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1.
Transplant Proc ; 49(1): 16-25, 2017.
Article in English | MEDLINE | ID: mdl-28104126

ABSTRACT

BACKGROUND: Kidneys from non-heart-beating donors are thought to be marginal, and careful evaluation is required. Mass analyzed data are limited, and each transplant surgeon must evaluate these organs on the basis of their own experience. METHODS: We analyzed the data of 589 kidneys used for kidney transplantation from 304 non-heart-beating donors from January 2002 through December 2013 at the Japan Organ Transplant Network West Japan Division. The age of the donors, cause of death, and total ischemic time of more than 24 hours were factors that influenced the graft survival of the organs. RESULTS: On the other hand, the final serum creatinine level before donation (maximum, 12.4 mg/dL), the presence and duration of anuria (maximum, 92 hours), and the presence of cannulation did not influence the graft survival rate. CONCLUSIONS: In multivariate analysis of Cox proportional hazards regression analysis, graft survival was significantly related to the age of the donor (over 70 years of age), cause of death (atherosclerotic disease), and total ischemic time of more than 24 hours.


Subject(s)
Donor Selection/methods , Graft Survival , Heart Arrest , Kidney Transplantation , Tissue Donors , Adult , Age Distribution , Age Factors , Cause of Death , Cold Ischemia , Creatinine/blood , Female , Humans , Japan , Kidney , Kidney Transplantation/methods , Kidney Transplantation/mortality , Male , Middle Aged , Proportional Hazards Models , Risk Factors , Survival Rate , Time Factors
2.
Blood Purif ; 32(1): 57-62, 2011.
Article in English | MEDLINE | ID: mdl-21346337

ABSTRACT

BACKGROUND/AIMS: Rapid removal of plasma amyloid-ß (Aß) by blood purification may serve as a peripheral Aß sink from the brain for Alzheimer's disease therapy. We investigated the reduction of plasma Aß during hemodialysis and cognitive states. METHODS: Aß concentrations and Mini-Mental State Examinations (MMSE) were investigated in 37 hemodialysis patients (68.9 ± 4.1 years). RESULTS: The dialyzers effectively removed Aß(1-40) and Aß(1-42), 63.9 ± 14.4 and 51.6 ± 17.0% at 4 h dialysis, resulting in the reduction of Aßs in whole-body circulation by 51.1 ± 8.9 and 32.7 ± 12.0%, respectively. Although the plasma Aßs before dialysis (750.8 ± 171.3 pg/ml for Aß(1-40)) were higher than those reported for Alzheimer's disease patients, the cognitive states of hemodialysis patients were relatively normal, especially of longer dialysis vintages. CONCLUSIONS: Dialyzers effectively reduced Aßs in whole-body circulation. Repeated rapid decrease of plasma Aßs might maintain cognitive state.


Subject(s)
Alzheimer Disease/blood , Alzheimer Disease/therapy , Amyloid beta-Peptides/blood , Brain/metabolism , Peptide Fragments/blood , Renal Dialysis/statistics & numerical data , Aged , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Alzheimer Disease/psychology , Amyloid beta-Peptides/isolation & purification , Brain/pathology , Brain/physiopathology , Cognition , Enzyme-Linked Immunosorbent Assay , Humans , Male , Middle Aged , Neuropsychological Tests , Peptide Fragments/isolation & purification
5.
Brain Res ; 916(1-2): 76-84, 2001 Oct 19.
Article in English | MEDLINE | ID: mdl-11597593

ABSTRACT

Extracts from dopamine (DA)-depleted striatal tissue (lesion extract) and from intact striatal tissue (intact extract) were prepared, and trophic activities in these extracts were evaluated using survival and neurite extension of DAergic neurons as indices. Levels of brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), glial cell-line derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) in extracts were measured using enzyme-linked immunosorbent assay (ELISA). The lesion extract exhibited a stronger trophic activity on survival and neurite extension of DAergic neurons than intact extract. In lesion extract, bFGF was slightly and GDNF was significantly increased, while BDNF and NT-3 were the same level in each extract. The peak increase of bFGF and GDNF was during 2 to 3 weeks after DA depletion. Trophic activity of extract was strongly attenuated after immunoprecipitation of GDNF and partly attenuated after immunoprecipitation of bFGF. In parallel immunohistological study, no significant variations were found for striatal microtubule-associated protein-2 (MAP-2)- nor OX-41-immunoreactive cells, while the number of strongly labeled glial fibrillary acidic protein (GFAP)-immunoreactive cells were increased in DA-depleted striatum, suggesting reactive gliosis. Data suggest that bFGF is a minor, while GDNF is a major component of trophic activity for DAergic neurons in DA-depleted striatum, and increased bFGF and GDNF levels may be mediated partly by reactive gliosis.


Subject(s)
Cell Survival/physiology , Dopamine/deficiency , Nerve Growth Factors , Nerve Tissue Proteins/metabolism , Neurites/drug effects , Neuroprotective Agents/metabolism , Parkinson Disease/metabolism , Substantia Nigra/drug effects , Animals , Astrocytes/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Extracts/chemistry , Cell Extracts/pharmacology , Cell Survival/drug effects , Cells, Cultured/cytology , Cells, Cultured/drug effects , Cells, Cultured/metabolism , Fibroblast Growth Factor 2/metabolism , Fibroblast Growth Factor 2/pharmacology , Glial Cell Line-Derived Neurotrophic Factor , Glial Fibrillary Acidic Protein/metabolism , Heparin , Immunohistochemistry , Microtubule-Associated Proteins/metabolism , Neostriatum/metabolism , Neostriatum/physiopathology , Nerve Tissue Proteins/pharmacology , Neurites/metabolism , Neurites/ultrastructure , Neuroprotective Agents/pharmacology , Neurotrophin 3/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/physiopathology , Rats , Rats, Wistar , Substantia Nigra/growth & development , Substantia Nigra/metabolism
6.
Neurosci Res ; 39(3): 269-80, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11248366

ABSTRACT

In brain slices from young (postnatal day (P) 10--15) rat somatosensory cortex, real-time neuronal intracellular Cl(-) concentration ([Cl(-)](i)) recordings were made by an optical technique measuring 6-methoxy-N-ethlquinolinium iodide (MEQ) fluorescence. Oxygen--glucose deprivation (in vitro model of ischemia) induced a long-lasting [Cl(-)](i) increase preceded by a rapid, transient [Cl(-)](i) decrease that could not be inhibited by blockers of Cl(-) pumps, Cl(-) channels, or Cl(-) antiporters, but was sensitive to cation-Cl(-) cotransporter inhibitors (bumetanide and furosemide). Use of low external Na(+) or high external K(+) revealed that the Na(+),K(+)-2Cl(-) cotransporter was inhibited by bumetanide and furosemide, whereas the K(+)-Cl(-) cotransporter was preferentially inhibited by furosemide under our experimental conditions. With a reduced inward driving force for Na(+) (reducing Na(+),K(+)-2Cl(-) cotransport), the transient [Cl(-)](i) decrease was only rarely induced by oxygen-glucose deprivation. In contrast, with a reduced outward driving force for K(+) (reducing K(+)-Cl(-) cotransport), the transient [Cl(-)](i) decrease still occurred. These results suggest that the transient [Cl(-)](i) decrease was primarily mediated by a rapid inhibition of the inwardly directed Na(+),K(+)-2Cl(-) cotransporter. Reverse transcriptase-polymerase chain reaction (RT-PCR) experiments suggested that the isoform involved is NKCC1. We hypothesize that the initial rapid Cl(-) efflux might effectively delay the irreversible Cl(-) influx that mediates neuronal injury.


Subject(s)
Carrier Proteins/metabolism , Chlorides/metabolism , Potassium/metabolism , Pyramidal Cells/metabolism , Sodium-Potassium-Chloride Symporters , Sodium/metabolism , Somatosensory Cortex/metabolism , Animals , Carrier Proteins/drug effects , Cell Hypoxia/physiology , Fluorescent Dyes/pharmacokinetics , Glucose/deficiency , Ion Transport/drug effects , Ion Transport/physiology , Pyramidal Cells/drug effects , Quinolinium Compounds/pharmacokinetics , RNA, Messenger/metabolism , Rats , Rats, Wistar , Somatosensory Cortex/drug effects
7.
Hypertens Res ; 24(1): 83-5, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11213034

ABSTRACT

We report the case of a young pregnant woman with bilateral renovascular hypertension due to renal microaneurysms from an unknown cause, who had a successful delivery. Pregnancy did not affect the disease activity even in the postpartum period. Her blood pressure was maintained within the normal range by administration of labetalol. Although the angiographic appearance of the symmetrical aneurysms in both renal artery beds from the interlobular to arcuate artery levels suggested polyarteritis nodosa of multiple microaneurysms in the bilateral interlobular arteries, the clinical features suggested other causes of renovascular hypertension, such as fibromuscular dysplasia and/or congenital microaneurysms. We were thus unable to reach a definitive diagnosis.


Subject(s)
Aneurysm/pathology , Hypertension, Renovascular/pathology , Pregnancy Complications, Cardiovascular/pathology , Renal Artery/pathology , Adrenergic beta-Antagonists/therapeutic use , Adult , Aneurysm/complications , Aneurysm/diagnostic imaging , Angiography , Female , Humans , Hypertension, Renovascular/complications , Hypertension, Renovascular/drug therapy , Labetalol/therapeutic use , Pregnancy , Radionuclide Imaging , Renal Artery/diagnostic imaging
8.
J Neurotrauma ; 17(3): 251-60, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10757330

ABSTRACT

The striatum, together with the hippocampus, is one of the most vulnerable regions in the brain. Recently, genetic abnormalities or mutations have been linked to various neurodegenerative diseases, that is, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), etc., but the processes from genetic abnormality to the final phenotypic expression are not well understood. Disturbances in energy metabolism especially in mitochondrial energy compromise could facilitate genetic abnormalities and enhance neuronal cell death. Here, we report that the striatum is the most vulnerable brain region to systemic intoxication with 3-nitropropionic acid (3-NPA), an inhibitor of succinate dehydrogenase inducing energy compromise. We hypothesize that the striatum-specific lesion by 3-NPA is due to cummulative insults characteristic to the striatum including glutamatergic excitotoxicity, dopaminergic toxicity, vulnerability of the lateral striatal artery and high activity in the glutamate-transporter. The former two are extravascular in origin while the latter two are intra-/perivascular. We also discuss the possibility that a high turnover rate in metabolism of nitric oxide (NO) might underlie the vulnerability of the lateral striatal artery. We posit that systemic intoxication with 3-NPA offers a good animal model to investigate the pathophysiology of neuronal/glial cell death, neurodegenerative disease, dysfunction of the blood-brain barrier (BBB), neuroimmune disorders, and stroke.


Subject(s)
Energy Metabolism/physiology , Mitochondria/metabolism , Neostriatum/metabolism , Animals , Antihypertensive Agents/pharmacology , Apoptosis/drug effects , Apoptosis/physiology , Cerebral Arteries/physiology , Cerebral Cortex/drug effects , Cerebral Cortex/physiology , Denervation , Dicarboxylic Acids/pharmacology , Dopamine/metabolism , Energy Metabolism/drug effects , Glutamic Acid/metabolism , Male , Mitochondria/drug effects , Motor Activity/drug effects , Neostriatum/drug effects , Neuroglia/drug effects , Neuroglia/metabolism , Nitro Compounds , Propionates/pharmacology , Pyrrolidines/pharmacology , Rats , Rats, Wistar
10.
Surg Today ; 29(3): 260-3, 1999.
Article in English | MEDLINE | ID: mdl-10192738

ABSTRACT

A case of double cancers of the lung and esophagus associated with a sarcoid-like reaction in their regional lymph nodes is reported. A 73-year-old man with hemosputum was found to have a mass in his right lower lung field on a chest X-ray. Based on a diagnosis of lung cancer, a right middle and lower lobectomy with a dissection of the lymph nodes was performed. Microscopically, a well developed granulomatous reaction was seen in the dissected mediastinal and hilar lymph nodes. Three years after the pulmonary resection, he was admitted to our hospital because of dysphagia. A diagnosis of lower esophageal cancer was made. A lower esophagectomy with a total gastrectomy was performed. A sarcoid-like reaction comprising epithelioid cells and giant cells was seen in the regional lymph nodes. No clinical findings indicative of systemic sarcoidosis were observed. This rare condition may therefore help to improve our overall understanding of the relationship between malignant neoplasms and sarcoid-like reactions in the regional lymph nodes.


Subject(s)
Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/pathology , Lung Neoplasms/pathology , Lymph Nodes/pathology , Neoplasms, Multiple Primary/pathology , Aged , Carcinoma, Squamous Cell/surgery , Esophageal Neoplasms/surgery , Esophagectomy , Gastrectomy , Granuloma/pathology , Humans , Lung Neoplasms/surgery , Lymphatic Metastasis , Male , Pneumonectomy , Sarcoidosis/pathology
11.
Neurosci Res ; 35(2): 101-12, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10616914

ABSTRACT

Astrocytes secreting a large amount of 3,4-dihydroxyphenylalanine (dopa) were generated by adenoviral transduction of the human tyrosine hydroxylase (TH) gene. After characterizing in vitro, the effect of transplantation of these astrocytes to the striatum of hemiparkinsonian model rats was investigated. Subconfluent cortical astrocytes were infected by replication-defect adenovirus type 5 carrying the human TH-1 gene or the LacZ reporter gene under the promoter of the glial fibrillary acidic protein (AdexGFAP-HTH-1, AdexGFAP-NL-LacZ). Dopa secretion was not evident at 3 days after the transduction of the HTH-1 gene but it increased from 7 days up to at least 4 months. The secretion was substrate (tyrosine)-dependent, and was enhanced by loading tetrahydrobioputerin (BH4) concentration-dependently. One-third of the hemiparkinsonian model rats, that were transplanted the HTH-1 gene-transduced astrocytes or introduced the direct injection of the viral vector to the striatum, showed a reduction of methamphetamine-induced rotations for at least 6 weeks. Apomorphine-induced rotation was decreased to the 50% level of the control's, but the reduction was obtained equally by the transplantation of HTH-1 gene-transduced or LacZ reporter gene-transduced astrocytes, or by the introduction of HTH-1 or LacZ gene carrying adenovirus. Treatment with FK506 for 3 weeks improved the late-phase apomorphine-induced rotations following the introduction of the HTH-1 gene carrying adenovirus. Histological examination revealed that, in animals that showed a reduction of methamphetamine-rotation, the TH positive astrocytes-like cells were distributed widely in the host striatum for at least 4 weeks. The number of TH positive astrocytes-like cells and their immunoreactivity decreased after 6 weeks when OX-41 positive microglias/macrophages were infiltrated. Data indicate that the adenoviral transduction of the human TH gene to astrocytes and its introduction to the striatum is a promising approach for the treatment of Parkinson's disease. However, the further technical improvements are required to optimize the adenoviral gene delivery, such as the control of viral toxicity and the regulation of the immune response.


Subject(s)
Adenoviridae/genetics , Astrocytes/transplantation , Dihydroxyphenylalanine/biosynthesis , Parkinson Disease/therapy , Tyrosine 3-Monooxygenase/biosynthesis , Animals , Animals, Newborn , Apomorphine , Astrocytes/cytology , Astrocytes/enzymology , Astrocytes/virology , Cells, Cultured , Corpus Striatum/enzymology , Corpus Striatum/pathology , Corpus Striatum/virology , Dihydroxyphenylalanine/genetics , Female , Genetic Vectors/genetics , Graft Rejection , Humans , Immunosuppressive Agents/pharmacology , Methamphetamine , Mice , Mice, Inbred ICR , Parkinson Disease/enzymology , Parkinson Disease/pathology , Postural Balance/drug effects , Rats , Rats, Wistar , Sensation Disorders/chemically induced , Sensation Disorders/prevention & control , Tacrolimus/pharmacology , Transfection , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/pharmacology , beta-Galactosidase/genetics , beta-Galactosidase/metabolism
12.
Neuroscience ; 87(2): 497-507, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9740408

ABSTRACT

The differential effects of 3-nitropropionic acid on cultured neurons and astrocytes (of cortical and striatal origin) were examined by studying intracellular Ca2+ changes using imaging techniques with fura-2. The neurons and astrocytes whose intracellular Ca2+ concentration was recorded were identified later by immunocytochemical staining for microtubule-associated protein 2 and glial fibrillary acidic protein, respectively. 3-Nitropropionic acid (1.7 mM) irreversibly increased intracellular Ca2+ in astrocytes (27%) and, to a significantly smaller extent, in neurons (10%). The latency to onset of the intracellular Ca2+ increase was longer in neurons (45 min) than in astrocytes (29 min). Thus, a differential susceptibility of astrocytes and neurons was observed. The 3-nitropropionic acid-induced astrocytic and neuronal Ca2+ accumulations were both due to influx of Ca2+, as the increases were absent in Ca2+-free medium. An inhibitor of the Na+-Ca2+ exchanger (2',4'-dichlorobenzamil), greatly reduced the intracellular Ca2+ increase in astrocytes, but not in neurons. This indicates that the intracellular Ca2+ increase in astrocytes is primarily mediated by a reverse operation of the Na+-Ca2+ exchange system, whereas in neurons it is mediated by a different mechanism. In addition, we noted that astrocytic cell death occurred in 9% of cells at 60 min or more after the start of a 40 min perfusion with 3-nitropropionic acid, while only 4% of neurons died. In astrocytes, cell death was preceded by blebbing of the cell membrane, and by a sustained increase in intracellular Ca2+ followed by an abrupt further elevation occurring just before cellular collapse. The present results indicate that astrocytes are more vulnerable than neurons to 3-nitropropionic acid-induced cellular Ca2+ overload and toxicity, and hence support the hypothesis that, in part, 3-nitropropionic acid-induced neurotoxicity could be secondary to astrocytic cell death caused by Ca2+ overload.


Subject(s)
Astrocytes/drug effects , Calcium Signaling/physiology , Calcium/toxicity , Neurons/drug effects , Neurotoxins/pharmacology , Propionates/pharmacology , Amiloride/analogs & derivatives , Amiloride/pharmacology , Animals , Astrocytes/metabolism , Calcium/metabolism , Calcium Signaling/drug effects , Cell Death/drug effects , Female , Immunohistochemistry , Neurons/metabolism , Nitro Compounds , Pregnancy , Rats , Rats, Wistar , Sodium-Calcium Exchanger/metabolism
13.
Am J Physiol ; 274(2): R398-405, 1998 02.
Article in English | MEDLINE | ID: mdl-9486297

ABSTRACT

Thermoregulatory mechanisms are influenced by the temperature of the postnatal environment. Animals reared in cool environments are more tolerant of cold as adults, whereas those reared in warm conditions are more tolerant of heat. Because diet-induced and thermoregulatory thermogenesis share common features, studies examined the impact of rearing temperature on weight gain and fat accumulation. Rats reared at 18 degrees C gained more weight and accumulated more fat in abdominal depots than animals reared at 30 degrees C when both were housed at a common temperature, responses that were exacerbated by ad libitum access to sucrose. Male rats reared at 30 degrees C were less affected by sucrose than 18 degrees C-reared males, whereas female rats reared at 18 or 30 degrees C were similarly susceptible. During exposure to 18 degrees C, fat accumulation in abdominal depots increased in males but decreased in females. These data suggest that early temperature exposure influences weight gain and fat accumulation in later life, a difference that is most apparent when animals are housed at a common temperature.


Subject(s)
Adipose Tissue/growth & development , Body Composition , Temperature , Weight Gain , Abdomen , Animals , Body Temperature Regulation , Dietary Sucrose/administration & dosage , Eating , Female , Male , Rats , Sex Characteristics
14.
J Neurophysiol ; 79(1): 430-8, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9425211

ABSTRACT

Slices of somatosensory cortex taken from immature rats on postnatal day (P)7-14 were labeled with fura-2. Intracellular Ca2+ concentration ([Ca2+]i) was monitored in identified pyramidal cells as the ratio of fluorescence intensities (RF340/F380) during oxygen-glucose deprivation. The RF340/F380 ([Ca2+]i) of individual pyramidal cells was monitored in each of the cortical layers II-VI simultaneously. Neurons in all neocortical layers exhibited significant increases in [Ca2+]i that varied with the duration of oxygen-glucose deprivation. Individual neurons responded to oxygen-glucose deprivation with abrupt increases in [Ca2+]i after various latencies. The ceiling level of the [Ca2+]i increase differed from cell to cell. Neurons in layer II/III showed significantly greater increases in [Ca2+]i than those in layers IV, V, or VI. Kynurenic acid, a nonselective glutamate receptor antagonist, and bicuculline, a selective gamma-aminobutyric acid (GABA)A receptor antagonist, suppressed the intracellular Ca2+ accumulation induced by oxygen-glucose deprivation in all neocortical layers examined. After kynurenic acid, but not after bicuculline, there was no longer a differential [Ca2+]i increases in layer II/III. Both 2-amino-5-phosphonopentanoic acid (AP5), a selective N-methyl-D-aspartate (NMDA) receptor antagonist, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist, strongly suppressed the intracellular Ca2+ accumulation induced by oxygen-glucose deprivation in all layers. The laminar difference in terms of the [Ca2+]i increases was abolished by AP5, but not by CNQX. These results indicate that layer II/III cells are the most prone to oxygen-glucose deprivation-induced intracellular Ca2+ accumulation, and that this is primarily mediated by NMDA receptors. Thus, layer II/III neurons would be more likely to suffer cellular Ca2+ overload and excitotoxicity during ischemia than layer IV-VI cells. Such a differential laminar vulnerability might play an important role in determining the pathological characteristics of the immature cortex and its sequelae later in life.


Subject(s)
Calcium/metabolism , Cell Hypoxia/physiology , Excitatory Amino Acid Antagonists/pharmacology , Neocortex/physiology , Pyramidal Cells/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Somatosensory Cortex/physiology , 2-Amino-5-phosphonovalerate/pharmacology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , Bicuculline/pharmacology , Fura-2 , GABA-A Receptor Antagonists , Glucose/metabolism , In Vitro Techniques , Kinetics , Kynurenic Acid/pharmacology , Neocortex/drug effects , Pyramidal Cells/drug effects , Rats , Rats, Wistar , Receptors, Glutamate/physiology , Somatosensory Cortex/drug effects
15.
J Neurophysiol ; 79(1): 439-46, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9425212

ABSTRACT

We have studied the effects of gamma-aminobutyric acid (GABA) and of reducing the Cl- gradient on the [Ca2+]i in pyramidal neurons of rat somatosensory cortex. The Cl- gradient was reduced either with furosemide or by oxygen-glucose deprivation. Immature slices taken at postnatal day (P)7-14 were labeled with fura-2, and [Ca2+]i was monitored in identified pyramidal cells in layer II/III as the ratio of fluorescence intensities (RF340/F380). The magnitude of the [Ca2+]i increases induced by oxygen-glucose deprivation was significantly reduced (by 44%) by bicuculline (10 microM), a GABAA receptor antagonist. Under normal conditions, GABA generally did not raise [Ca2+]i, although in some neurons a small and transient [Ca2+]i increase was observed. These transient [Ca2+]i increases were blocked by Ni2+ (1 mM), a blocker of voltage-dependent Ca2+ channels (VDCCs). Continuous perfusion with GABA did not cause a sustained elevation of [Ca2+]i but bicuculline caused [Ca2+]i oscillations. After inhibition of Cl- extrusion with furosemide (1.5 mM), GABA induced a large [Ca2+]i increase consisting of an initial peak followed by a sustained phase. Both the initial and the sustained phases were eliminated by bicuculline (10 microM). The initial but not the sustained phase was abolished by Ni2+. In the presence of Ni2+, the remaining sustained response was inhibited by the addition of 2-amino-5-phosphonopentanoic acid (AP5, 20 microM), a selective N-methyl-D-aspartate (NMDA) receptor antagonist. Thus the initial peak and the sustained phase of the GABA-evoked [Ca2+]i increase were mediated by Ca2+ influx through VDCCs and NMDA receptor channels, respectively, and both phases were initiated via the GABAA receptor. These results indicate that, in neocortical pyramidal neurons, a reduction in the Cl- gradient converts the GABAA receptor-mediated action from nothing or virtually nothing to a large and sustained accumulation of cellular Ca2+. This accumulation is the result of Ca2+ influx mainly through the NMDA receptor channel. Thus GABA, normally an inhibitory transmitter, may play an aggravating role in excitotoxicity if a shift in the Cl- equilibrium potential occurs, as reported previously, during cerebral ischemia.


Subject(s)
Bicuculline/pharmacology , Calcium/metabolism , Cell Hypoxia/physiology , Chlorides/metabolism , Furosemide/pharmacology , Pyramidal Cells/physiology , Receptors, GABA-A/physiology , Somatosensory Cortex/physiology , gamma-Aminobutyric Acid/pharmacology , 2-Amino-5-phosphonovalerate/pharmacology , Animals , Animals, Newborn , Excitatory Amino Acid Antagonists/pharmacology , Fura-2 , Glucose/metabolism , In Vitro Techniques , Kinetics , Models, Neurological , Nickel/pharmacology , Pyramidal Cells/drug effects , Rats , Rats, Wistar , Receptors, GABA-A/drug effects , Receptors, N-Methyl-D-Aspartate/physiology
16.
Neurosci Res ; 32(4): 363-71, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9950064

ABSTRACT

Simultaneous recording of changes in intracellular Cl- concentration ([Cl-]i) in individual neurons situated in different layers (e.g. II/III-VI) of neocortical slices was found to be feasible by means of optical fluorescence measurements using 6-methoxy-N-ethylquinolinium iodide (MEQ). Gamma-aminobutyric acid (GABA) caused a measurable increase in [Cl-]i in adult neocortical neurons, but a decrease in immature neurons. Developmental changes in the function of the Cl- pump and cation-Cl- co-transporters were evaluated using inhibitors such as furosemide (FURO), ethacrynic acid (ETA), and bumetanide (BMT). However, it was found that these inhibitors absorb and/or emit light of the wavelength that is used for the optical imaging of MEQ. In addition, quenching of MEQ fluorescence by Cl- and leakage of loaded MEQ was significantly enhanced at a higher temperature, which will limit experimentation at > 30 degrees C. Estimation of [Cl-]i in individual neurons in slices was made possible by calibrating intracellular MEQ fluorescence signals at known Cl- concentrations ([Cl-]) in the presence of tributyltin, a Cl(-)-OH- antiporter, nigericin, a K+-H+ antiporter, and KSCN. This enables comparison of [Cl-]i between neurons in different slices. Thus, optical imaging of [Cl-]i in brain slices can provide valuable spatial information about [Cl-]i dynamics and homeostasis, although it should be emphasized that the technique does have some limitations.


Subject(s)
Chloride Channels/metabolism , Neocortex/metabolism , Animals , Animals, Newborn , Chloride Channels/drug effects , Feasibility Studies , Fluorescent Dyes , Neocortex/drug effects , Neurotransmitter Agents/pharmacology , Quinolinium Compounds , Rats , Rats, Wistar , gamma-Aminobutyric Acid/pharmacology
17.
Hokkaido Igaku Zasshi ; 73(6): 557-69, 1998 Nov.
Article in Japanese | MEDLINE | ID: mdl-10036614

ABSTRACT

It is thought that the senescence accelerated mouse (SAM) strains are very useful for examination of the aging mechanism. In particular, SAMP8 is useful since this substrain shows age-related deterioration of learning ability. One of the most attractive hypotheses of aging is that aging is a result of long-term exposure to free radicals generated through the glucose metabolism, and it is possible that oxygen radicals might be involved in the aging mechanism of SAM. In the present study, to elucidate the relation between free radicals and aging acceleration in SAMP8, we examined the changes in food intake, body weight and spontaneous motor activity. Biochemical analyses of blood glucose, cholesterol, triglyceride, total protein and albumin in SAMP8 and R1 mice were also performed. In addition, the amounts of ATP, creatine phosphate (Cr-P) and lipid peroxide in the brains of SAMP8 and R1 mice were measured. As for SAMP8, an increase in food intake and a decrease in body weight and spontaneous motor activity were observed as compared with SAMR1 control mice. These results may indicate that energy metabolism is abnormal in SAMP8. The lipid peroxide level in the brain of SAMP8 at 3 months of age was significantly lower than that of the control mice. However, the ATP and Cr-P amounts in the SAMP8 brain were same as those in the control mice at the same age. These results suggest that generation of free radicals decreases due to lowered glucose metabolism and that the amount of ATP production in the brain of SAMP8 is lower than that of the control mice. In conclusion the aging of SAMP8 may result from a decrease of the glucose metabolism and of the utilization of ATP rather than from injury caused by free radicals induced through the glucose metabolism.


Subject(s)
Adenosine Triphosphate/metabolism , Aging/metabolism , Glucose/metabolism , Animals , Body Weight , Brain/metabolism , Disease Models, Animal , Eating/physiology , Female , Free Radicals/metabolism , Mice , Mice, Inbred Strains , Motor Activity/physiology
18.
Neurosci Res ; 28(3): 209-21, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9237269

ABSTRACT

To evaluate the possibility that dopamine (DA) denervation enhances the trophic activity in striatum, normal or DA-depleted striatal tissue extract (N- or L-extract, respectively) was obtained, and their trophic effects on PC12D cells were investigated from the viewpoints of differentiation using morphological and electrophysiological analyses. Treatment with N- or L-extract induced neurite outgrowth in a concentration-dependent manner, and induced the enlargement of cell size. These effects were stronger in L-extract than in N-extract. Cation currents were investigated in whole cell patch-clamp mode. Development of cation current started with delayed-rectifier type K+ current (IK) and transient type K+ current (IA), followed by Ca2+ current (ICa) and tetrodotoxin-sensitive Na+ current (INa). INa was expressed more frequently in L-extract treated cells than N-extract treated cells at D7-9. The larger IK amplitude in L-extract treatment at D7-9 seemed to be related to the expression of INa. Development of IA was similar at any stage for both treatments. ICa development started at D3-5 after treatments, and the amplitude and current density were similar in both treatments. ICa was strongly blocked by omega-conotoxin GVIA (3 microM), indicating that N-type channels were mainly expressed after treatments. The data suggests that L-extract has stronger effects to hasten the differentiation of PC12D cells than N-extract by promoting the neurite outgrowth, cell enlargement and expression of voltage-dependent cation channels, especially INa and IK.


Subject(s)
Dopamine/physiology , Neostriatum/physiology , Animals , Axons/drug effects , Axons/physiology , Calcium Channels/drug effects , Cell Size/drug effects , Denervation , Electrophysiology , Female , Fibroblast Growth Factor 2/pharmacology , Ion Channel Gating/drug effects , Neostriatum/ultrastructure , Nerve Growth Factors/pharmacology , Neurites/drug effects , Neurites/ultrastructure , PC12 Cells , Patch-Clamp Techniques , Potassium Channels/drug effects , Rats , Rats, Wistar , Sodium Channels/drug effects , Tissue Extracts/pharmacology
19.
Neurosci Res ; 27(4): 343-55, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9152047

ABSTRACT

Mechanisms underlying the selective vulnerability of the lateral striatal area to the toxic effects of 3-nitropropionic acid (3-NPA) were investigated in rats. A single exposure to 3-NPA (20 mg/kg, s.c.) induced no deficits in behavior and histology, but subsequent injection produced motor symptoms, catalepsy, lip smacking, abnormal gait, paddling, rolling, opisthotonos, tremor, recombence, somnolence and so on, in 30% of the animals within a few hours. Diffusion-weighted magnetic resonance imaging of the brains revealed an area of high signal intensity in the bilateral striata. By this stage (within a few hours), striatal astrocytes had become swollen and disintegrated. Extravasation of immunoglobulin G was detected, indicating blood-brain barrier (BBB) dysfunction. Electron microscopy revealed edema and disorganization of structures inside the astrocytic end-feet around the branches of the lateral striatal artery. Neurons were less vulnerable than astrocytes to the 3-NPA injury. Treatment of the rats with D2 receptor agonist prior to exposure to 3-NPA attenuated the behavioral abnormalities and histological damage whereas pretreatment with D2 antagonist exacerbated these changes. The concentrations of extracellular dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) were both increased in rats exposed to 3-NPA. In vitro imaging of astrocytes revealed a progressive increase in [Ca2+]i after superfusion with 3-NPA, and the 'ceiling' level was maintained even after extensive washing. DA superfusion also increased the astrocytic [Ca2+]i and this increase was reversible. Data indicate that 3-NPA-induced striatal damage was associated with astrocytic cell death and dysfunction of the BBB. Intracellular edema and extreme Ca2+ overload induced by the toxin were further aggravated by an increase in the level of DA activity. These factors acting either singly or in combination may trigger astrocyte destruction.


Subject(s)
Astrocytes/drug effects , Blood-Brain Barrier/drug effects , Dopamine/toxicity , Neostriatum/cytology , Neurotoxins/toxicity , Propionates/toxicity , Animals , Behavior, Animal/drug effects , Calcium/metabolism , Cell Death/drug effects , Dopamine/metabolism , Dopamine Antagonists/pharmacology , Image Processing, Computer-Assisted , Immunohistochemistry , Magnetic Resonance Imaging , Male , Microdialysis , Microscopy, Electron , Neostriatum/drug effects , Nitro Compounds , Rats , Rats, Wistar
20.
J Chem Neuroanat ; 10(3-4): 209-12, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8811425

ABSTRACT

Systemically administered 3-nitropropionic acid (3-NPA) that inhibits the mitochondrial oxidative phosphorylation induces selective lesions in the striatum. To investigate the nature of these selective lesions, we administered 3-NPA (20 mg/kg, s.c. daily for 2 or 3 days) to Wistar rats and investigated the behavioral disturbance, striatal lesions and their variations after modulating the activity of nitric oxide synthase (NOS). On the second or third day of 3-NPA administration, half the animals manifested behavioral disturbances (paddling, rolling, tremor, abnormal gait, and recumbence). A strong extravasation of immunoglobulin G (IgG) and a decrease in immunoreaction for glial fibrillary acidic protein (GFAP) were detected, and iNOS-like (iNOS-L) immunoreactive small cells appeared in the lateral and central striatum especially around the vessels. A week later, lesions lacking GFAP-immunoreaction were detected in the striatum in survived animals. Pretreatment with N-nitro-L-arginine methyl ester (L-NAME) along with each injection of 3-NPA did not improve the behavioral disturbances nor the survival rate, but attenuated the extravasation of IgG and iNOS-L immunoreaction. Pretreatment with aminoguanidine or FK506 improved the behavioral symptoms and survival rate. Extravasation of IgG and expression of iNOS-L immunoreactivity were attenuated, and the striatal lesion was reduced. Data indicate the involvement of NO in the high vulnerability of the striatum, and that iNOS, one of inflammatory markers, is induced following exposure to 3-NPA.


Subject(s)
Antihypertensive Agents/pharmacology , Neostriatum/drug effects , Nitric Oxide Synthase/metabolism , Propionates/pharmacology , Animals , Astrocytes/chemistry , Behavior, Animal/drug effects , Cell Death/drug effects , Dyspnea/chemically induced , Enzyme Inhibitors/pharmacology , Glial Fibrillary Acidic Protein/analysis , Guanidines/pharmacology , Immunohistochemistry , Immunosuppressive Agents/pharmacology , Injections, Subcutaneous , Male , NG-Nitroarginine Methyl Ester/pharmacology , Neostriatum/immunology , Neostriatum/metabolism , Neuritis/chemically induced , Neurotoxins/pharmacology , Nitric Oxide/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/immunology , Nitro Compounds , Rats , Rats, Wistar , Tacrolimus/pharmacology
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