[Protection of excitotoxicity].
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Animals↗
Biomedical subjects
S Kwak
Publications and source records attributed to S Kwak.
Selective degeneration of inhibitory interneurons in the rat spinal cord induced by intrathecal infusion of acromelic acid.
We investigated the characteristics of the neurotoxicity mediated by non-N-methyl-D-aspartic acid (NMDA)-type glutamate receptors in the spinal cord by infusing rats intrathecally with three specific agonists (acromelic acid A (ACRO), kainic acid and 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)). When ACRO was infused intrathecally continuously for 2 h, the rats developed dose-dependent flaccid paraplegia during the infusion, followed by pure motor, rigid-spastic, long-lasting paraparesis (ED50: 220 pmol/h). The paraparetic rats showed selective degeneration of interneurons in the spinal cord with about 50% loss of their contents of glycine and aspartic and glutamic acids. The alpha-motoneurons in the ventral horns were largely free from permanent damage. These changes were selectively ameliorated by concomitant administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist at non-NMDA receptors. Kainate induced long-lasting paraplegia with neuronal damage at doses about 40-times higher than those of ACRO that caused paraplegia. When examined 30 days after kainate infusion, the neurotransmitter markers had decreased markedly in the lumbar cords of the rats with long-lasting paraplegia. Intrathecal infusion of large doses of AMPA caused long-lasting flaccid paraplegia, which were accompanied by extensive necrosis in the caudal spinal cord. It seems that ACRO exerts its unique pharmacological actions by activating a subclass of non-NMDA receptors distinct from those activated by kainate and AMPA, and may become a useful tool for investigating the biological roles of glutamate receptors.
Animals↗
Increased Cu/Zn superoxide dismutase-like immunoreactivity in the swollen axons of rats intoxicated chronically with beta,beta'-iminodipropionitrile.
Demonstration of a genetic linkage between the Cu/Zn superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis (ALS) has aroused interest in the role of SOD1 in spinal motoneuronal death. We used chronically beta,beta'-iminodipropionitrile (IDPN)-intoxicated rats as a model of ALS and investigated SOD1 changes in the spinal cord by immunocytochemical and in situ hybridization techniques. Compared with control rats, SOD1-like immunoreactivity (SOD1-IR) increased in swollen axons of the proximal spinal roots, but not in motoneuronal and dorsal root ganglion neuronal cell bodies where SOD1 gene transcription did not increase. The present data indicate that treatment with IDPN induces accumulation of SOD1 in the swollen axons by blocking slow axonal flow, suggesting the possibility that increased SOD1-IR in ALS is induced by axonal flow blockade.
Amyotrophic Lateral Sclerosis↗
Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson disease: a light and electron microscopic immunocytochemical study.
Copper-zinc superoxide dismutase (SOD1)-like immunoreactivity has been demonstrated in Lewy body-like inclusions (LIs) in brain tissues from patients with familial and sporadic amyotrophic lateral sclerosis. Using immunocytochemistry, we studied Lewy bodies (LBs), the original inclusions from which the term LI was derived, in five patients with Parkinson disease (PD). Surprisingly, many LBs were immunostained by an antibody against SOD1. There were two types of staining pattern: a diffuse pattern, and a peripheral pattern with an unstained core. An immunoelectron microscopic study demonstrated that the immunoreactive products were restricted to the fibrillary profiles, sparing the unstructured core. Our results showed that SOD1-like immunoreactivity occurred frequently in LBs and LIs, suggesting that a common cytopathological process is responsible for the formation of LB-type neuronal intracytoplasmic inclusions. Our results also suggest that SOD1 plays a role in the neurodegeneration associated with PD.
Aged↗
Superficial temporal artery--middle cerebral artery anastomosis for acute cerebral ischemia: the effect of small augmentation of blood flow.
In order to evaluate the effectiveness of acute cerebral revascularisation, we conducted a review of 70 patients with acute arterial occlusion or severe stenosis. Of these, 35 underwent emergency superficial temporal artery--middle cerebral artery (STA-MCA) anastomosis (surgical group) and the other 35 were treated conservatively (non-surgical group) at different times. Statistical analysis indicated that the two groups were homogeneous for the prognostic indicators. Seven days after admission, neurological symptoms and signs improved in 43% of patients in the surgical group and in 29% of the non-surgical group, however, this difference was not significant. The ratios of independent life at 3 months were 51% and 31%, respectively (not significant). Subgroup analyses indicated that final outcomes for patients with mild to moderate paresis on admission were significantly better in the surgical group than in the non-surgical group (94% vs. 53%, p < 0.01). The ratios of haemorrhagic infarction, neurological worsening, and mortality were comparable between the two groups. Time of ischaemia is a less important factor in the criteria for surgical selection. Acute revascularisation in selected patients does improve a natural course and could be a therapeutic option for acute cerebral ischaemia.
Adult↗
Acute and late neurotoxicity in the rat spinal cord in vivo induced by glutamate receptor agonists.
We investigated glutamate receptor-mediated neurotoxicity in vivo by means of infusing three specific agonists for non-NMDA receptors (acromelic acid A (ACRO), kainic acid and 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)) into the adult rat spinal subarachnoid space. ACRO induced long-lasting pure motor, rigid-spastic paraparesis in a dose-dependent manner (EC50: 220 pmol/h) that was accompanied by selective degeneration of spinal interneurons; leaving large anterior horn cells intact. Kainate and AMPA induced paraplegia but with relatively non-selective neuronal damage when given in doses more than 40-fold larger than those required for ACRO. When AMPA (> 100 nmol/h) was infused continuously using a mini-osmotic pump for more than 2 days, rats displayed progressive changes in motor behavior due to extensive damage in the caudal spinal cord where small neurons in the dorsal horns were the most vulnerable. Co-administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) specifically prevented neurotoxicity, suggesting a non-NMDA receptor-mediated mechanism. These results indicate that the non-NMDA receptor is heterogeneous, mediating neuronal damage with different selectivity. It is also suggested that chronic activation of glutamate receptors is capable of inducing slowly progressive neuronal death, which suggests relevance to the pathogenesis of ALS.
Animals↗
Substance P is a possible neurotransmitter in the rat spinothalamic tract.
In order to shed some light on the neurotransmitters in the spinothalamic tract (STT), we examined, biochemically and immunohistochemically, the contents of various neurotransmitter candidates in the terminal field of the STT after cervical hemi-chordotomy (HC) and dorsal quadrant-chordotomy (dQC) in the rat. Substance P (SP), calcitonin gene-related peptide (CGRP), enkephalin, neuropeptide Y, neurotensin, oxytocin and dynorphin A were analyzed immunohistochemically. The contents of neuropeptides (SP, CGRP and cholecystokinin octapeptide) were measured by radioimmunoassay and those of amino acids (aspartic acid, glutamic acid, gamma-aminobutyric acid (GABA) and glycine) and noradrenaline were determined using high-performance liquid chromatography. Cervical hemi-chordotomy, but not dQC, caused significant decreases of the SP-like immunoreactivity in and SP content of the ventral thalamus on the ipsilateral side, compared with that on the contralateral side and of rats subjected to sham-operation. However, neither HC nor dQC resulted in any changes in the ventral thalamic contents of other putative neurotransmitters examined. These results suggest that, in rats, the STT contains SP and that SP-positive fibers run in the ventral half of the ascending spinal tract at the cervical level.
Amino Acids↗
Percutaneous balloon catheter dilatation of benign ureteral strictures: effect of multiple dilatation procedures on long-term patency.
OBJECTIVE: The purpose of this study was to evaluate the long-term efficacy of multiple percutaneous balloon dilatations of benign ureteral strictures. Percutaneous dilatation of ureteral strictures with a balloon catheter was done as an alternative to open surgical repair. MATERIAL AND METHODS: Twenty-eight benign ureteral strictures (in 23 patients) were dilated. These included 21 postoperative strictures, 18 of which were at ureteroenteric anastomosis, three postradiation strictures, and four strictures of unknown origin. If the stenosis persisted, dilatation was repeated (maximum of four dilatations at 1-month intervals). Patients were reevaluated with sonography at 1-month intervals after stent removal. RESULTS: The procedure was considered a technical success if there was no radiographic evidence of a stricture or if hydronephrosis improved on the sonographic examination. Clinical success was determined by stable or improved renal function. All dilatations were technically successful. Fifteen (54%) of the 28 ureters remained patent 1 month after the final dilatation and removal of the stent. Of these 15, 12 were patent 2 months after stent removal, and only five were free of stenosis at the 9-month follow-up, making overall success 18%. All five of these ureters were in the subgroup of patients with ureteroenteric strictures. CONCLUSION: Balloon dilatation of ureteral strictures is technically successful; however, long-term results are poor. Multiple dilatations are of no benefit in maintaining ureteral patency.
Adolescent↗
Age-related multifactorial causes of neurological deterioration after early surgery for aneurysmal subarachnoid hemorrhage.
The factors contributing to neurological deterioration after early surgery for aneurysmal subarachnoid hemorrhage (SAH) were investigated. One hundred forty-two patients who underwent surgery within 3 days after SAH and recovered consciousness were divided into three age groups: 49 years of age or younger (Group A), 50 to 64 years old (Group B), and 65 years of age or older (Group C). Among these, 40 patients (28%) overall showed neurological deterioration; these cases were analyzed in detail. Although the highest incidence of deterioration was noted in patients in Group C (42%), angiographic vasospasm, quantified by measuring the change in the ratio of the diameters of the intracranial arteries to the extracranial internal carotid artery, was negatively correlated with age. In elderly patients, the severity of angiographic vasospasm was not related to the reversibility of symptoms or the outcome. At the time of aggravation, associated systemic complications such as cardiac decompensation, hypoxia, and electrolyte imbalance were noted in two (18%) of 11 patients in Group A, five (38%) of 13 in Group B, and eight (50%) of 16 in Group C, and these complications were significantly correlated with poor outcome in Group C. Although arterial narrowing is a leading cause of neurological deterioration after early aneurysmal surgery, the etiology is often multifactorial, especially in elderly patients, suggesting that hypervolemic therapy, which might provoke various complications, should be performed carefully under intensive monitoring.
Adult↗
The time course of recognition of novel melodies.
Seven experiments explored the time course of recognition of brief novel melodies. In a continuous-running-memory task, subjects recognized melodic transpositions following delays up to 2.0 min. The delays were either empty or filled with other melodies. Test items included exact transpositions (T), same-contour lures (SC) with altered pitch intervals, and different-contour lures (DC); DCs differed from Ts in the pattern of ups and downs of pitch. With this design, we assessed subjects' discrimination of detailed changes in pitch intervals (T/SC discrimination) as well as their discrimination of contour changes (T/DC). We used both artificial and "real" melodies. Artificial melodies differed in conformity to a musical key, being tonal or atonal. After empty delays, T/DC discrimination was superior to T/SC discrimination. Surprisingly, after filled delays, T/SC discrimination was superior to T/DC. When only filled delays were tested, T/SC discrimination did not decline over the longest delays. T/DC performance declined more than did T/SC performance across both empty and filled delays. Tonality was an important factor only for T/SC discrimination after filled delays. T/DC performance was better with rhythmically intact folk melodies than with artificial isochronous melodies. Although T/SC performance improved over filled delays, it did not overtake T/DC performance. These results suggest that (1) contour and pitch-interval information make different contributions to recognition, with contour dominating performance after brief empty delays and pitch intervals dominating after longer filled delays; (2) a coherent tonality facilitates the encoding of pitch-interval patterns of melodies; and (3) the rich melodic-rhythmic contours of real melodies facilitate T/DC discrimination. These results are discussed in terms of automatic and controlled processing of melodic information.
Adult↗
Late-onset selective neuronal damage in the rat spinal cord induced by continuous intrathecal administration of AMPA.
Neurotoxicity mediated by 1-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) was investigated by infusing this agent continuously for 7 days intrathecally to adult rats using a mini-osmotic pump. Behavioral changes were apparent only after the second postoperative day, when the rats displayed hindlimb palsy or incontinence of urine. The behavioral deficits became progressively severe and the rats usually displayed both hindlimb paraplegia and incontinence of urine by the 7th postoperative day. These progressive behavioral deficits were induced in a dose-dependent manner in the rats that received AMPA at a dose of > 100 pmol/h (100 microM at 1 microliter/h, 17 nmol in total dose). The severity of behavioral deficits was in parallel with that of neuropathological changes in the lumbosacral cords. In spinal segments rostrally adjacent to those with severe pathological changes, only the neurons in the dorsal horns (Rexed's laminae II-IV) were destroyed with intense gliosis. These changes were not induced by infusing AMPA for 1 day. The concomitant administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist for non-N-methyl-D-aspartate (NMDA) receptors, with AMPA, but not that of 2-amino-5-phosphonovalerate (APV), an antagonist for NMDA receptor, prevented induction of the behavioral and neuropathological changes. The findings of the present study suggest that this late-onset, selective neurotoxicity is mediated by AMPA-type glutamate receptors.
Animals↗
Agonists for metabotropic glutamate receptors in the rat delay recovery from halothane anesthesia.
Intraventricular injection of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), a potent agonist for metabotropic glutamate receptors, to rats retarded dose-dependently the recovery from halothane anesthesia at a dose range from 30 to 300 pmol/rat. At a dose of 300 pmol/rat, recovery was prolonged up to about 630% of the control. (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) also delayed recovery, but doses much higher than those of DCG-IV were required (about 300 and 1000 times, respectively). These results suggest that some agonists for a certain kind of metabotropic glutamate receptors have a central depressant action in the rat.
Adenylyl Cyclase Inhibitors↗
Chromosomal localization of four human VH1-like protein-tyrosine phosphatases.
Four human protein-tyrosine phosphatase (PTPase) genes of the VH1-like subclass were cloned by low-stringency screening of a genomic library. These genes were localized to their respective chromosomes by G-banding and fluorescence in situ hybridization. The genes were localized to unique regions of different chromosomes: CL100, a stress-induced PTPase, to 5q35; PAC-1, a mitogen-induced nuclear PTPase, to 2q11;hVH-3 to 10q25; and hVH-4 to 10q11.
Amino Acid Sequence↗
Ataxia-ameliorating effects of YM-14673, a potent analog of thyrotropin releasing hormone, in ataxic mutant mice.
The effects of YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]- L-histidyl-L-prolinamide dihydrate), a potent analog of thyrotropin releasing hormone (TRH), on the behavior of ataxic mutant mice (staggerer, realer, Purkinje cell degeneration and weaver mice) were investigated in comparison with those of TRH in an open-field apparatus. The fall index, the ratio of the number of falls to the distance moved, was defined as an index for ataxia. YM-14673 reduced the fall index in all types of ataxic mice examined and was more potent than TRH in reeler, staggerer and Purkinje cell degereration mice. YM-14673 may have a beneficial effect on patients with spinocerebellar degeneration.
Animals↗
Multicatalytic proteinase is associated with characteristic oval structures in cortical Lewy bodies: an immunocytochemical study with light and electron microscopy.
The ATP-ubiquitin-dependent proteolytic pathway (ubiquitin pathway) is believed to be involved in the formation of various neuronal inclusion bodies including Lewy bodies (LBs), a pathological hallmark of Parkinson disease and diffuse Lewy body disease (DLBD). Since multicatalytic proteinase (MCP) is involved in the ubiquitin pathway, an investigation of whether MCP is involved in neuronal inclusion bodies would provide a clue to the mechanism underlying the formation of neuronal inclusion bodies as well as to the pathogenesis of degenerative neurological disorders. In this study, we investigated detailed immunolocalization of MCP in LBs in DLBD brains using light and electron microscopy. We raised three different monoclonal antibodies against purified human MCP. Each of them recognized different sets of MCP subunits on Western blotting. Immunohistochemically, anti-MCP antibodies recognized all ubiquitin-positive cortical LBs in situ as well as those isolated from frozen DLBD cortices, suggesting that MCP is present in LBs as a whole molecule exhibiting protease activity. In electron microscopy, MCP immunoreactivity (MCP-IR) was exclusively localized on a characteristic oval structure with an approximate diameter of 100 nm. This structure was distributed throughout the LBs and was devoid of ubiquitin immunoreactivity. Treatment of isolated LBs with 2% SDS, but not with 0.5% Triton X-100, removed this structure from LBs in which fibrous materials predominated. Ubiquitin immunoreactivity was also decreased in isolated LBs treated with 2% SDS, suggesting that the fibrous structures in LBs were not ubiquitinated in situ. Thus, it is suggested that LBs are subjected to a proteolytic process in which MCP plays a role via processing of specific components of LBs.
Aged↗
[Toxicity of AMPA, an excitatory amino acid, to rat spinal cord neurons under intrathecal administration].
The neurotoxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), an agonist for glutamate receptors, was investigated by infusing adult rats with this agent intrathecally for either a short term (2 hours) or a long term (7 days) using a mechanical pump or a mini-osmotic pump, respectively. In the short-term infusion group, spasticity of the hindlimbs developed during infusion at 0.5 nmol/h or more of AMPA, tremors at 50 nmol/h or more, and flaccidity at 65 nmol/h or more. One day later, flaccid paralysis of the hindlimbs and urinary incontinence were observed in the rats that received 50 nmol/h (total dose: 100 nmol) or more of AMPA. These symptoms were thought to be permanent. On the other hand, in the long-term infusion group, behavioral changes were apparent only after second postoperative day, when rats displayed hindlimb palsy or urinary incontinence. Behavioral deficits became progressively severe, and rats usually displayed both hindlimb paraplegia and urinary incontinence by the 7th postoperative day. These progressive behavioral deficits were induced in a dose-dependent manner in rats that received AMPA at doses greater than 0.1 nmol/h. Gliosis with neuronal loss involving the partial (lumbar segments) and whole (sacral segments) gray matter of the spinal cord was induced in rats that received AMPA at doses greater than 50 nmol/h in the short-term infusion group and greater than 0.1 nmol/h in the long-term infusion group.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
trk immunoreactivity at neuronal dendrite and cell body.
Neurotrophins homologous to the nerve growth factor (NGF) bind the neurotrophic receptors of the trk gene family. Since the target tissues release these neurotrophic factors to the neuron, it has been believed that their trophic effects are mediated by the retrograde axonal transport. However it remains an open question whether the neurotrophins act through the autocrine or the paracrine mechanisms, since the protein-level expression of trk has not been studied so far. We have made polyclonal antibodies against the recombinant proteins of chicken trkC and rat trkB. These antibodies showed immunoreactivity at the dendrite and the cell body of neuron. This subcellular localization strongly suggests the autocrine or the paracrine mechanism of the neurotrophic factors. At the same time, our data provide basic knowledge to decide where to deliver these neurotrophic factors in the therapy of neurodegenerative diseases.
Amino Acid Sequence↗
New, potent kainate derivatives: comparison of their affinity for [3H]kainate and [3H]AMPA binding sites.
Newly synthesized kainate derivatives, 4-(2-hydroxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (HFPA and 4-(2-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA), were potent inhibitors of [3H]kainate binding to the rat spinal cord synaptic membranes, comparable in their effectiveness to kainate and domoate, whereas acromelic acid A (ACRO-A) and B (ACRO-B) was much less effective than kainate. ACRO-A, MFPA and HFPA all inhibited [3H]AMPA binding. These novel kainate analogues provide new pharmacological tools for analyzing the mechanisms underlying activation of kainate/AMPA receptors.
Amino Acids↗