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Biomedical subjects

A Akaike

Publications and source records attributed to A Akaike.

At least 109 records · Page 6Linked to original sources
PubMed1994

Prostaglandin E2 protects cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity.

The effects of prostaglandin (PG) E2 on glutamate-induced cytotoxicity were examined using primary cultures of rat cortical neurons. The cell viability was significantly reduced when cultures were briefly exposed to either glutamate or N-methyl-D-aspartate (NMDA) then incubated with normal medium for 1 h. Similar cytotoxicity was observed with the brief application of ionomycin, a calcium ionophore, and S-nitrosocysteine, a nitric oxide (NO)-generating agent. PGE2 at concentrations of 0.01-1 microM dose-dependently ameliorated the glutamate-induced cytotoxicity. PGE1, butaprost, an EP2 receptor agonist, and 8-bromo-cAMP were also effective in protecting cultures against glutamate cytotoxicity. By contrast, neither 17-phenyl-omega-trinor-PGE2, an EP1 receptor agonist, nor M&B 28767, an EP3 receptor agonist, affected glutamate-induced cytotoxicity. NMDA-induced cytotoxicity was ameliorated by PGE2, butaprost, MK-801, N-omega-nitro-L-arginine, a NO synthase inhibitor, and hemoglobin, which binds NO. These agents excluding MK-801 ameliorated the ionomycin-induced cytotoxicity. The cytotoxicity induced by S-nitrosocysteine was prevented only by hemoglobin but not by the other agents including PGE2. These findings indicate that PGE2 protects cultured cortical neurons against NMDA receptor-mediated glutamate neurotoxicity via EP2 receptors. EP2 receptor stimulation may suppress a step in NO formation triggered by Ca(2+)-influx through NMDA receptors.

Animals↗
PubMed1994

Dopamine-induced protection of striatal neurons against kainate receptor-mediated glutamate cytotoxicity in vitro.

The effects of dopamine on glutamate-induced cytotoxicity were examined using the primary cultures of rat striatal neurons. Cell viability was significantly reduced by exposure of cultures to glutamate or kainate for 24 h. In contrast, similar application of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) did not induce cytotoxicity. Kainate-induced cytotoxicity was significantly inhibited by kynurenate but not by MK-801. Dopamine at concentrations of 1-100 microM dose-dependently reduced kainate-induced cytotoxicity. Forskolin also significantly reduced kainate cytotoxicity. The neuroprotective effect of dopamine was antagonized by SCH 23390, a D1 receptor antagonist, but not by domperidone, a D2 receptor antagonist. Moreover, kainate-induced cytotoxicity was prevented by SKF 38393, a D1 receptor agonist, or forskolin but not by quinpirole, a D2 receptor agonist. The patch clamp study revealed that the same striatal neurons responded to both kainate and NMDA. During voltage clamp recording, neither kainate-induced currents nor NMDA-induced currents were affected by dopamine. Moreover, dopamine did not affect glutamate- or kainate-induced Ca2+ influx measured with fura-2. These findings indicate that dopamine prevents kainate receptor-mediated cytotoxicity without affecting the kainate receptor activities and intracellular Ca2+ movement. Dopamine-induced neuroprotection may be mediated by an increased intracellular cAMP formed following activation of D1 receptors.

Animals↗
PubMed1994

Nicotine-induced protection of cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity.

The effects of nicotine on glutamate-induced cytotoxicity were examined using primary cultures of rat cortical neurons. The cell viability was significantly reduced when cultures were briefly exposed to glutamate or N-methyl-D-aspartate (NMDA) then incubated with normal medium for 1 h. A 1-h exposure of the cultures to kainate or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) reduced cell viability. Incubating cultures with nicotine for 1-24 h protected cortical neurons against glutamate cytotoxicity. Maximum protection against glutamate cytotoxicity was induced with a 2-h nicotine incubation. Exposure to nicotine for up to 2 h did not affect cell viability by itself although cell viability was reduced in a time-dependent manner when the exposure exceeded 4 h. Neuroprotection by nicotine was dependent on both the concentration and incubation period. Nicotine reduced the NMDA cytotoxicity but did not attenuate that of kainate and AMPA. The neuroprotective effects of nicotine against glutamate cytotoxicity were antagonized by mecamylamine and hexamethonium but not by atropine. These results indicate that nicotinic receptor stimulation induces neuroprotection against glutamate cytotoxicity mediated by NMDA receptors.

Animals↗
PubMed1994

Mobilization of intracellular Ca2+ and stimulation of cyclic AMP production by kappa opioid receptors expressed in Xenopus oocytes.

The intracellular metabotropic pathway, following kappa opioid receptor activation, was investigated in the Xenopus oocyte translation system. When oocytes were injected with cRNA for kappa opioid receptor cDNA, U50488H rarely evoked phospholipase C-mediated, oscillatory Cl- current responses. However, after the oocytes were incubated with staurosporine, both the occurrence and the amplitude of U50488H-evoked responses were increased. The U50488H-evoked response was antagonized by naloxone and inhibited by pretreatment of the oocytes with pertussis toxin. When oocytes were coinjected with RNAs encoding kappa opioid receptor and cystic fibrosis transmembrane conductance regulator (CFTR), treatment of the oocytes with forskolin and 3-isobutyl-1-methylxanthine (IBMX) evoked a smooth-shaped Cl- current flowing through the CFTR channels. The forskolin/IBMX-evoked response was never inhibited but was greatly potentiated in the presence of U50488H, indicating stimulation of adenylyl cyclase by U50488H. This U50488H-induced potentiation of CFTR channel opening was antagonized by naloxone and inhibited by pretreatment with pertussis toxin. These results suggest that kappa opioid receptors mobilize intracellular Ca2+ and stimulate cyclic AMP production by coupling positively to both phospholipase C and adenylyl cyclase via pertussis toxin-sensitive GTP-binding proteins in the oocytes.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Protective effect of ginseng saponins against impaired brain growth in neonatal rats exposed to ethanol.

This study was performed to determine the active constituents of the root of Panax ginseng C. A. Mayer in the amelioration of ethanol-induced impediment of brain growth in the neonatal stage. To establish an animal model of the brain growth impediment caused by ethanol, ethanol (6 g/kg s.c.) was administered to rat pups on postnatal day 6, which corresponded to the third trimester of pregnancy for humans. Brain weight, especially cerebellar weight, was significantly reduced in the ethanol-exposed pups. In contrast, neither separation from dams nor pentobarbital treatment affected brain weight. A saponin fraction of ginseng extract prevented this ethanol-induced reduction of brain weight. Some ginseng saponins including ginsenosides Rg1, Rb2, Rd, Rf and Re effected stimulated a potent recovery of cerebellum growth in this animal model.

Animals↗
PubMed1994

[Glutamate neurotoxicity and neuroprotective factors].

Glutamate is acknowledged as an excitatory neurotransmitter in the vertebrate central nervous system (CNS). Glutamate is also postulated to play an important role in the pathogenesis of the neuronal cell loss that is associated with several neurological disease states in the CNS. Glutamate cytotoxicity in the cortical and retinal neurons in culture is mediated by nitric oxide (NO). As the excitatory action of glutamate is regulated by other neurotransmitters, the cytotoxic action of glutamate may be affected by other endogenous substances. We have used the term "neuroprotective factor" for endogenous substances having neuroprotective actions against glutamate cytotoxicity. We have previously found that cholecystokinin (CCK) prevented glutamate toxicity in the cortical neurons in culture. The evidence has suggested that CCKB-receptor stimulation causes suppression of a step in NO formation triggered by N-methyl-D-aspartate (NMDA) receptors. Nicotinic acetylcholine also protected cultured cortical neurons against NMDA receptor-mediated glutamate toxicity. In the cultured retinal neurons, dopamine prevented NMDA receptor-mediated glutamate cytotoxicity via D1-receptors. These substances may have a role to promote cell survival in the life-regulatory function of the CNS.

Acetylcholine↗
PubMed1994

Protective action of dopamine against glutamate neurotoxicity in the retina.

PURPOSE: The electrophysiologic study using patch-clamp techniques demonstrated that NMDA-induced currents had properties similar to those recorded in the brain. METHODS: Primary cultures obtained from the fetal rat retina (gestation days 16 to 19) were used for the experiment. Immunocytochemical and electrophysiologic studies were done to identify the cultured cells. The neurotoxic effects of glutamate or N-methyl-D-aspartate (NMDA) on the retinal cultures were quantitatively assessed using the trypan blue exclusion method. RESULTS: The immunocytochemical study revealed that the major component of the rat retinal cultures was neurons including amacrine cells. The electrophysiologic study using patch-clamp techniques demonstrated that exposure to NMDA-induced currents with properties characteristic of those recorded in the brain. Brief exposure of these neurons to glutamate or NMDA induced delayed cell death. Glutamate neurotoxicity was prevented by the application of dopamine and forskolin. The protective action of dopamine was antagonized by a D1 receptor antagonist (SCH 23390) but not by D2 receptor antagonists (domperidone and sulpiride). A D1 receptor agonist (SKF 38393) protected glutamate-induced neurotoxicity in a concentration-dependent manner, whereas a D2 receptor agonist (quinpirole) did not affect it. CONCLUSIONS: These findings demonstrate that dopamine protects retinal neuronal cells against NMDA receptor-mediated glutamate neurotoxicity via D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Protective effect of nerve growth factor against glutamate-induced neurotoxicity in cultured cortical neurons.

The effect of recombinant human nerve growth factor (hNGF) and mouse NGF on cultured rat cortical neurons was examined. The DNA fragment coding the human NGF gene was isolated and inserted downstream from the SV40 promoter in a plasmid containing the dihydrofolate reductase cDNA, and this plasmid was introduced into Chinese hamster ovary (CHO) cells to establish cells producing recombinant hNGF. The recombinant hNGF protein secreted by CHO cells was confirmed to be biologically active in an assay using PC12 cells. Brief exposure of cortical cells to glutamate followed by incubation with glutamate-free medium reduced cell viability by 60-70% when compared with the control culture. Simultaneous addition of recombinant hNGF or mouse NGF to rat cortical cultures with glutamate did not affect this reduction of cell viability. However, 24 h pretreatment of rat cortical cultures with recombinant hNGF or mouse NGF resulted in a significant reduction of glutamate-induced neuronal damage. Mouse NGF also protected cortical neurons against N-methyl-D-aspartate (NMDA)- and kainate-induced neuronal damage. These findings suggest that NGF can protect cortical neurons against glutamate-induced neurotoxicity.

Animals↗
PubMed1993

Brain-derived neurotrophic factor pretreatment exerts a partially protective effect against glutamate-induced neurotoxicity in cultured rat cortical neurons.

The effect of recombinant brain-derived neurotrophic factor (BDNF) on cultured rat cortical neurons was examined. Brief exposure of cortical neurons to glutamate followed by incubation with glutamate-free medium reduced cell viability by 60-70% when compared with the control value. Simultaneous addition of recombinant BDNF to rat cortical cultures with glutamate did not affect this reduction of cell viability. However, 24 h pretreatment of rat cortical cultures with recombinant BDNF resulted in a significant reduction of glutamate-induced neuronal damage. These findings suggest that BDNF can protect cortical neurons against glutamate-induced neurotoxicity.

Animals↗
PubMed1993

Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons.

The effects of methylcobalamin, a vitamin B12 analog, on glutamate-induced neurotoxicity were examined using cultured rat cortical neurons. Cell viability was markedly reduced by a brief exposure to glutamate followed by incubation with glutamate-free medium for 1 h. Glutamate cytotoxicity was prevented when the cultures were maintained in methylcobalamin-containing medium. Glutamate cytotoxicity was also prevented by chronic exposure to S-adenosylmethionine, which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and S-adenosylmethionine also inhibited the cytotoxicity induced by N-methyl-D-aspartate or sodium nitroprusside that releases nitric oxide. In cultures maintained in a standard medium, glutamate cytotoxicity was not affected by adding methylcobalamin to the glutamate-containing medium. In contrast, acute exposure to MK-801, a NMDA receptor antagonist, prevented glutamate cytotoxicity. These results indicate that chronic exposure to methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity.

Animals↗
PubMed1993

L-dopa induces Ca(2+)-dependent and tetrodotoxin-sensitive release of endogenous glutamate from rat striatal slices.

L-DOPA (10-1000 microM) concentration-dependently released glutamate (Glu) from superfused rat striatal slices. D-DOPA and dopamine (300 microM) produced no effects. The L-DOPA-induced release of Glu was not affected by 3-hydroxybenzylhydrazine (20 microM), an L-aromatic amino acid decarboxylase inhibitor. L-DOPA methyl ester (200 microM), a selective L-DOPA antagonist, antagonized the effect of L-DOPA in a competitive manner. Ca2+ deprivation and tetrodotoxin decreased L-DOPA (300 microM)-induced release of Glu. These findings indicate that L-DOPA induces a transmitter-like release of Glu via activation of a recognition site for itself.

Animals↗
PubMed1993

Effects of protein kinase C on the muscarinic excitation of rat adrenal chromaffin cells.

The role of protein kinase C (PKC) in the muscarinic excitation of chromaffin cells freshly isolated from rat adrenal medullae was examined by the patch-clamp recording method. Acetylcholine and McN-A-343, a M1-receptor agonist, depolarized the cell and induced action potentials. Phorbol 12,13-dibutyrate (PDBu), an activator of PKC, increased acetylcholine-induced firing concomitant with a persistent depolarization. Under voltage-clamp recording, both McN-A-343 and PDBu decreased the cesium-sensitive K+ current, which was induced by shifting the membrane potential between -140 mV and -40 mV. These results suggested that the stimulation of muscarinic M1-receptors by cholinergic drugs activated phospholipase C to degrade phosphoinositide, consequently producing diacylglycerol, and diacylglycerol activates PKC to induce excitation of adrenal chromaffin cells.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1993

Blockade of retinal NMDA receptors by sodium nitroprusside is probably due to nitric oxide formation.

Effects of a nitric oxide (NO)-producing agent, sodium nitroprusside, on N-methyl-D-aspartate (NMDA) receptor activation in the cultured retinal neurons of rats were examined. NMDA in a Mg(2+)-free medium evoked inward currents at the resting membrane potential. Inward currents were also evoked by kainate. Sodium nitroprusside markedly reduced the NMDA-induced currents without affecting those induced by kainate. These results suggest the possible existence of a negative feed back system of NO which serves to regulate the activation of NMDA receptors in retinal neurons.

Animals↗
PubMed1993

Ifenprodil prevents glutamate cytotoxicity via polyamine modulatory sites of N-methyl-D-aspartate receptors in cultured cortical neurons.

Neuroprotective effects of ifenprodil, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, against glutamate cytotoxicity were examined in cultured rat cortical neurons. The viability of the cultures was markedly reduced by a 10-min exposure to glutamate followed by incubation with glutamate-free medium for 60 min. Ifenprodil and its derivative SL 82.0715 dose-dependently prevented cell death induced by glutamate. The NMDA antagonists MK-801 and 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid also prevented glutamate cytotoxicity with a potency similar to that of ifenprodil. Ifenprodil as well as MK-801 prevented NMDA-induced cytotoxicity, but did not affect kainate-induced cytotoxicity. Glutamate cytotoxicity was inhibited by removing extracellular Ca++ during and immediately after glutamate exposure. Ifenprodil and MK-801 reduced NMDA-induced Ca++ influx measured with rhod-2. Either spermidine, a polyamine modulatory site agonist, or glycine, a strychnine-insensitive glycine site agonist, potentiated NMDA- and glutamate-induced cytotoxicity. The protective effects of ifenprodil against NMDA- and glutamate-induced cytotoxicity were significantly reduced by spermidine, but not by glycine. These findings indicate that ifenprodil protects cortical neurons against glutamate cytotoxicity by selective antagonism of the polyamine modulatory site of the NMDA receptor complex.

Animals↗
PubMed1992

Mechanisms of cholecystokinin-induced protection of cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity.

The protective effects of cholecystokinin (CCK) against glutamate-induced cytotoxicity were examined using cultured neurons obtained from the rat cerebral cortex. Cell viability was significantly reduced when the cultures were briefly exposed to glutamate or N-methyl-D-aspartate (NMDA) and then incubated with normal medium for 60 min. A 60-min exposure to kainate also reduced cell viability. CCK protected cortical neurons against glutamate-, NMDA- and kainate-induced cytotoxicity. Glutamate- and NMDA-induced cytotoxicity was also reduced by N omega-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor. However, CCK did not prevent the cytotoxic effects of sodium nitroprusside (SNP) which spontaneously releases NO. Moreover, CCK did not affect NMDA-induced Ca2+ influx measured with rhod-2, a fluorescent Ca2+ indicator. Therefore, release of a NO-like factor from the cerebral cortex was assayed using the thoracic artery in vitro. When the artery was incubated with minced cerebral tissues, glutamate elicited marked relaxation. SNP also elicited relaxation of the smooth muscle. CCK inhibited glutamate-induced relaxation but did not affect that induced by SNP. These results indicate that CCK prevents NMDA receptor-mediated cytotoxicity without reducing the Ca2+ influx. It is suggested that CCK inhibits NO-formation triggered by NMDA receptor activation.

Amino Acids↗
PubMed1992

Ionic mechanisms involved in muscarinic regulation of neuronal and paraneuronal activity.

The characteristics of neuronal and paraneuronal muscarinic inhibition and excitation were analyzed using rat caudate nucleus (CN) slices and isolated chromaffin cells obtained from the rat adrenal medulla. In CN neurons, either acetylcholine (ACh), carbachol, or muscarine inhibited orthodromically activated firing, while nicotine had no effect on neuronal activity. Muscarine decreased the amplitude of EPSPs without altering the resting membrane potential (RMP), input impedance and EPSP time courses. These results indicate that muscarinic receptors produce the presynaptic inhibition of synaptic transmission in the CN. In adrenal chromaffin cells, it was found that ACh, muscarine, and nicotine all increased extracellularly recorded firing. During voltage clamp recording at the RMP, ACh induced a transient inward current (fast response) followed by a long-lasting current (slow response). Muscarine induced the slow response, whereas nicotine induced the fast response. Muscarine reduced the inward K+ current produced by the application of a high K+ medium to cells. During patch clamp recording, muscarine decreased the opening rate of the single K+ channels. These results indicate that the muscarinic excitation of adrenal chromaffin cells was triggered by a reduction in the number of active K+ channels at the RMP.

Animals↗
PubMed1991

Cholecystokinin-induced protection of cultured cortical neurons against glutamate neurotoxicity.

The effects of cholecystokinin (CCK) on glutamate-induced neurotoxicity were examined using cultured rat cortical neurons. Brief exposure of glutamate followed by an incubation with normal solution for more than 60 min reduced cell viability by 60-70%, compared with control values. Glutamate-induced neurotoxicity was significantly inhibited by MK-801 and ketamine, which are non-competitive blockers of N-methyl-D-aspartate (NMDA) receptors. Octapeptide CCK-8S and CCK-related decapeptide ceruletide at concentrations of 10(-9)-10(-7) M dose-dependently reduced glutamate-induced neurotoxicity. A desulfated analog CCK-8NS, which acts selectively as an antagonist of CCKB receptors, also reduced glutamate neurotoxicity. The neuroprotective effects of CCK were antagonized by L-365260, a CCKB receptor antagonist, but not by L-364718, a CCKA receptor antagonist. These results suggest that CCK protects cortical neurons against NMDA receptor-mediated glutamate neurotoxicity via CCKB receptors.

Animals↗