PubMed Health⌕ Search

Biomedical subjects

M Tohda

Publications and source records attributed to M Tohda.

At least 37 records · Page 2Linked to original sources
PubMed1996

Permanent occlusion of bilateral internal carotid arteries produces cognitive deficits in two learning behavior tasks.

We investigated the effects of permanent bilateral occlusion of the internal carotid arteries (2ICAO) on the learning and memory performances in rats to evaluate the permanent 2ICAO rats as a model for vascular dementia. The learning and memory performance was tested by a step-through passive avoidance task and an 8-arm radial maze task. Permanent 2ICAO decreased cerebral blood flows in the cortex and hippocampus by 46.3 +/- 3.3 and 21.1 +/- 4.6%, respectively, when measured at 15 min after occlusion. In the passive avoidance task, the 2ICAO rats showed no impairment of learning or of memory retention when tested 1 h after learning trial, while they showed a shorter latency than sham-operated rats when tested 24 h after learning trial. In the radial maze learning task, the non-pretrained 2ICAO rats showed impairment. The pretrained 2ICAO rats had no deficit in the radial maze retention task but they showed impaired performance when a 3-min delay was interposed in the task. These results suggest that permanent 2ICAO is a useful animal model for studying vascular dementia.

Animals↗
PubMed1995

Hyperactivity of central noradrenergic and CRF systems is involved in social isolation-induced decrease in pentobarbital sleep.

The modulatory effects of the central noradrenergic and CRF systems on the pentobarbital-induced hypnotic activity were investigated in socially isolated mice. Pentobarbital-induced sleeping time decreased depending on the duration of isolation period and reached the minimum at 4 weeks after the isolation. The intermale aggressive behavior tested in isolated mice increased along with the decrease of hypnotic activity of pentobarbital. I.c.v. injection of CRF (corticotropin-releasing factor; 0.6-2.1 nmol) and i.p. injection of yohimbine (0.5-1 mg/kg), an alpha 2-adrenoceptor antagonist, significantly decreased the pentobarbital-induced sleeping time in group-housed but not in socially isolated mice while alpha-helical CRF9-41 (alpha hCRF; 3.3-6.5 nmol i.c.v.), a CRF antagonist, and clonidine (12.5-100 micrograms/kg i.p. and 7.5-15 nmol i.c.v.), an alpha 2-adrenoceptor agonist, recovered the hypnotic activity of pentobarbital decreased by social isolation to the level in group-housed mice without changing the activity observed in group-housed animals. alpha hCRF (6.5 nmol i.c.v.) significantly abolished the yohimbine (1 mg/kg i.p.)-induced decrease in the hypnotic activity of pentobarbital in group-housed mice. Propranolol (50-100 nmol i.c.v. and 5-10 mg/kg i.p.), a beta-adrenoceptor antagonist, and prazosin (5-10 nmol i.c.v. and 250-500 micrograms/kg i.p.), an alpha 1-adrenergic antagonist, significantly and dose-dependently recovered the hypnotic activity of pentobarbital in socially isolated mice to the level in group-housed mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Agents↗
PubMed1995

Possible involvement of botulinum ADP-ribosyltransferase sensitive low molecular G-protein on 5-hydroxytryptamine (5-HT)-induced inositol phosphates formation in 5-HT2c cDNA transfected cells.

To clarify the involvement of botulinum ADP-ribosyltransferase sensitive low molecular G-proteins in 5-hydroxytryptamine (5-HT)-induced stimulation of phosphatidylinositol turnover, we examined the effects of 5-HT on inositol phosphates formation in COS 7 cells transfected with 5-HT2c receptor cDNA, but did not in non-transfected or vector-transfected cells. A typical 5-HT2c receptor antagonist mianserin (0.3-3 microM) inhibited the 5-HT-induced inositol phosphates formation. Treatment with botulinum toxin D preparation (20 micrograms/ml, 8 h) that contained botulinum C3 ADP-ribosyltransferase, blocked the 5-HT-induced inositol phosphate formation, although botulinum toxin A preparation that did not contain the enzyme did not have an influence. These results support our previous findings suggesting that low molecular weight G-proteins ADP-ribosylated by botulinum ADP-ribosyltransferase are involved in phospholipase C activity.

ADP Ribose Transferases↗
PubMed1995

Inhibitory effects of antidepressants on NMDA-induced currents in Xenopus oocytes injected with rat brain RNA.

Although it has been reported that desipramine affects ion-channel activity of NMDA receptor/ion-channel complexes, the binding sites remain unclear. To identify the binding site, influences of desipramine on NMDA-induced current were examined in Xenopus oocytes injected with rat brain RNA and compared with those of blockers, MK-801, Zn2+ and Mg2+. Application of 100 microM desipramine irreversibly inhibited NMDA-induced inward current as well as 1 microM MK-801. Mg2+ and Zn2+ showed a reversible inhibition. Pretreatment with Mg2+ or Zn2+ abolished the irreversible inhibition of desipramine. In contrast, the irreversible inhibition of desipramine was still observed after application of Mg2+ and Zn2+. These results suggest that Mg2+/Zn2+ and desipramine bind on different sites from each other and affect the cation permeability via different mechanisms. Regarding inhibitory effects of other antidepressant drugs, imipramine and setiptiline were found to markedly inhibit NMDA current, while maprotiline, amitriptyline and lofepramine slightly inhibited the current. Mianserin, a potent antagonist of 5-HT1c receptors, however, had no influence.

Animals↗
PubMed1995

Studies on the activation mechanisms of guanylyl cyclase by serotonin, probably through a novel subtype of serotonin receptor (5-HTGC).

Characterization of the serotonin-induced increase in guanosine 3',5'-cyclic monophosphate (cyclic GMP) was investigated and compared with that induced by atrial natriuretic peptide (ANP) in NG108-15 cells. The cyclic GMP formed by serotonin or ANP was transported in a similar manner to the extracellular medium, although the cyclic GMP formed by bradykinin was not. Serotonin and ANP raised cyclic GMP additively. Serotonin-induced cyclic GMP formation was completely inhibited by pretreatment with 100 nM 12-o-tetradecanoylphorbol 13-acetate (TPA), although that induced by ANP was only partially inhibited and the effects were blocked by pretreatment with staurosporin. In membrane preparations, ANP stimulated cyclic GMP formation in the presence of ATP, but serotonin did not. Serotonin-stimulated cyclic GMP formation was found to occur in neuroblastoma N18TG-2, but not in glioma C6Bu-1. These results suggest that a novel subtype of serotonin receptors (5-HTGC) which stimulates membrane-bound guanylyl cyclase, different from that stimulated by natriuretic peptide, may exist especially in neurons.

Animals↗
PubMed1995

Inhibitory effect of alkaloids extracted from the stem bark of Hunteria zeylanica on 5-lipoxygenase activity in vitro.

The effects of alkaloid extract from the stem bark of Hunteria zeylanica Gard. (H. zeylanica) on the activities of cyclooxygenase and 5-lipoxygenase in A23187-stimulated rat mast cells were investigated. H. zeylanica alkaloid extract (0.3-300 micrograms/ml) inhibited leukotriene C4 (LTC4) production by 5-lipoxygenase in a concentration-dependent manner and it blocked the production by 50% at 300 micrograms/ml. On the other hand, the extract had no effect on prostaglandin D2 (PGD2) production by cyclooxygenase. Neither (-)-eburnamine nor pleiomutinine, major constituents of H. zeylanica alkaloid extract, inhibited the production of PGD2 and LTC4 in the A23187-stimulated mast cells. The inhibition of arachidonic acid metabolism via 5-lipoxygenase pathway may be due to minute amounts of other components as stated in the Discussion.

Alkaloids↗
PubMed1995

A novel factor, TA20, involved in neuronal differentiation: cDNA cloning and expression.

Combined treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) and dibutyryl cyclic AMP (diBu-cAMP) induced significantly longer neurites than treatment with each alone in NG108-15 cells. We performed differential screening to identify genes expressed only by treatment with TPA plus diBu-cAMP but not by that with diBu-cAMP for 72 h alone in NG108-15 cells, and isolated a novel gene, TA20. Over-expression of the gene in NG108-15 and neuroblastoma N18TG-2 cells caused intense neurite elongation and suppressed cell growth. TA20 did not cause, however, any morphological changes in glioma C6Bu-1 cells. These results suggest that TA20 is a novel neuronal differentiation factor.

Animals↗
PubMed1994

Distinct induction of c-fos mRNA in NG108-15 cells transfected with muscarinic m1 and m3 receptors.

The differences of intracellular signalling mechanisms between muscarinic acetylcholine m1 and m3 receptors, which are coupled with polyphosphoinositide turnover, were examined by using m1- and m3-transfected NG108-15 cells. The c-fos mRNA was induced by 1 mM acetylcholine peak at 60 min in both m1 and m3 cells. The c-fos induction in m1 cells was inhibited by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM) and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), but was not inhibited by prolonged treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA), suggesting that intracellular Ca2+ and calmodulin are involved in the induction. The c-fos induction in m3 cells was inhibited by BAPTA-AM and prolonged treatment with TPA, but was not influenced by W-7, suggesting that protein kinase C is mainly involved in m3-induced c-fos expression. Acetylcholine induced an increase in inositol phosphates and a transient increase in the intracellular concentration of Ca2+ in both m1 and m3 cells. Sustained stimulation of acetylcholine strongly increased the inositol monophosphate content in m3 cells, but that of inositol trisphosphate and inositol diphosphate in m1 cells. These results suggest that the difference between m1- and m3-induced c-fos mRNA induction mechanisms is due to the difference in respective properties in polyphosphoinositide turnover.

Acetylcholine↗
PubMed1994

[3H]Rolipram binding and phosphodiesterase activity in neuroblastoma N18TG-2 and glioma C6Bu-1.

To clarify the functional significance of type IV phosphodiesterase (PDEIV) in neurons and glia cells [3H]rolipram binding and phosphodiesterase (PDE) activity were examined in cytosol and membrane fractions of neuroblastoma N18TG-2 and glioma C6Bu-1 cells. [3H]Rolipram binding was highly observed in cytosolic fractions of N18TG-2 compared to C6Bu-1. Binding was hardly observed in membrane fractions of both types of cells. Rolipram strongly (70%) inhibited the hydrolytic activity of cAMP in cytosolic fractions of N18TG-2. The activity in cytosol fractions of C6Bu-1 was slightly (20%) inhibited by rolipram. These results suggest that PDEIV plays important roles in neurons.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Inhibitory effects of botulinum toxin on 5-HT1C receptor-induced Cl- current in Xenopus oocytes.

Several low molecular weight G proteins have been identified, but their functional roles remain unclear. To clarify the involvement of low molecular weight G protein in receptor-stimulated turnover of polyphosphoinositide (PI) turnover, influences of botulinum toxins on serotonin (5-HT)-stimulated Cl- current mediated by PI turnover were investigated using Xenopus oocytes injected with rat brain mRNA. Treatment with botulinum toxin C, D or purified ADP-ribosyltransferase of botulinum toxin (botulinum toxin C3 enzyme) inhibited the 5-HT-induced Cl- current in oocytes, and ADP-ribosylated 23 kDa proteins. Both botulinum toxin C3 enzyme-induced inhibition of the current and ADP-ribosylation were suppressed by pretreatment with antibotulinum toxin C3 enzyme antibody. Botulinum toxin D treatment of oocytes was ineffective in the response of Cl- current induced by injection of 50 pmol inositol 1,4,5-trisphosphate and 50 pmol Ca2+. It is suggested that low molecular weight G proteins ADP-ribosylated by botulinum toxin C3 enzyme are involved in phospholipase C activation in Xenopus oocytes.

ADP Ribose Transferases↗
PubMed1993

Drugs acting on the intracellular signalling system.

Cellular response to extracellular messages is a basic process to maintain and to support cell life. Several signalling molecules important as sites of therapeutic drug action are involved in the response. Recent studies on life sciences have elucidated molecular properties of intracellular signalling factors and mechanisms of cascading. Novel drugs acting on signalling molecules and possessing new sites and mechanisms of action have been found. This article summarizes the properties (subtypes, structures, functions) of signalling factors (receptors, ion channels, GTP binding proteins, second messenger-generating enzymes, second messenger-metabolizing enzymes, second messengers protein kinases, protein phosphatases) and lists in Tables A-H drugs that act on signalling molecules and which should find clinical use.

Animals↗
PubMed1993

Increase in neurite formation and acetylcholine release by transfection of growth-associated protein-43 cDNA into NG108-15 cells.

We previously reported that growth-associated protein-43 (GAP-43) could be involved in the maintenance of elongated neurites and that a decline in protein kinase C activity may be involved in accumulation of GAP-43. In the present study, to clarify the functional significance of GAP-43 for neurite maintenance and acetylcholine (ACh) release, we prepared NG-G11 cells by transfection of GAP-43 cDNA into NG108-15 cells. NG-G11 cells expressed GAP-43 mRNA at levels approximately twice that in nontransfected or vector-transfected cells under control conditions and after treatment with dibutyryl cyclic AMP (diBu-cAMP) or 12-O-tetradecanoylphorbol 13-acetate (TPA) plus diBu-cAMP. Neurite outgrowth after addition of diBu-cAMP was greater in NG-G11 than in control cells. In NG-G11 cells, neurites elongated by treatment with diBu-cAMP for 72 h were maintained after removal of the drug. Treatment with TPA plus diBu-cAMP for 24 h induced neurite outgrowth in NG-G11 cells, although control cells required 72 h. Depolarization by 50 mM KCl induced ACh release in both NG-G11 and control cells treated with diBu-cAMP or TPA/diBu-cAMP. Although removal of the drugs following diBu-cAMP treatment reversed ACh release to nontreated levels in control cells, a high-K(+)-induced level of ACh release remained in NG-G11 cells after removal of diBu-cAMP. ACh release induced by TPA plus diBu-cAMP for 24 h was further enhanced after removal of the drugs in NG-G11 cells, but it was not seen in control cells. These results suggest that levels of GAP-43 mRNA are correlated with neurite maintenance and the level of ACh release. Thus, GAP-43 may be involved in neuronal differentiation in NG108-15 cells.

Acetylcholine↗
PubMed1992

Selective potentiation of N-methyl-D-aspartate-induced current by protein kinase C in Xenopus oocytes injected with rat brain RNA.

Glutamate receptors and protein kinase C (PKC) may play significant roles in long-term potentiation in hippocampus. To clarify the regulatory involvement of PKC in the functions of glutamate receptors, we examined the effects of PKC activation on current response induced by the activation of each subtype of glutamate receptor in Xenopus oocytes injected with rat brain RNA. Treatment with the PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), potentiated N-methyl-D-aspartate (NMDA)-induced current by about 2.5-fold, although it did not affect kainate-induced current at all. Quisqualate-mediated oscillatory current was almost abolished by this treatment. The TPA-induced potentiation of NMDA current was suppressed by staurosporine, an inhibitor of protein kinases. Pretreatment with 4-O-methyl-TPA, an inactive phorbol ester, had no effect on NMDA current. Current response mediated by NMDA receptors would thus appear to be modulated by PKC.

Animals↗
PubMed1992

Involvement of growth-associated protein-43 with irreversible neurite outgrowth by dibutyryl cyclic AMP and phorbol ester in NG108-15 cells.

Simultaneous treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) and dibutyryl cyclic AMP (diBu-cAMP) for 72 h induced neurites in NG108-15 cells significantly longer than treatment with each alone. Treatment for 72 h with both drugs induced irreversible neurite extension and a decline in protein kinase C activity, although neurites extended by diBu-cAMP alone disappeared after the withdrawal of the drug. The expression of growth-associated protein-43 (GAP-43) mRNA was also observed by a combined application of TPA and diBu-cAMP. The increased level of GAP-43 mRNA induced by treatment with both drugs for 72 h was maintained at least 24 h after withdrawal of the drugs. In cells transfected with GAP-43 cDNA, neurites induced by treatment with diBu-cAMP alone for 72 h were maintained at least 48 h after removal of the drugs. These results suggest that GAP-43 could be involved in the maintenance of elongated neurites and that a decline in protein kinase C activity may be involved in the accumulation of GAP-43.

Animals↗
PubMed1992

Tryptophan inhibits the [3H]glutamate uptake into Xenopus oocytes injected with rat brain mRNA.

We characterized the glutamate (Glu) uptake in Xenopus oocytes injected with rat brain mRNA. The Glu uptake into oocytes was higher in mRNA-injected oocytes than in vehicle-injected ones. Na+ omission or addition of tryptophan inhibited the uptake in mRNA-injected oocytes, although it did not affect that in vehicle-injected oocytes. These results suggest that Glu transporters with a tryptophan sensitivity different from that of Glu transporters in native oocytes are expressed after injection of rat brain mRNA.

Amino Acid Transport System X-AG↗
PubMed1991

Biphasic effects of mianserin and desipramine on serotonin-evoked current and Cl- efflux in Xenopus oocytes.

Serotonin (5-HT, 1 microM) elicited two phases of Cl- inward current in Xenopus oocytes injected with rat brain mRNA: a transient current (T-current), which was generated rapidly (within 1 min), and a sustained current (S-current), which persisted for 10 min. Each type of 5-HT-evoked response was time-dependent after mRNA injection. The T-current was generated at 20-30 h and the S-current at 30-40 h. Although mianserin at 0.1 microM completely inhibited the T-current, 10 microM mianserin was required to suppress the S-current. 5-HT also caused Cl- efflux from oocytes preloaded with 36Cl-. Cl- efflux during 1 min, corresponding to the T-current, was inhibited by 0.1 microM mianserin. A higher concentration of mianserin (10 microM) was required to block the efflux for 10 min, corresponding to the S-current, as well as the current response. Desipramine selectively inhibited the T-current and Cl- efflux for 1 min. The mechanisms underlying the different sensitivity to mianserin of oocytes injected with rat brain mRNA are discussed.

Animals↗
PubMed1991

Inhibitory effects of KN-62, a specific inhibitor of Ca/calmodulin-dependent protein kinase II, on serotonin-evoked C1-current and 36-C1-efflux in Xenopus oocytes.

To clarify the details of the involvement of Ca(2+)-calmodulin in gating of C1-channels, effects of a novel calmodulin-dependent protein kinase II (CaMK II) inhibitor, KN-62, on C1-current and C1-efflux induced by serotonin (5-HT) were investigated in Xenopus oocyte injected with rat brain mRNA. 5-HT evoked inward current on voltage clamp condition at -60 mV in a concentration-dependent manner. The 5-HT (1 microM)-evoked current was blocked by preperfusion with 1 microM KN-62 also inhibited acetylcholine- and inositol 1,4,5-trisphosphate-evoked current. Furthermore, 5-HT enhanced Cl- efflux about 2.5-fold from the oocyte preinjected with 36Cl-, and the effects were inhibited by KN-62 as well. These results suggest that CaMK II is activated by Ca(2+)-calmodulin and opens Cl- channels to induce CL- efflux in Xenopus oocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗