using this method, the addition of Manda (2.88 mg/ml) to brain homogenates of adult rats (0.06 mg/ml) had an additive inhibitory effect on lipid peroxidation compared with control adult rats not treated with Manda. Incubation of brain homogenates with Manda for 2 h and 3 h, significantly inhibited the increase in lipid peroxides (malondialdehydes and 4-hydroxyalkenals) levels in aged rats due to auto-oxidation. In addition, oral administration of Manda significantly suppressed the age-related increase in lipid peroxidation in the hippocampus and striatum, although such change was not observed in the cerebral cortex. Although Manda contains trace level of alpha-tocopherol, the level of alpha-tocopherol in Manda did no correlate with its antioxidant effect. Our results suggest that Manda protects against age-dependent oxidative neuronal damage caused by oxidative stress and that this protective effect may be due, in part, to its scavenging activity against free radicals.

Aging↗

PubMed1997

Late-onset lipid peroxidation and neuronal cell death following transient forebrain ischemia in rat brain.

We previously reported that iron deposition was seen in the cerebral cortex and hippocampal CA1 area late after transient forebrain ischemia generated by four-vessel occlusion in rats. Iron deposition in the hippocampal CA1 area was coupled with delayed pyramidal cell death, while that in the cerebral cortex was not accompanied by neuronal death or atrophy until 6 months after ischemia. Iron is involved in the formation of free radicals, thus contributing to lipid peroxidation. To elucidate whether this iron has deleterious effects on neurons, we investigated changes in the levels of lipid peroxidation and resulting neuronal damage in this ischemia model. The level of malondialdehyde plus 4-hydroxynonenal as major decomposition products of lipid peroxidation, monitored for 6 months beginning just after 30 min of transient forebrain ischemia, was significantly increased in the cerebral cortex at 6 months, and in the striatum from 1 week to 6 months compared to that in sham-operated controls. Histological changes were also examined up to 1 year after reperfusion by immunohistochemical methods. In contrast with the hippocampus and striatum, the cerebral cortex did not develop severe neuronal cell death and atrophy until 1 year after the ischemic insult. We showed that lipid peroxidation took place not only immediately after ischemia-reperfusion but also late after the ischemic insult in regions where iron was deposited, and we showed that neuronal cell death in the cerebral cortex appeared extremely late, suggesting that iron-mediated lipid peroxidation may be of importance in some slowly progressive forms of neurodegeneration.

Age of Onset↗

PubMed1997

Different effects of oxidative stress on activation of transcription factors in primary cultured rat neuronal and glial cells.

We compared the cytotoxic effects of oxidative stress on neuronal and glial cells in vitro by examining the cell viability and changes in DNA-binding activities of transcription factors, AP-1 and CREB, using Trypan blue exclusion and electrophoretic mobility shift assay (EMSA), respectively. Neurotoxin 6-hydroxydopamine (6-OHDA) and H2O2 reduced the viability of both types of cells in time- and concentration-dependent manner. Both neurotoxins dose-dependently decreased DNA-binding activities in neuronal cells. The results of cell viability assay suggested that these changes may reflect the reduction in neuronal cell viability. In contrast, both reagents increased DNA-binding activities in glial cells, although they decreased cell numbers. These results suggest that the effects of oxidative stress on transcription factors is different in neuronal and glial cells. We also examined the effect of brain-derived neurotrophic factor (BDNF) on 6-OHDA- or H2O2-induced changes in DNA-binding activities. In neuronal cells, pre-treatment with BDNF prevented the decrease in DNA-binding activities induced by 6-OHDA or H2O2. In glial cells, the effect of BDNF on oxidative stress-induced changes in DNA-binding activities in the 6-OHDA-treated group were opposite to those in H2O2-treated group. Our results suggest that 6-OHDA and H2O2 may exert their cytotoxic mechanisms through different signal transduction systems.

Animals↗

PubMed1997

Thyrotropin releasing hormone prevents abnormalities of cortical acetylcholine and monoamines in mice following head injury.

We investigated the effects of thyrotropin releasing hormone (TRH) on changes in cortical concentrations of acetylcholine (ACh) and monoamines produced by concussion in mice. Concussion was induced by dropping a metal rod on the head, and the concentration of ACh, norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the cerebral cortex were measured by HPLC. We also examined the arousal effects of 0.5 mg/kg of TRH and 0.015 mg/kg of L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide (MK-771), a TRH analogue, injected intraperitoneally 10 min before concussion, on neurotransmitter concentrations. Mice were sacrificed at 25 (representing the righting reflex time) and 210 s (representing spontaneous movement time). At 25 s after concussion, the concentration of ACh was significantly higher than in control mice, but pretreatment with TRH and MK-771 prevented the rise in ACh. In contrast, head injury significantly reduced NE concentration. TRH and MK-771 also prevented the fall in NE. Concussion did not change cortical concentrations of DA and 5-HT. Our results suggest that disturbances of consciousness produced by concussion may be due to increased ACh and diminished NE in the cerebral cortex. Our findings also suggest that the arousal effects of TRH on concussion-induced disturbances of consciousness are due to normalization of cortical cholinergic and noradrenergic neuronal systems.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Genetic association between susceptibility to Parkinson's disease and alpha1-antichymotrypsin polymorphism.

The apolipoprotein E (ApoE*) gene is a major risk factor of developing Alzheimer's disease (AD) and the alpha1-antichymotrypsin (ACT) polymorphism is likely to modify susceptibility of the ApoE* gene for AD. Because pathogenesis of AD is partly similar to that in idiopathic Parkinson's disease (PD), we investigated the distribution of genotypes of the ApoE and the ACT in patients with PD. The number of individuals with two copies of the ACT-A allele (ACT-AA genotype) in patients with PD increased significantly compared to that in healthy controls (19.9% versus 8.3%, P < 0.02), and the ACT-A allele frequency in patients with PD was significantly higher than that in healthy controls (chi2 = 5.96, df = 1, P < 0.015). The odds ratio for developing PD in individuals with the ACT-AA genotype was 3.36 compared to individuals with two copies of another allele, the ACT-T allele (ACT-TT genotype). There was no association between ApoE genotypes and susceptibility to PD. These data suggest that the etiological basis of PD might be partly similar to that of AD and the ACT gene might be one of the susceptibility factors for PD.

Adult↗

PubMed1997

Ketoprofen, a non-steroidal anti-inflammatory drug prevents the late-onset reduction of muscarinic receptors in gerbil hippocampus after transient forebrain ischemia.

Ischemia-induced hippocampal late-onset reduction of muscarinic acetylcholine receptors (LORMAR) begins as late as 7 days after transient forebrain ischemia in the gerbil, but it precedes to completion of neuronal death in the CA1 region. We previously reported that post-ischemic administration of cyclosporin A prevented LORMAR with suppression of astroglial and microglial activation. In the present study, we showed that the chronic post-ischemic administration of a non-steroidal anti-inflammatory drug, ketoprofen (5 mg/kg, subcutaneously, twice a day for 14 days) significantly reduced LORMAR both 14 days and 21 days after 5-min transient ischemia. This protective effect of ketoprofen against LORMAR suggests that the non-steroidal anti-inflammatory drugs is clinically efficacious in the treatment of LORMAR, a sequela of cerebral ischemia.

Animals↗

PubMed1997

Direct evidence of high DNA binding activity of transcription factor AP-1 in rheumatoid arthritis synovium.

OBJECTIVE: To investigate the possible activation of transcription factor AP-1 in rheumatoid arthritis (RA) and its involvement in the pathogenesis of RA. METHODS: Synovial tissues and peripheral blood samples were obtained from 25 patients with RA and 5 patients with osteoarthritis (OA) during arthroplasty and synovectomy. The synovial tissue was digested with collagenase and separated into adherent and nonadherent cells by plastic-adhesion methods. Nuclear extracts obtained from each sample were examined by electrophoretic mobility shift assay to determine the DNA binding activity of AP-1. The expression of c-fos and c-jun messenger RNA (mRNA) was examined by in situ reverse transcription assay. RESULTS: A markedly high DNA binding activity of AP-1 was detected in the synovial tissues of RA patients, while virtually no activity or only a little activity was observed in OA patients. Following separation of adherent and nonadherent cells, the AP-1 activity was mainly detected in adherent cells, which consisted of synovial cells and macrophages. However, the activity was significantly higher in the mononuclear cells infiltrating into RA synovium than in RA peripheral blood mononuclear cells. The high DNA binding activity of AP-1 in RA correlated with the expression of c-fos and c-jun mRNA in situ. Furthermore, AP-1 binding activity also correlated with disease activity. CONCLUSION: In RA synovium, AP-1 DNA binding activity was constitutively up-regulated. These findings suggest that AP-1 may play an important role in the pathogenesis of RA, including synovial hyperplasia and abnormal immune responses.

Aged↗

PubMed1997

Effects of lecithinized SOD on contusion injury in rats.

To analyze the effect of lecithinized superoxide dismutase (SOD) on superoxide accumulation after traumatic injury, the expression of Cu,Zn-SOD mRNA was examined after contusion in rat using Northern blotting. As determined by specific gravity, lecithinized SOD decreased brain edema. The expression of Cu,Zn-SOD mRNA increased at the core, peripheral and contralateral hemisphere of injury. These increases were then suppressed by lecithinized SOD. Our results support the hypothesis that superoxide may play an important role in edema formation after contusion, and that lecithinized SOD appears to prevent brain edema through a protective effect against superoxide injury.

Animals↗

PubMed1997

Chronic administration of Oren-gedoku-to (TJ15) inhibits ischemia-induced changes in brain indoleamine metabolism and muscarinic receptor binding in the Mongolian gerbil.

We examined the effect of Oren-gedoku-to (TJ15), which is a traditional herbal Kampo prescription used as an anti-cerebral apoplexy agent on these changes. Chronic pre- and post-ischemia TJ15 oral administration almost completely abolished the ischemia-induced muscarinic receptor reduction and 5-hydroxyindoleacetic acid level increase. These results suggest that TJ15 prevents cholinergic synaptic dysfunction and serotonergic presynaptic hyperactivity induced by transient ischemia.

Acetylcholine↗