bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats
Authors: Begon Sophie , Pickering Gisèle , Eschalier Alain , Mazur André , Rayssiguier Yves , Dubray Claude 
Published: January 2005

Magnesium (Mg)‐deficient rats develop a mechanical hyperalgesia which is reversed by a N‐Methyl‐D‐Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor‐channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non‐NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg‐deficient rats.
Hyperalgesic Mg‐deficient rats were administered intrathecally (10 μl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h.
Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 μmol) as well as NMDA receptor antagonists such as MK‐801 (0.6, 6.0, 60 nmol), AP‐5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose‐dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibitor (1, 10.4, 104.2 nmol) and 7‐NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 μmol kg−1, i.p.) induced an anti‐hyperalgesic effect in a dose‐dependent manner. SR‐140333 (0.15, 1.5, 15 nmol) and SR‐48968 (0.17, 1.7, 17 nmol), antagonists of neurokinin receptors, produced a significant, but moderate, increase in vocalization threshold.
These results demonstrate that Mg‐deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non‐NMDA receptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.

British Journal of Pharmacology (2001) 134, 1227–1236; doi:10.1038/sj.bjp.0704354
Differential involvement of the sigma1 (σ1) receptor in the anti‐amnesic effect of neuroactive steroids, as demonstrated using an in vivo antisense strategy in the mouse
Authors: Maurice Tangui , Phan Vân‐Ly , Urani Alexandre , Guillemain Isabelle 
Published: January 2005

The sigma1 (σ1) receptor cDNA was cloned in several animal species. Molecular tools are now available to identify its endogenous effectors, such as neuroactive steroids, and to establish its precise physiological role. In particular, the σ1 receptor is involved in memory processes, as observed in pharmacological and pathological rodent models of amnesia.
In order to establish the involvement of σ1 receptors in memory, a 16‐mer oligodeoxynucleotide antisense to the σ1 receptor cDNA (aODN), and its mismatched control (mODN) were prepared and centrally administered into the mouse brain. The anti‐amnesic effects induced by the selective σ1 agonist PRE‐084 and the steroid dehydroepiandrosterone (DHEA) sulphate or pregnenolone sulphate were examined in ODN‐treated animals.
The aODN treatment failed to affect the dissociation constant (Kd) but significantly decreased the number of σ1 sites (Bmax) labelled with [3H]‐(+)‐SKF‐10,047 in the hippocampus and cortex. In these structures, the in vivo binding levels were also diminished, according to the dose and number of injections, as compared with control animals injected with saline or mODN.
Cannulation and injections failed to affect the open‐field behaviour of the animals. However, the anti‐amnesic effects of PRE‐084 and DHEA sulphate against the dizocilpine‐induced impairments were blocked after aODN treatment in the short‐ and long‐term memory tests. The anti‐amnesic effects of pregnenolone sulphate remained unchanged.
These observations bring a molecular basis to the modulatory role of σ1 receptors in memory, and reveal that the anti‐amnesic action of neuroactive steroids may not similarly involve an interaction with σ1 receptors.

British Journal of Pharmacology (2001) 134, 1731–1741; doi:10.1038/sj.bjp.0704355
Macrophage Stimulating Protein (MSP) evokes superoxide anion production by human macrophages of different origin
Authors: Brunelleschi Sandra , Penengo Lorenza , Lavagno Luisa , Santoro Claudio , Colangelo Donato , Viano Ilario , Gaudino Giovanni 
Published: January 2005

Macrophage Stimulating Protein (MSP), a serum factor related to Hepatocyte Growth Factor, was originally discovered to stimulate chemotaxis of murine resident peritoneal macrophages. MSP is the ligand for Ron, a member of the Met subfamily of tyrosine kinase receptors. The effects of MSP on human macrophages and the role played in human pathophysiology have long been elusive.
We show here that human recombinant MSP (hrMSP) evokes a dose‐dependent superoxide anion production in human alveolar and peritoneal macrophages as well as in monocyte‐derived macrophages, but not in circulating human monocytes. Consistently, the mature Ron protein is expressed by the MSP responsive cells but not by the unresponsive monocytes. The respiratory burst evoked by hrMSP is quantitatively higher than the one induced by N‐formylmethionyl‐leucyl‐phenylalanine and similar to phorbol myristate acetate‐evoked one.
To investigate the mechanisms involved in NADPH oxidase activation, leading to superoxide anion production, different signal transduction inhibitors were used. By using the non selective tyrosine kinase inhibitor genistein, the selective c‐Src inhibitor PP1, the tyrosine phosphatase inhibitor sodium orthovanadate, the phosphatidylinositol 3‐kinase inhibitor wortmannin, the p38 inhibitor SB203580, the MEK inhibitor PD098059, we demonstrate that hrMSP‐evoked superoxide production is mediated by tyrosine kinase activity, requires the activation of Src but not of PI 3‐kinase. We also show that MAP kinase and p38 signalling pathways are involved.
These results clearly indicate that hrMSP induces the respiratory burst in human macrophages but not in monocytes, suggesting for the MSP/Ron complex a role of activator as well as of possible marker for human mature macrophages.

British Journal of Pharmacology (2001) 134, 1285–1295; doi:10.1038/sj.bjp.0704356
Somatostatin release by glutamate in vivo is primarily regulated by AMPA receptors
Authors: Hathway G J , Humphrey P P A , Kendrick K M 
Published: January 2005

We have used in vivo microdialysis in anaesthetized rats to investigate whether levels of striatal somatostatin (SRIF) can be increased in response to application of the ionotropic glutamate receptor agonists AMPA and NMDA.
Application of both AMPA and NMDA (10, 50, 100 and 500 μM) for 20 min periods produced concentration‐dependent increases in the extracellular levels of SRIF. A 500 μM dose of each compound was shown to be the most potent concentration tested, increasing levels of SRIF by 32 fold (NMDA) and 35 fold (AMPA). At lower concentrations (10 μM) NMDA failed to evoke significant amounts of SRIF while AMPA increased levels of the peptide 2.3 fold.
Application of the respective receptor antagonists APV (NMDA receptor) and DNQX (AMPA receptor) abolished the abilities of the agonists to evoke release of SRIF. Interestingly DNQX abolished the ability of NMDA to evoke release of the peptide as well.
The ability of both AMPA and NMDA to evoke increases in the levels of extracellular SRIF further illustrates the reciprocal relationship that exists between SRIF and glutamate in the striatum which impacts particularly on dopaminergic functioning in this region.

British Journal of Pharmacology (2001) 134, 1155–1158; doi:10.1038/sj.bjp.0704362
Effect of P‐glycoprotein modulators on the pharmacokinetics of camptothecin using microdialysis
Authors: Tsai T H , Lee C H , Yeh P H 
Published: January 2005

By performing microdialysis, this study investigated the pharmacokinetics of unbound camptothecin in rat blood, brain and bile in the presence of P‐glycoprotein mediated transport modulators (cyclosporin A, berberine, quercetin, naringin and naringenin). Pharmacokinetic parameters of camptothecin were assessed using a non‐compartmental model.
Camptothecin rapidly crosses the blood‐brain barrier (BBB) within 20 min after camptothecin administration. The disposition of camptothecin in rat bile appeared to have a slow elimination phase and a peak concentration after 20 min of camptothecin administration. The area under the concentration versus time curve (AUC) for camptothecin in bile significantly surpassed that in blood, suggesting active transport of hepatobiliary excretion.
In the presence of cyclosporin A camptothecin AUC, in the brain, was significantly elevated but no significant change in the presence of berberine, quercetin, naringin and naringenin.
With treatment by smaller doses of quercetin (0.1 mg kg−1), naringin (10 mg kg−1) and naringenin (10 mg kg−1), they significantly diminished the camptothecin AUC in bile, but was not altered by the treatment of berberine (20 mg kg−1), a higher dose of quercetin (10 mg kg−1), and cyclosporin A treated (20 mg kg−1) and pretreated groups.
The distribution ratio (AUCbile/AUCblood) of camptothecin in bile was decreased in the cyclosporin A, quercetin, naringin and naringenin treated groups. However, the distribution ratio in the brain was increased in the cyclosporin A groups, but was decreased in the groups treated with quercetin, naringin and naringenin. These results revealed that P‐glycoprotein might modulate hepatobiliary excretion and BBB penetration of camptothecin.

British Journal of Pharmacology (2001) 134, 1245–1252; doi:10.1038/sj.bjp.0704363
Chronic morphine induces up‐regulation of the pro‐apoptotic Fas receptor and down‐regulation of the anti‐apoptotic Bcl‐2 oncoprotein in rat brain
Authors: Boronat M Assumpció , García‐Fuster M Julia , García‐Sevilla Jesús A 
Published: January 2005

This study was designed to assess the influence of activation and blockade of the endogenous opioid system in the brain on two key proteins involved in the regulation of programmed cell death: the pro‐apoptotic Fas receptor and the anti‐apoptotic Bcl‐2 oncoprotein.
The acute treatment of rats with the μ‐opioid receptor agonist morphine (3 – 30 mg kg−1, i.p., 2 h) did not modify the immunodensity of Fas or Bcl‐2 proteins in the cerebral cortex. Similarly, the acute treatment with low and high doses of the antagonist naloxone (1 and 100 mg kg−1, i.p., 2 h) did not alter Fas or Bcl‐2 protein expression in brain cortex. These results discounted a tonic regulation through opioid receptors on Fas and Bcl‐2 proteins in rat brain.
Chronic morphine (10 – 100 mg kg−1, 5 days, and 10 mg kg−1, 13 days) induced marked increases (47 – 123%) in the immunodensity of Fas receptor in the cerebral cortex. In contrast, chronic morphine (5 and 13 days) decreased the immunodensity of Bcl‐2 protein (15 – 30%) in brain cortex. Chronic naloxone (10 mg kg−1, 13 days) did not alter the immunodensities of Fas and Bcl‐2 proteins in the cerebral cortex.
The concurrent chronic treatment (13 days) of naloxone (10 mg kg−1) and morphine (10 mg kg−1) completely prevented the morphine‐induced increase in Fas receptor and decrease in Bcl‐2 protein immunoreactivities in the cerebral cortex.
The results indicate that morphine, through the sustained activation of opioid receptors, can promote abnormal programmed cell death by enhancing the expression of pro‐apoptotic Fas receptor protein and damping the expression of anti‐apoptotic Bcl‐2 oncoprotein.

British Journal of Pharmacology (2001) 134, 1263–1270; doi:10.1038/sj.bjp.0704364
Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use‐dependent block of skeletal muscle Na+ channels enhancing the antimyotonic activity in vivo
Authors: Talon Sophie , De Luca Annamaria , De Bellis Michela , Desaphy Jean‐François , Lentini Giovanni , Scilimati Antonio , Corbo Filomena , Franchini Carlo , Tortorella Paolo , Jockusch Harald , Conte Camerino Diana 
Published: January 2005

Searching for the structural requirements improving the potency and the stereoselectivity of Na+ channel blockers as antimyotonic agents, new derivatives of tocainide, in which the chiral carbon atom is constrained in a rigid α‐proline or pyrrolo‐imidazolic cycle, were synthesized as pure enantiomers.
Their ability to block Na+ currents, elicited from −100 to −20 mV at 0.3 Hz (tonic block) and 2 – 10 Hz (use‐dependent block) frequencies, was investigated in vitro on single fibres of frog semitendinosus muscle using the vaseline‐gap voltage‐clamp method.
The α‐proline derivative, To5, was 5 and 21 fold more potent than tocainide in producing tonic and 10 Hz‐use‐dependent block, respectively. Compared to To5, the presence of one methyl group on the aminic (To6) or amidic (To7) nitrogen atom decreased use‐dependence by 2‐ and 6‐times, respectively. When methylene moieties were present on both nitrogen atoms (To8), both tonic and use‐dependent block were reduced.
Contrarily to tocainide, all proline derivatives were stereoselective in relation to an increased rigidity. A further increase in the molecular rigidity as in pyrrolo‐imidazolic derivatives markedly decreased the drug potency with respect to tocainide.
Antimyotonic activity, evaluated as the shortening of the time of righting reflexes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more effective for R‐To5 than for R‐Tocainide.
Thus, constraining the chiral centre of tocainide in α‐proline cycle leads to more potent and stereoselective use‐dependent Na+ channel blockers with improved therapeutic potential.

British Journal of Pharmacology (2001) 134, 1523–1531; doi:10.1038/sj.bjp.0704366
Regulation of VEGF‐induced endothelial cell PAF synthesis: role of p42/44 MAPK, p38 MAPK and PI3K pathways
Authors: Bernatchez Pascal N , Allen Bruce G , Gélinas David S , Guillemette Gaétan , Sirois Martin G 
Published: January 2005

Vascular endothelial growth factor (VEGF) is a potent angiogenic and inflammatory mediator. We have recently shown that this latter effect requires the activation of Flk‐1 receptor and subsequent endothelial cell (EC) PAF synthesis. However, the intracellular events that regulate EC PAF synthesis upon Flk‐1 stimulation by VEGF remain to be elucidated.
Using specific inhibitors and Western blot analysis, we herein report that in bovine aortic endothelial cells (BAEC), VEGF induces the synthesis of PAF through the cascade activation of Flk‐1 receptor, phospholipase Cγ (PLCγ), protein kinase C (PKC) and p42/44 mitogen‐activated protein kinases (MAPK).
Moreover, we demonstrate that VEGF‐mediated PAF synthesis requires the activation of p38 MAPK, likely by directing the conversion of lyso‐PAF to PAF.
Interestingly, we observed that VEGF also promoted the activation of the phosphatidyl inositol‐3‐phosphate kinase (PI3K) pathway, and that its blockade potentiated PAF synthesis following a VEGF treatment. Consequently, it appears that the PI3K pathway acts as a negative regulator of EC PAF synthesis.
Taken together, these results allow a better understanding of the intracellular events activated upon EC stimulation by VEGF, and shed a new light on the mechanisms by which VEGF induces PAF synthesis.

British Journal of Pharmacology (2001) 134, 1253–1262; doi:10.1038/sj.bjp.0704367
Impairment of myocardial contractility by anticancer anthracyclines: role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue
Authors: Minotti Giorgio , Parlani Massimo , Salvatorelli Emanuela , Menna Pierantonio , Cipollone Amalia , Animati Fabio , Maggi Carlo A , Manzini Stefano 
Published: January 2005

The anticancer anthracycline doxorubicin (DOX) causes cardiotoxicity. Enzymatic reduction of a side chain carbonyl group converts DOX to a secondary alcohol metabolite that has been implicated in cardiotoxicity. We therefore monitored negative inotropism, assessed as inhibition of post‐rest contractions, in rat right ventricle strips exposed to DOX or to analogues forming fewer amounts of their alcohol metabolites (epirubicin, EPI, and the novel disaccharide anthracycline MEN 10755).
Thirty μM EPI exhibited higher uptake than equimolar DOX, but formed comparable amounts of alcohol metabolite due to its resistance to carbonyl reduction. MEN 10755 exhibited also an impaired uptake, and consequently formed the lowest levels of alcohol metabolite. Accordingly, DOX and EPI inhibited post‐rest contractions by ∼40 – 50%, whereas MEN 10755 inhibited by ∼6%.
One hundred μM EPI exhibited the same uptake as equimolar DOX, but formed ∼50% less alcohol metabolite. One hundred μM MEN 10755 still exhibited the lowest uptake, forming ∼60% less alcohol metabolite than EPI. Under these conditions DOX inhibited post‐rest contractions by 88%. EPI and MEN 10755 were ∼18% (P<0.05) or ∼80% (P<0.001) less inhibitory than DOX, respectively.
The negative inotropism of 30 – 100 μM DOX, EPI, or MEN 10755 correlated with cellular levels of both alcohol metabolites (r=0.88, P<0.0001) and carbonyl anthracyclines (r=0.79, P<0.0001). Nonetheless, multiple comparisons showed that alcohol metabolites were ∼20 – 40 times more effective than carbonyl anthracyclines in inhibiting contractility. The negative inotropism of MEN 10755 was therefore increased by chemical procedures, like side chain valeryl esterification, that facilitated its uptake and conversion to alcohol metabolite but not its retention in a carbonyl form.
These results demonstrate that secondary alcohol metabolites are important mediators of cardiotoxicity. A combination of reduced uptake and limited conversion to alcohol metabolite formation might therefore render MEN 10755 more cardiac tolerable than DOX and EPI.

British Journal of Pharmacology (2001) 134, 1271–1278; doi:10.1038/sj.bjp.0704369
N‐[3,4‐dimethoxycinnamoyl]‐anthranilic acid (tranilast) suppresses microglial inducible nitric oxide synthase (iNOS) expression and activity induced by interferon‐γ (IFN‐γ)
Authors: Platten Michael , Wick Wolfgang , Wischhusen Jörg , Weller Michael 
Published: January 2005

Microglial cells up‐regulate inducible nitric oxide synthase (iNOS) expression in response to various pro‐inflammatory stimuli including interferon‐γ (IFN‐γ), allowing for the release of nitric oxide (NO). Tranilast (N‐[3,4‐dimethoxycinnamoyl]‐anthranilic acid) is an antiallergic compound with suppressive effects on the activation of monocytes.
Here, we show that N9 murine microglial cells express iNOS mRNA and protein and release nitric oxide into the culture medium in response to IFN‐γ (200 u ml−1) as measured by Northern and Western blot analyses and Griess assay.
Exposure to non‐toxic doses of tranilast (30 – 300 μM) leads to a concentration‐dependent inhibition of IFN‐γ‐induced (200 u ml−1) iNOS mRNA and protein expression. This is paralleled by a suppression of NO‐release into the cell culture medium.
Inhibition of IFN‐γ‐induced iNOS mRNA expression by tranilast is paralleled by an inhibition of nuclear factor‐κB (NF‐κB) activation and phosphorylation of inhibitory κB (IκB) as determined by Western blot analyses and NF‐κB reporter gene assay.
These results suggest that tranilast‐mediated suppression of microglial iNOS activity induced by IFN‐γ involves the inhibition of NF‐κB‐dependent iNOS mRNA expression.

British Journal of Pharmacology (2001) 134, 1279–1284; doi:10.1038/sj.bjp.0704373
Changes in blood glucose and plasma insulin levels induced by bradykinin in anaesthetized rats
Authors: Damas Jacques , Hallet Claude , Lefebvre Pierre J 
Published: January 2005

The influence of bradykinin (BK) on blood glucose and plasma insulin levels was investigated in anaesthetized rats.
Blood glucose level was dose‐dependently increased by intravenous infusion of BK. This effect of BK was enhanced by captopril, an inhibitor of angiotensin‐converting enzyme (ACE). Des‐Arg9‐bradykinin (DABK), a kinin B1 receptor agonist, did not modify blood glucose levels while the effect of BK was inhibited by Hoe‐140, a kinin B2 receptor antagonist. The effect of BK was reduced by the NO‐synthase inhibitor, Nω‐nitro‐L‐arginine methyl ester (L‐NAME), and by the cyclo‐oxygenase inhibitor, indomethacin.
The effect of BK was suppressed by the association of propranolol with phentolamine or phenoxybenzamine. It was also reduced by hexamethonium, a ganglion‐blocking drug. In adrenalectomized rats, the infusion of BK slightly decreased blood glucose levels.
The hyperglycaemic effect of adrenaline was suppressed by propranolol associated with phentolamine or phenoxybenzamine, but it was not modified by L‐NAME.
Infusion of BK did not modify plasma insulin levels. However, after phentolamine and propranolol, BK induced a transient 2 fold rise in plasma insulin levels. The release of insulin was dose‐dependent and inhibited by Hoe‐140.
We conclude that infusion of BK induces, via a stimulation of B2 receptors, the release of NO and of prostanoids. The latter agents activate through a reflex pathway the release of catecholamines from the adrenal medulla. This release increases blood glucose levels and reduces plasma insulin levels. After adrenoceptor inhibition, BK induces a secretion of insulin, via the stimulation of B2 receptors.

British Journal of Pharmacology (2001) 134, 1312–1318; doi:10.1038/sj.bjp.0704374
Effects of carbamazepine on the first ovulation in gonadotropin‐primed immature female rats
Authors: Tamura Kazuhiro , Yatabe Yoriko , Sakamoto Hajime , Hosokawa Masakiyo , Kobayashi Kaoru , Chiba Kan , Kogo Hiroshi 
Published: January 2005

The effects of carbamazepine (CBZ) and its possible mechanisms on the first ovulation were investigated in immature female rats. The first ovulation was induced by administration of equine chorionic gonadotropin (eCG) at 0800 h at 26 days of age.
A single s.c. injection of 360 mg kg−1 CBZ at 1300 h on the first pro‐oestrus (day 28) completely inhibited the first ovulation on the morning of day 29. A marked elevation in 13, 14‐dihydro‐prostaglandin F2α (13, 14H2‐PGF2α) forming capacity, a sensitive indicator of luteinizing hormone (LH) surge, was not detected in the CBZ‐treated group at 0800 h on day 29 (72 h after eCG treatment). The elevation in serum LH levels at 57 h after eCG treatment was not observed in the CBZ‐treated group, either. The blocking of the first ovulation and 13, 14H2‐PGF2α forming capacity were recovered by an i.p. injection of human CG on day 28 in all animals.
However, the first ovulation was not blocked by repeated injections of 360 mg kg−1 CBZ at 1300 h once daily for 3 days (days 26 – 28). The repeated injections of CBZ caused a great fall (64% decrease) in the serum levels of CBZ at 4 h after the final CBZ injection as compared with the case of a single injection of CBZ and resulted in a delay for 5 h the occurrence of LH surge, which is normally observed around 57 h after eCG injection.
A significant increase in the activity of microsomal CBZ catabolism by the repeated injections of CBZ was quantitatively verified by the HPLC analysis. But, the activity of CBZ metabolism in the single injected‐animals showed almost similar levels to that in the control.
The present results demonstrated that a single injection of CBZ blocks the ovulation by inhibiting LH surge but that the failure of the inhibition of ovulation by repeated injections of CBZ is due to a decrease in serum CBZ levels mediated through CBZ‐induced hepatic enzyme induction.

British Journal of Pharmacology (2001) 134, 1328–1334; doi:10.1038/sj.bjp.0704375