bluuebunny/crossref_metadata_2025_split huggingface dataset:
E‐p‐Methoxycinnamic acid protects cultured neuronal cells against neurotoxicity induced by glutamate
Authors: Kim So Ra , Sung Sang Hyun , Jang Young Pyo , Markelonis George J , Oh Tae H , Kim Young Choong 
Published: January 2005

We previously reported that four new phenylpropanoid glycosides and six known cinnamate derivatives isolated from roots of Scrophularia buergeriana Miquel (Scrophulariaceae) protected cultured cortical neurons from neurotoxicity induced by glutamate. Here, we have investigated the structure‐activity relationships in the phenylpropanoids using our primary culture system.
The α,β‐unsaturated ester moiety and the para‐methoxy group in the phenylpropanoids appeared to play a vital role in neuroprotective activity. This suggested that E‐p‐methoxycinnamic acid (E‐p‐MCA) might be a crucial component for their neuroprotective activity within the phenylpropanoid compounds. E‐p‐MCA significantly attenuated glutamate‐induced neurotoxicity when added prior to an excitotoxic glutamate challenge.
The neuroprotective activity of E‐p‐MCA appeared to be more effective in protecting neurons against neurotoxicity induced by NMDA than from that induced by kainic acid. E‐p‐MCA inhibited the binding of [propyl‐2,3‐3H]‐CGP39653 and [2‐3H]‐glycine to their respective binding sites on rat cortical membranes. However, even high concentrations of E‐p‐MCA failed to inhibit completely [propyl‐2,3‐3H]‐CGP39653 and [2‐3H]‐glycine binding.
Indeed, E‐p‐MCA diminished the calcium influx that routinely accompanies glutamate‐induced neurotoxicity, and inhibited the subsequent overproduction of nitric oxide and cellular peroxide in glutamate‐injured neurons.
Thus, our results suggest that E‐p‐MCA exerts significant protective effects against neurodegeneration induced by glutamate in primary cultures of cortical neurons by an action suggestive of partial glutamatergic antagonism.

British Journal of Pharmacology (2002) 135, 1281–1291; doi:10.1038/sj.bjp.0704576
Algogen‐specific pain processing in mouse spinal cord: differential involvement of voltage‐dependent Ca2+ channels in synaptic transmission
Authors: Kato Akemi , Ohkubo Tsuyako , Kitamura Kenji 
Published: January 2005

The effects of intrathecal (i.t.) administration of N‐, P/Q‐ or L‐type voltage‐dependent Ca2+‐channel blockers were tested in two pain models involving bradykinin (BK)‐ and α,β‐methylene ATP (α,βmeATP)‐induced activation of primary afferent neurons in mice.
The nociceptive response (amount of time spent licking and biting the hindpaw) induced by intraplantar injection of BK (500 pmol mouse−1) was significantly attenuated by both ω‐conotoxin GVIA (N‐type blocker) and calciseptine (L‐type) but not by ω‐agatoxin IVA (P/Q‐type).
The nociceptive response induced in a similar way by α,βmeATP (100 nmol) was significantly inhibited by both the above N‐ and P/Q‐type Ca2+‐channel blockers but not by the L‐type blocker.
The nociceptive responses elicited by BK and α,βmeATP were dose‐dependently inhibited by a tachykinin‐NK1‐receptor antagonist (L‐703,606) and an N‐methyl‐D‐aspartate (NMDA)‐receptor antagonist (D‐AP5), respectively.
Intrathecal administration of substance P (SP) (1.8 nmol) or NMDA (350 pmol) elicited algesic responses, such as licking, biting and scratching of the hindquarters. The SP‐induced algesic behaviour was significantly inhibited by the L‐type blocker but not by the N‐type. The NMDA‐induced response was not affected by either the N‐ or the P/Q‐type blocker.
These findings suggest that BK and ATP most likely excite different types of sensory neurons in the periphery and that within the spinal cord the former stimulates peptidergic transmission regulated by presynaptic N‐ and postsynaptic L‐type Ca2+ channels, while the latter stimulates glutamatergic transmission regulated by presynaptic N‐ and P/Q‐type channels.

British Journal of Pharmacology (2002) 135, 1336–1342; doi:10.1038/sj.bjp.0704578
Allergenic sensitization prevents upregulation of haemopoiesis by cyclo‐oxygenase inhibitors in mice
Authors: Lintomen Letícia , Gaspar Elsas Maria Ignez C , Maximiano Elisabeth Santos , Affonso de Paula Neto Heitor , Joseph Danielle , Vargaftig B Boris , Xavier Elsas P 
Published: January 2005

We evaluated whether immunization affects bone‐marrow responses to indomethacin, because allergenic sensitization and challenge upregulate responses to haemopoietic cytokines (including IL‐5‐driven eosinopoiesis) in murine bone‐marrow, while indomethacin upregulates haemopoiesis and protects bone‐marrow from radiation damage.
Progenitor (semi‐solid) and/or precursor (liquid) cultures were established from bone‐marrow of: (a) normal mice; (b) ovalbumin‐sensitized mice, with or without intranasal challenge. Cultures were established with GM‐CSF (2 ng ml−1) or IL‐5 (1 ng ml−1), respectively, alone or associated with indomethacin (10−7 – 10−11 M) or aspirin (10−7 – 10−8 M). Total myeloid colony numbers and numbers of eosinophil‐peroxidase‐positive cells were determined at day 7.
In naïve BALB/c mice, indomethacin (10−7 – 10−9 M) increased GM‐CSF‐stimulated myeloid colony formation (P=0.003 and P=0.009, respectively). In contrast, it had no effect on bone‐marrow of ovalbumin‐sensitized and challenged mice. Indomethacin (10−7 – 10−9 M) also increased eosinophil precursor responses to IL‐5 in bone‐marrow of naïve (P<0.001 and P=0.002 respectively), but not sensitized‐challenged mice. Aspirin (10−7 M) had similar effects, equally abolished by sensitization. Enhancement of haemopoiesis by indomethacin required adherent cells from naïve bone‐marrow. Nonadherent cells responded to IL‐5 but not to indomethacin. Indomethacin was effective on bone‐marrow from sham‐sensitized, ovalbumin‐challenged, but not from sensitized, saline‐challenged mice. Plasma transfer from immune mice abolished eosinophil precursor responses to indomethacin in bone‐marrow of naïve recipients. This was not prevented by previous removal of antibody from immune plasma.
COX inhibitors enhance haemopoiesis in naïve but not allergic mice. Responsiveness to indomethacin can be abolished either by active sensitization or by immune plasma transfer. Specific antibody is not involved.

British Journal of Pharmacology (2002) 135, 1315–1323; doi:10.1038/sj.bjp.0704580
Characterization of pre‐ and postsynaptic muscarinic receptors in circular muscle of pig gastric fundus
Authors: Leclere Pascal G , Lefebvre Romain A 
Published: January 2005

This study investigated the subtype of muscarinic receptors on the cholinergic neurones and smooth muscle in the circular muscle of the pig gastric fundus.
Muscarinic antagonists, except MT‐3, concentration‐dependently inhibited the contractions induced by a given concentration of acetylcholine. Concentration‐response curves by acetylcholine were shifted rightwards in a parallel manner without depression of the maximum by the muscarinic antagonists, except by MT‐3 that induced a leftward shift. Correlation of the pIC50 and pA2 values with published pKi values for the five muscarinic receptor subtypes suggests that the muscarinic receptors on pig gastric fundus circular muscle belong to the M3 subtype.
Electrically‐evoked contractions (40 V, 4 Hz, 0.25 ms, 2 min) were concentration‐dependently inhibited by the muscarinic antagonists except for methoctramine and AF‐DX 116, that increased the amplitude of the electrically‐induced contractions in lower concentrations. MT‐3 tended to increase the electrically‐induced contractions.
The antagonists, except MT‐3, concentration‐dependently increased the electrically‐induced tritium outflow (40 V, 4 Hz, 0.25 ms, 2 min) after incubation of the tissues with [3H]‐choline. MT‐3 (3×10−8 and 10−7 M) decreased the electrically‐induced tritium release. Correlation of the pIC50 values with published pKi values for the different muscarinic receptor subtypes yielded a significant and comparable correlation for M1, M3, M4 and M5 receptors.
These results suggest that the postsynaptic receptors in circular muscle of the pig gastric fundus belong to the M3 subtype. However, the presynaptic receptor could not be clearly defined, although it does certainly not belong to the M2 subtype.

British Journal of Pharmacology (2002) 135, 1245–1254; doi:10.1038/sj.bjp.0704582
The effects of neuroleptics on the GABA‐induced Cl−current in rat dorsal root ganglion neurons: differences between some neuroleptics
Authors: Yokota Kenjiro , Tatebayashi Hideharu , Matsuo Tadashi , Shoge Takashi , Motomura Haruhiko , Matsuno Toshiyuki , Fukuda Akira , Tashiro Nobutada 
Published: January 2005

Several neuroleptics inhibited the 3 μMγ‐aminobutyric acid induced‐chloride current (GABA‐current) on dissociated rat dorsal root ganglion neurons in whole‐cell patch‐clamp investigations.The IC50for clozapine, zotepine, olanzapine, risperidone and chlorpromazine were 6.95, 18.26, 20.30, 106.01 and 114.56 μM, respectively. The values for the inhibitory effects of neuroleptics on the GABA (3 μM)‐current, which were calculated by the fitting Hill's equations where the concentrations represent the mean therapeutic blood concentrations, were ranked clozapine>zotepine>chlorpromazine>olanzapine>risperidone. These inhibitory effects, weighted with the therapeutic concentrations of neuroleptics, were correlated with the clinical incidences of seizure during treatment with neuroleptics.Clozapine reduced the picrotoxin‐inhibiton, and may compete with a ligand of the t‐butylbicyclophosphorothionate (TBPS) binding site.Haloperidol and quetiapine did not affect the peak amplitude of the GABA (3 μM)‐current. However, haloperidol reduced the clozapine‐inhibition, and may antagonize ligand binding to TBPS binding site.Neuroleptics including haloperidol and quetiapine enhanced the desensitization of the GABA (3 μM)‐current. However, haloperidol and quetiapine at 100 μMinhibited the desensitization at the beginning of application.Blonanserin (AD‐5423) at 30 and 50 μMpotentiated the GABA (3 μM)‐current to 170.1±6.9 and 192.0±10.6% of the control current, respectively. Blonanserin shifted GABA concentration‐response curve leftward. Blonanserin only partly negatively interacted with diazepam. The blonanserin‐potentiation was not reversed by flumazenil. Blonanserin is not a benzodiazepine receptor agonist.The various effects of neuroleptics on the GABA‐current may be related to the clinical effects including modifying the seizure threshold.British Journal of Pharmacology(2002)135, 1547–1555; doi:10.1038/sj.bjp.0704608
Quercetin as a novel activator of L‐type Ca2+channels in rat tail artery smooth muscle cells
Authors: Saponara Simona , Sgaragli Giampietro , Fusi Fabio 
Published: January 2005

The aim of this study was to investigate the effects of quercetin, a natural polyphenolic flavonoid, on voltage‐dependent Ca2+channels of smooth muscle cells freshly isolated from the rat tail artery, using either the conventional or the amphotericin B‐perforated whole‐cell patch‐clamp method.Quercetin increased L‐type Ca2+current [ICa(L)] in a concentration‐ (pEC50=5.09±0.05) and voltage‐dependent manner and shifted the maximum of the current‐voltage relationship by 10 mV in the hyperpolarizing direction, without, however, modifying the threshold and the equilibrium potential for Ca2+. Quercetin‐induced ICa(L)stimulation was reversible upon wash‐out. T‐type Ca2+current was not affected by quercetin.Quercetin shifted the voltage dependence of the steady‐state inactivation and activation curves to more negative potentials by about 5.5 and 7.5 mV respectively, in the mid‐potential of the curves as well as increasing the slope of activation. Quercetin slowed both the activation and the deactivation kinetics of the ICa(L). The inactivation time course was also slowed but only at voltages higher than 10 mV. Moreover quercetin slowed the rate of recovery from inactivation.These results prove quercetin to be a naturally‐occurring L‐type Ca2+channel activator.British Journal of Pharmacology(2002)135, 1819–1827; doi:10.1038/sj.bjp.0704631
Generalized loss of inhibitory innervation reverses serotonergic inhibition into excitation in a rabbit model of TNBS‐colitis
Authors: Depoortere Inge , Thijs Theo , Peeters Theo L 
Published: January 2005

Inflammation may affect subpopulations of neurons of the myenteric plexus.
In the present study the effect of trinitrobenzene sulphonic acid (TNBS) induced colitis on nitrergic, purinergic and adrenergic inhibitory neurotransmission was studied as well as the consequences of the related changes on the response of 5‐HT agonists using these neurotransmitters to mediate their effect.
Strips from normal and colitis rabbits (135 mg kg−1 TNBS) were subjected to electrical field stimulation (EFS, 0.3 ms, 6V, 0.5 – 32 Hz, 10 s train). The response was measured isometrically in the absence or presence of L‐NAME, suramin, guanethidine, the 5‐HT agonists (5‐HT1/5A/7: 5‐carboxamidotryptamine (5‐CT), 5‐HT2: α‐methyl‐5‐HT, 5‐HT3: 2‐methyl‐5‐HT, 5‐HT4: 5‐methoxytryptamine (5‐MeOT)) or a combination.
In normal strips L‐NAME (1 – 32 Hz), suramin (0.5 – 2, 8 Hz) and guanethidine (4, 16, 32 Hz) increased the response to EFS. This effect was abolished in inflamed strips and was accompanied by a decrease in nNOS expression.
In normal strips all 5‐HT agonists induced pronounced (5‐CT, α‐methyl‐5‐HT) or small (2‐methyl‐5‐HT, 5‐MeOT) inhibitory neural responses. In inflamed strips this was reversed to cholinergic excitatory responses.
The effect of inflammation on the 5‐HT4 response was mimicked by preincubation of normal strips with L‐NAME or suramin. Accordingly, in inflamed strips L‐NAME or suramin did not affect the excitatory effects of 5‐MeOT.
TNBS‐colitis abolishes nitrergic, purinergic and adrenergic neurotransmission. This reverses serotonergic inhibition into excitation.

British Journal of Pharmacology (2002) 135, 2011–2019; doi:10.1038/sj.bjp.0704648
Second messenger‐dependent protein kinases and protein synthesis regulate endogenous secretin receptor responsiveness
Authors: Ghadessy Roxana S , Kelly Eamonn 
Published: January 2005

The present study investigated the role of second messenger‐dependent protein kinase A (PKA) and C (PKC) in the regulation of endogenous secretin receptor responsiveness in NG108‐15 mouse neuroblastoma×rat glioma hybrid cells.In whole cell cyclic AMP accumulation studies, activation of PKC either by phorbol 12‐myristate 13‐acetate (PMA) or by purinoceptor stimulation using uridine 5′‐triphosphate (UTP) decreased secretin receptor responsiveness. PKC activation also inhibited forskolin‐stimulated cyclic AMP accumulation but did not affect cyclic AMP responses mediated by the prostanoid‐IP receptor agonist iloprost, or the A2adenosine receptor agonist 5′‐(N‐ethylcarboxamido) adenosine (NECA).In additivity experiments, saturating concentrations of secretin and iloprost were found to be additive in terms of cyclic AMP accumulation, whereas saturating concentrations of NECA and iloprost together were not. This suggests compartmentalization of Gs‐coupling components in NG108‐15 cells and possible heterologous regulation of secretin receptor responsiveness at the level of adenylyl cyclase activation.Cells exposed to the PKA inhibitor H‐89, exhibited a time‐dependent increase in secretin receptor responsiveness compared to control cells. This effect was selective since cyclic AMP responses to forskolin, iloprost and NECA were not affected by H‐89 treatment. Furthermore, treatment with the protein synthesis inhibitor cycloheximide produced a time‐dependent increase in secretin receptor responsiveness.Together these results indicate that endogenous secretin receptor responsiveness is regulated by PKC, PKA and protein neosynthesis in NG108‐15 cells.British Journal of Pharmacology(2002)135, 2020–2028; doi:10.1038/sj.bjp.0704655
Differential contributions of nitric oxide synthase isoforms at hippocampal formation to negative feedback regulation of penile erection in the rat
Authors: Chang Alice Y. W. , Chan Julie Y. H. , Chan Samuel H. H. 
Published: January 2005

We established previously that a novel negative feedback mechanism for the regulation of penile erection, which is triggered by ascending sensory inputs initiated by tumescence of the penis, exists in the hippocampal formation (HF). This study further evaluated the participation of nitric oxide (NO) and the contribution of nitric oxide synthase (NOS) isoforms at the HF in this process.
Adult, male Sprague‐Dawley rats that were anaesthetized and maintained with chloral hydrate were used, and intracavernous pressure (ICP) recorded from the corpus cavernosum of the penis was employed as our experimental index for penile erection.
Microinjection bilaterally of a NO donor, S‐nitroso‐N‐acetylpenicillamine (0.25 or 1 nmoles), or the NO precursor, L‐arginine (1 or 5 nmoles), into the hippocampal CA1 or CA3 subfield or dentate gyrus elicited a significant reduction in baseline ICP.
Bilateral hippocampal application of a NO trapping agent, 2‐(4‐carboxyphenyl)‐4,4,5,5‐tetramethylimidazoline‐1‐oxyl‐3‐oxide (10 nmoles), significantly potentiated the elevation in ICP induced by intracavernous administration of papaverine (400 μg).
Microinjection bilaterally into the HF of equimolar doses (0.5 or 2.5 pmoles) of two selective neuronal NOS inhibitors, 7‐nitroindazole or Nω‐propyl‐L‐arginine; or equimolar doses (50 or 250 pmoles) of two selective inducible NOS inhibitors, aminoguanidine or S‐methylisothiourea, significantly enhanced the magnitude and/or duration of the papaverine‐induced elevation in ICP. In contrast, hippocampal application of a potent endothelial NOS inhibitor, N5‐(1‐iminoethyl)‐L‐ornithine (18 or 92 nmoles), was ineffective. Neither of these inhibitors, furthermore, affected baseline ICP.
These results suggest that NO generated via both neuronal and inducible NOS at the HF may participate in negative feedback regulation of penile erection.

British Journal of Pharmacology (2002) 136, 1–8; doi:10.1038/sj.bjp.0704657
Characterization of cocaine and antidepressant‐sensitive norepinephrine transporters in rat placental trophoblasts
Authors: Jayanthi Lankupalle D , Vargas Gricelly , DeFelice Louis J 
Published: January 2005

This paper reports on a primary cell culture system that predominately expresses native norepinephrine (NE) transporters (NETs), and is amenable to biophysical as well as biochemical analyses.
Previous research has identified human and rat placentas as rich sources of NET. We have exploited this to develop primary cultures of rat placental trophoblasts. NE uptake in these cultures is about 10 times higher when compared to 5HT uptake. The presence of NET protein is revealed by immunoblot analysis, while there is no detectable SERT protein.
NE transport in rat trophoblasts is sensitive to NET‐specific antagonists, desipramine (DS) and nisoxetine (NX), but not to the dopamine‐transporter (DAT) specific antagonist, GBR12909 or to the serotonin (5HT) transporter (SERT) specific antagonist paroxetine (PX). Drugs of abuse such as cocaine and amphetamine also inhibit NE transport in these cells. Together these results suggest that rat placental trophoblasts predominately express NET over other monoamine transporters.
Patch‐clamp analysis reveals that NETs in intact rat trophoblasts are electrogenic. Comparison of NE uptake with NE‐induced currents suggests that these two modes of transporter activity are differentially regulated.

British Journal of Pharmacology (2002) 135, 1927–1934; doi:10.1038/sj.bjp.0704658
Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat
Authors: Kanie Noriyasu , Kamata Katsuo 
Published: January 2005

The biosynthesis of endothelin‐1 is increased in the diabetic state. So this peptide may cause diabetic vascular complications. We tested this possibility by chronically administering J‐104132, a potent orally active mixed antagonist of endothelin A and B (ETA/ETB) receptors to streptozotocin (STZ)‐induced diabetic rats and focusing on changes in endothelial function.
The acetylcholine (ACh)‐induced endothelium‐dependent relaxation was impaired in diabetic rats and this impairment was significantly attenuated following chronic administration of J‐104132 (10 mg kg−1, p.o., daily for 4 weeks).
In an in vitro experiment using aortae from diabetic rats, the ACh‐induced relaxation was not changed by the presence of J‐104132 (3×10−9 M).
The expression levels of the mRNA for endothelial nitric oxide synthase was comparable among aortae from the three groups (control, diabetic and chronically J‐104132‐treated diabetic).
The amount of superoxide anion was significantly greater in aortae from diabetic rats than in controls. Chronic J‐104132 treatment significantly decreased the level of superoxide anion in diabetic rats.
The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was significantly increased in STZ‐induced diabetic rats and this increase was completely prevented by chronic administration of J‐104132.
These results suggest that in STZ‐induced diabetic rats, ET‐1 may be directly involved in impairing endothelium‐dependent relaxation via increased superoxide‐anion production.

British Journal of Pharmacology (2002) 135, 1935–1942; doi:10.1038/sj.bjp.0704659
Receptor subtypes Y1 and Y5 mediate neuropeptide Y induced feeding in the guinea‐pig
Authors: Lecklin Anne , Lundell Ingrid , Paananen Leena , Wikberg Jarl E S , Männistö Pekka T , Larhammar Dan 
Published: January 2005

Neuropeptide Y (NPY) is one of the most potent stimulants of food intake. It has been debated which receptor subtype mediates this response. Initially Y1 was proposed, but later Y5 was announced as a ‘feeding’ receptor in rats and mice. Very little is known regarding other mammals. The present study attempts to characterize the role of NPY in feeding behaviour in the distantly related guinea‐pig. When infused intracerebroventricularly, NPY dose‐dependently increased food intake.
PYY, (Leu31,Pro34)NPY and NPY(2 – 36) stimulated feeding, whereas NPY(13 – 36) had no effect. These data suggest that either Y1 or Y5 receptors or both may mediate NPY induced food intake in guinea‐pigs.
The Y1 receptor antagonists, BIBO 3304 and H 409/22 displayed nanomolar affinity for the Y1 receptor (Ki values 1.1±0.2 nM and 5.6±0.9 nM, respectively), but low affinity for the Y2 or Y5 receptors. When guinea‐pigs were pretreated with BIBO 3304 and H 409/22, the response to NPY was inhibited.
The Y5 antagonist, CGP 71683A had high affinity for the Y5 receptor (Ki 1.3±0.05 nM) without having any significant activities at the Y1 and Y2 receptors. When CGP 71683A was infused into brain ventricles, the feeding response to NPY was attenuated.
The present study shows that NPY stimulates feeding in guinea‐pigs through Y1 and Y5 receptors. As the guinea‐pig is very distantly related to the rat and mouse, this suggests that both Y1 and Y5 receptors may mediate NPY‐induced hyperphagia also in other orders of mammals.

British Journal of Pharmacology (2002) 135, 2029–2037; doi:10.1038/sj.bjp.0704667