bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of S‐adenosyl‐L‐methionine on chronic mild stress‐induced anhedonia in castrated rats
Authors: Benelli A , Filaferro M , Bertolini A , Genedani S 
Published: January 2005

S‐adenosyl‐L‐methionine (SAMe) is the most important methyl donor in the brain and is essential for polyamine synthesis. Methyl group deficiency in the brain has been implicated in depression; on the other hand, polyamines enhance phosphorylation processes, and phosphorylation of functional proteins in neurons is involved in the therapeutic mechanisms of antidepressants.
The effect of SAMe in an animal model of ‘depression’, the chronic mild stress‐induced anhedonia, was studied using long‐term castrated male and female Lister hooded rats.
Chronic daily exposure to an unpredictable sequence of mild stressors produced, within 3 weeks, a significant reduction of the consumption of a sucrose solution. SAMe (100, 200 or 300 mg kg−1 daily i.m.) while having no influence on sucrose intake in non‐stressed animals, dose‐dependently reinstated sucrose consumption within the first week of treatment, both in male and in female stressed rats. Imipramine (10 mg kg−1 daily i.p.) produced a similar effect after a 3 week treatment.
Similarly, a palatable food reward‐induced place preference conditioning was developed in SAMe (200 or 300 mg kg−1 daily i.m.)‐ and in imipramine (10 mg kg−1 daily i.p.)‐treated chronically stressed animals (males and females), whilst it could not be obtained in vehicle‐treated rats.
Moreover, the same doses of SAMe (but not of imipramine) restored the exploratory activity and curiosity for the environment (rearing), in the open‐field test.
While imipramine caused a blockade of the growth throughout the treatment, SAMe produced only a transient growth arrest during the first week of treatment.
These results show that SAMe reverses an experimental condition of ‘depression‐like’ behaviour in rats, the effect being more rapid and complete than that of imipramine, and without apparent side effects.

British Journal of Pharmacology (1999) 127, 645–654; doi:10.1038/sj.bjp.0702589
Extracellular adenosine concentrations during in vitro ischaemia in rat hippocampal slices
Authors: Latini Serena , Bordoni Francesca , Pedata Felicita , Corradetti Renato 
Published: January 2005

The application of an ischaemic insult in hippocampal slices results in the depression of synaptic transmission, mainly attributed to the activation of A1 adenosine receptors by adenosine released in the extracellular space.
To estimate the concentration of endogenous adenosine acting at the receptor level during an ischaemic episode, we recorded field e.p.s.ps (fe.p.s.ps) from hippocampal slices, and evaluated the ability of the selective A1 receptor antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX), to reverse the fe.p.s.p. depression induced by in vitro ischaemia. A relationship between the IC50 of an antagonist and the endogenous concentration of a neurotransmitter has been used for pharmacological analysis.
The complete and reversible depression of fe.p.s.p. in the CA1 region induced by 5 min ischaemia was decreased in the presence of DPCPX (50–500 nM). 8‐Phenyltheophylline (10 μM) abolished the depression of fe.p.s.ps during the ischaemic period, while a small (peak effect 12±4%) decrease in fe.p.s.ps was observed during the initial phase of reperfusion.
In the time‐interval of maximal depression of fe.p.s.ps., IC50 and adenosine concentration changed as function of time with a good degree of correlation. The maximal value of adenosine concentration was 30 μM.
Our data provide an estimation of the adenosine concentration reached at the receptor level during an ischaemic episode, with a higher time discrimination (15 s) than that achieved with any biochemical approach. This estimation may be useful in order to establish appropriate concentrations of purinergic compounds to be tested for their pharmacological effects during an ischaemic episode.

British Journal of Pharmacology (1999) 127, 729–739; doi:10.1038/sj.bjp.0702591
Modulation of afferent‐evoked neurotransmission by 5‐HT3 receptors in young rat dorsal horn neurones in vitro: a putative mechanism of 5‐HT3 induced anti‐nociception
Authors: Khasabov S G , Lopez‐Garcia J A , Asghar A U R , King A E 
Published: January 2005

The in vitro hemisected spinal cord from young rat was used to investigate the mechanism of serotoninergic modulation of primary afferent‐mediated synaptic transmission in the dorsal horn through activation of the 5‐HT3 receptor.
Dorsal root‐evoked excitatory post‐synaptic potentials (DR‐EPSPs) were recorded intracellularly from dorsal horn neurones. Extracellular recordings of the population primary afferent depolarization (PAD) and the dorsal rootevoked dorsal root reflex (DR‐DRR) were made from segmental dorsal roots.
5‐Hydroxytryptamine (5‐HT) and the selective 5‐HT3 receptor agonist 1‐(m‐chloro‐phenyl)‐biguanide hydrochloride (m‐ChPB) (10 and 50 μM) induced statistically significant reductions of the DR‐EPSP amplitude (P<0.001) and duration (P<0.001) in the majority of dorsal horn neurones. The 5‐HT3 receptor selective antagonists 3‐Tropanyl‐indole‐3‐carboxylate hydrochloride (Tropisetron, 10 μM) and N‐(1‐Azabicyclo[2.2.2]oct‐3‐yl)‐6‐chloro‐4‐methyl‐3‐oxo‐3,4‐dihydro‐2H‐1,4‐benzoxazine‐8‐carboxamide (Y‐25130, 10 μM) abolished m‐ChPB‐induced DR‐EPSP attenuation and partially blocked the 5‐HT effect.
m‐ChPB (50 μM)‐induced DR‐EPSP amplitude and duration attenuation was retained in the presence of the GABAA receptor antagonist bicuculline (30 μM), the GABAB receptor antagonist saclofen (50 μM) and the opioid receptor antagonist naloxone (50 μM).
Both 5‐HT and m‐ChPB (10 and 50 μM) induced a PAD but the mean peak amplitude of 5‐HT‐induced PAD was significantly greater than PAD to m‐ChPB (98.6±12 μV compared to 51.8±10 μV for 50 μM of agonist, respectively). Tropisetron partially reduced 5‐HT‐induced PAD and abolished m‐ChPB‐induced PAD. 5‐HT, but not m‐ChPB, significantly (P<0.001) reduced the peak amplitude of the DR‐DRR and this action of 5‐HT was unaffected by Tropisetron or Y‐25130.
These data provide experimental evidence for a putative cellular mechanism at the level of the dorsal horn for anti‐nociceptive effects of 5‐HT3 receptor activation. This 5‐HT3‐mediated modulation of sensory afferent transmission was evidently independent of inhibitory GABA‐ or opioid‐dependent interneuronal pathways. The extent to which the 5‐HT3 receptor could be involved in the operation of endogenous analgesia and sensory modulation by descending monoamine bulbo‐spinal pathways is discussed.

British Journal of Pharmacology (1999) 127, 843–852; doi:10.1038/sj.bjp.0702592
E5531, a synthetic non‐toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide
Authors: Kawata Tsutomu , Bristol John R , Rossignol Daniel P , Rose Jeffrey R , Kobayashi Seiichi , Yokohama Hiromitsu , Ishibashi Akira , Christ William J , Katayama Koichi , Yamatsu Isao , Kishi Yoshito 
Published: January 2005

The major pathological responses to Gram‐negative bacterial sepsis are triggered by endotoxin or lipopolysaccharide. As endotoxin is shed from the bacterial outer membrane, it induces immunological responses that lead to release of a variety of cytokines and other cellular mediators. As part of a program aimed at developing a therapeutic agent for septic shock, we have developed E5531, a novel synthetic lipopolysaccharide antagonist.
As measured by release by tumour necrosis factor‐α, human monocytes or whole blood can be activated by lipopolysaccharide, lipid A, and lipoteichoic acid (from Gram‐positive bacteria). E5531 potently antagonizes activation by all these agents while itself being devoid of agonistic activity.
The inhibitory activity of E5531 was dependent on time of addition. When 10 nM E5531 was added simultaneously with lipopolysaccharide or 1–3 h before addition of lipopolysaccharide, production of tumour necrosis factor‐α was inhibited by more than 98%. The addition of E5531 1 h after lipopolysaccharide reduced the efficacy of E5531 by 47%.
Antagonistic activity of E5531 was specific for lipopolysaccharide as it was ineffective at inhibiting interferon‐γ mediated NO release of RAW 264.7 cells, phorbor 12‐myristate 13‐acetate stimulated superoxide anion production in human neutrophils, concanavalin A stimulated mitogenic activity in murine thymocytes and tumor necrosis factor‐α induced E‐selectin expression in human umbilical vein endothelial cells.
E5531 as well as MY4, an anti‐CD14 antibody, inhibited radiolabelled lipopolysaccharide binding in human monocytes.
These results support our contention that E5531 is a potent antagonist of lipopolysaccharide‐induced release of tumour necrosis factor‐α and other cellular mediators and may be an effective therapeutic agent for human septic shock due to Gram‐negative bacteria.

British Journal of Pharmacology (1999) 127, 853–862; doi:10.1038/sj.bjp.0702596
Relevance of benzyloxy group in 2‐indolyl methylamines in the selective MAO‐B inhibition
Authors: Pérez Virgili , Marco José Luis , Fernández‐Álvarez Eldiberto , Unzeta Mercedes 
Published: January 2005

Previous studies with indolyl derivatives as monoamine oxidase (MAO) inhibitors have shown the relevance of the indole structure for recognition by the active site of this enzyme. We now report a new series of molecules with structural features which determine the selectivity of MAO inhibition.
A benzyloxy group attached at position 5 of the indole ring is critical for this selective behaviour. Amongst all of these benzyloxy‐indolyl methylamines, N‐(2‐propynyl)‐2‐(5‐benzyloxyindol)methylamine FA‐73 was the most potent MAO‐B ‘suicide’ inhibitor studied.
The Ki values for MAO‐A and MAO‐B were 800±60 and 0.75±0.15 nM, respectively. These data represent a selectivity value of 1066 for MAO‐B, being 48 times more selective than L‐deprenyl (Ki values of 376±0.032 and 16.8±0.1 nM for MAO A and MAO‐B, respectively). The IC50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150±8 μM for FA‐73 and 68±10 μM for L‐deprenyl whereas in human caudate tissue the IC50 values were 0.36±0.015 μM for FA‐73 and 0.10±0.007 μM for L‐deprenyl. Moreover, mouse brain MAO‐B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg−1 adminstration, MAO‐A activity was not affected.
These novel molecules should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non‐amphetamine‐like MAO‐B inhibitors with therapeutic potential for the treatment of neurological disorders.

British Journal of Pharmacology (1999) 127, 869–876; doi:10.1038/sj.bjp.0702600
Pharmacological modulation of secondary mediator systems–cyclic AMP and cyclic GMP–on inflammatory hyperalgesia
Authors: Cunha F Q , Teixera M M , Ferreira S H 
Published: January 2005

The objective of the present paper was to evaluate the relevance of neuronal balance of cyclic AMP and cyclic GMP concentration for functional regulation of nociceptor sensitivity during inflammation.
Injection of PGE2 (10–100 ng paw−1) evoked a dose‐dependent hyperalgesic effect which was mediated via a cyclic AMP‐activated protein kinase (PKA) inasmuch as hyperalgesia was blocked by the PKA inhibitor H89.
The PDE4 inhibitor rolipram and RP73401, but not PDE3 and PDE5 inhibitors potentiated the hyperalgesic effects of PGE2. The hyperalgesic effect of dopamine was also enhanced by rolipram. Moreover, rolipram significantly potentiated hyperalgesia induced by carrageenan, bradykinin, TNFα, IL‐1β, IL‐6 and IL‐8. This suggests that neuronal cyclic AMP mediates the prostanoid and sympathetic components of mechanical hyperalgesia. Moreover, in the neuron cyclic AMP is mainly metabolized by PDE4.
To examine the role of the NO/cyclic GMP pathway in modulating mechanical hyperalgesia, we tested the effects of the soluble guanylate cyclase inhibitor, ODQ. This substance counteracts the inhibitory effects of the NO donor, SNAP, on the hyperalgesia induced by PGE2.
The ODQ potentiated hyperalgesia induced by carrageenan, bradykinin, TNFα, IL‐1β, IL‐6 and IL‐8. In contrast, ODQ had no significant effect on the hyperalgesia induced by PGE2 and dopamine. This indicates that the hyperalgesic cytokines may activate soluble guanylate cyclase, which down‐regulate the ability of these substances to cause hyperalgesia. This event appears not to be mediated by prostaglandin or dopamine.
In conclusion, the results presented in this paper confirm an association between (i) hyperalgesia and elevated levels of cyclic AMP as well as (ii) antinociception and elevated levels of cyclic GMP. The intracellular levels of cyclic AMP that enhance hyperalgesia are controlled by the PDE4 isoform and appear to result in activation of protein kinase A whereas the intracellular levels of cyclic GMP results from activation of a soluble guanylate cyclase.

British Journal of Pharmacology (1999) 127, 671–678; doi:10.1038/sj.bjp.0702601
Protective effects of a superoxide dismutase mimetic and peroxynitrite decomposition catalysts in endotoxin‐induced intestinal damage
Authors: Salvemini Daniela , Riley Dennis P , Lennon Patrick J , Wang Zhi‐Qiang , Currie Mark G , Macarthur Heather , Misko Thomas P 
Published: January 2005

The relative contributions of superoxide anion (O2−) and peroxynitrite (PN) were evaluated in the pathogenesis of intestinal microvascular damage caused by the intravenous injection of E. coli lipopolysaccharide (LPS) in rats. The superoxide dismutase mimetic (SODm) SC‐55858 and the active peroxynitrite decomposition catalysts 5,10,15,20‐tetrakis(2,4,6‐trimethyl‐3,5‐disulphonatophenyl)‐porphyrinato iron (III) and 5,10,15,20‐tetrakis(N‐methyl‐4′‐pyridyl)‐porphyrinato iron (III) (FeTMPS, FeTMPyP respectively) were used to assess the roles of O2− and PN respectively.
The intravenous injection of LPS elicited an inflammatory response that was characterized by a time‐dependent infiltration of neutrophils, lipid peroxidation, microvascular leakage (indicative of microvascular damage), and epithelial cell injury in both the duodenum and jejunum.
Administration of the SODm SC‐55858, FeTMPS or FeTMPyP at 3 h post LPS reduced the subsequent increase in microvascular leakage, lipid peroxidation and epithelial cell injury. Inactive peroxynitrite decomposition catalysts exhibited no protective effects. Only, SC‐55858 inhibited neutrophil infiltration.
Our results suggest that O2− and peroxynitrite play a significant role in the pathogenesis of duodenal and intestinal injury during endotoxaemia and that their removal by SODm and peroxynitrite decomposition catalysts offers a novel approach to the treatment of septic shock or clinical conditions of gastrointestinal inflammation. Furthermore, the remarkable protection of the intestinal epithelium by these agents suggests their use during chemo‐ and radiation therapy, cancer treatments characterized by gastrointestinal damage. Potential mechanisms through which these radicals evoke damage are discussed.

British Journal of Pharmacology (1999) 127, 685–692; doi:10.1038/sj.bjp.0702604
Induction of apoptosis in human mitogen‐activated peripheral blood T‐lymphocytes by the ether phospholipid ET‐18‐OCH3: Involvement of the Fas receptor/ligand system
Authors: Cabaner Christelle , Gajate Consuelo , Macho Antonio , Muñoz Eduardo , Modolell Manuel , Mollinedo Faustino 
Published: January 2005

Activated T‐cells constitute a target for treatment of autoimmune diseases. We have found that the antitumour ether phospholipid 1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (ET‐18‐OCH3; edelfosine) induced dose‐ and time‐dependent apoptosis in human mitogen‐activated peripheral blood T‐lymphocytes, but not in resting T‐cells. T‐lymphocytes were stimulated with phytohemagglutinin and interleukin‐2 or with concanavalin A. Apoptosis was assessed by DNA fragmentation through cell cycle and TUNEL analyses, as well as through visualization of internucleosomal DNA fragmentation in agarose gels.
The ET‐18‐OCH3‐mediated apoptotic response in activated T‐lymphocytes was less intense than in human leukaemic T cell lines, such as Jurkat cells and Peer cells; namely about 25% apoptosis in activated T‐cells versus about 46–61% apoptosis in T leukaemic cells after 24 h treatment with 10 μM ET‐18‐OCH3.
The ET‐18‐OCH3 thioether analogue BM 41.440 (ilmofosine) showed a similar apoptotic capacity to that found with ET‐18‐OCH3 in activated T‐cells, whereas the phospholipid analogue hexadecylphosphocholine (miltefosine) failed to promote this response.
The uptake of [3H]‐ET‐18‐OCH3 was much larger in activated T‐cells than in resting lymphocytes.
Using a cytofluorimetric approach we have found that ET‐18‐OCH3 induced disruption of the mitochondrial transmembrane potential and production of reactive oxygen species in activated T‐cells, but not in resting lymphocytes.
ET‐18‐OCH3 induced an increase in Fas (APO‐1/CD95) ligand mRNA expression in activated T‐cells, and incubation with a blocking anti‐Fas (APO‐1/CD95) antibody partially inhibited the ET‐18‐OCH3‐induced apoptosis of activated T‐lymphocytes.
These results demonstrate that mitogen‐activated T‐cells, unlike resting lymphocytes, are able to take up significant amounts of ET‐18‐OCH3, and are susceptible to undergo apoptosis by the ether lipid via, in part, the Fas (APO‐1/CD95) receptor/ligand system. This ET‐18‐OCH3 apoptotic action can be of importance in the therapeutic action of this ether lipid in certain autoimmune diseases.

British Journal of Pharmacology (1999) 127, 813–825; doi:10.1038/sj.bjp.0702606
Comparative effects of several nitric oxide donors on intracellular cyclic GMP levels in bovine chromaffin cells: correlation with nitric oxide production
Authors: Ferrero Rut , Rodríguez‐Pascual Fernando , Miras‐Portugal Ma Teresa , Torres Magdalena 
Published: January 2005

Sodium nitroprusside, S‐nitroso‐N‐acetyl‐D,L‐penicillamine, Spermine NONOate and DEA NONOate raised cyclic GMP levels in bovine chromaffin cells in a time and concentration dependent manner with different potencies, the most potent being DEA/NO with an EC50 value of 0.38±0.02 μM.
Measurements of NO released from these donors revealed that DEA/NO decomposed with a half‐life (t1/2) of 3.9±0.2 min. The t1/2 for SPER/NO was 37±3 min. SNAP decomposed more slowly (t1/2=37±4 h) and after 60 min the amount of NO produced corresponded to less than 2% of the total SNAP present. The rate of NO production from SNAP was increased by the presence of glutathione.
For DEA/NO and SPER/NO there was a clear correlation between nitric oxide production and cyclic GMP increases. Their threshold concentrations were 0.05 μM and maximal effective concentration between 2.5 and 5 μM.
For SNAP, threshold activation was seen at 1 μM, whereas full activation required a higher concentration (500–750 μM). The dose‐response for SNAP increases in cyclic GMP was shifted nearly two orders of magnitude lower in the presence of glutathione. At higher concentrations an inhibition of cyclic GMP accumulation was found. This effect was not observed with either the nitric oxide‐deficient SNAP analogue or other NO donors.
Although NO‐donors are likely to be valuable for studying NO functions, their effective concentrations and the amount of NO released by them are very different and should be assessed in each system to ensure that physiological concentrations of NO are used.

British Journal of Pharmacology (1999) 127, 779–787; doi:10.1038/sj.bjp.0702607
Intravascular ATP and coronary vasodilation in the isolated working rat heart
Authors: Korchazhkina Olga , Wright Gordon , Exley Christopher 
Published: January 2005

Adenosine‐5′‐triphosphate (ATP) is a potent coronary vasodilator. Because of the efficient hydrolysis of ATP, adenosine‐5′‐diphosphate (ADP) and adenosine‐5′‐monophosphate (AMP) by ectonucleotidases located in the coronary endothelium ATP‐induced vasodilation may be mediated via both P1 (AMP and adenosine) and P2Y (ATP and ADP) receptors. We have used the change in total coronary resistance (TCR) induced by intravascular ATP in the isolated working rat heart to determine both the component of the vasodilation mediated via P2Y receptors and the identity of the subclass of receptor involved.
The dose response for ATP revealed a half maximal effect at an apparent ATP concentration of 0.08±0.009 μM. The response was saturated at apparent ATP concentrations greater than 0.23 μM. Contrary to much of the current literature, the perfusion of a 0.25 μM concentration of adenosine resulted in the identical response to an equimolar concentration of ATP suggesting a significant role for adenosine in coronary vasodilation.
The non‐selective P1 receptor antagonist 8‐(p‐Sulfophenyl)theophylline (8‐SPT) was used to show that the response to ATP was mediated via both P1 and P2Y receptors. Whilst 8‐SPT abolished the effect of adenosine it reduced the effect of ATP by only 50%. Thus, at a saturating concentration of ATP, P1 and P2Y receptors were shown to contribute equally to the observed vasodilation.
Uridine‐5′‐triphosphate (UTP), ADP and adenosine‐5′‐O‐thiotriphosphate (ATPγS) were used to characterize the component of coronary vasodilation that was mediated via P2Y receptors. UTP at 0.25 μM was ineffective and did not induce vasodilation. Perfusion with 0.25 μM ADP resulted in a vasodilation that was identical to 0.25 μM ATP. In the absence of 8‐SPT the perfusion of 0.25 μM ATPγS produced a vasodilation that was significantly (P<0.05) less than ATP. However, the vasodilation due to ATPγS, like that of adenosine, but unlike that of both ATP and ADP, was abolished in the presence of 8‐SPT. The ability of ADP to induce vasodilation combined with both the lack of response to UTP and the ability of 8‐SPT to abolish the vasodilation induced by ATPγS suggested very strongly that the component of ATP‐induced coronary vasodilation in the isolated working rat heart that was mediated via P2Y receptors was achieved by the action of ADP (and not ATP) at P2Y1 receptors.
These results suggest that the vasodilatory action of intravascular ATP in the coronary circulation should be attributed to the dual and equal activities of adenosine and ADP acting at P1 and P2Y1 receptors respectively.

British Journal of Pharmacology (1999) 127, 701–708; doi:10.1038/sj.bjp.0702610
Inverse agonist activities of β‐adrenoceptor antagonists in rat myocardium
Authors: Varma D R , Shen H , Deng X F , Peri K G , Chemtob S , Mulay S 
Published: January 2005

Negative inotropic effects of several β‐adrenoceptor (βAR) antagonists on electrically‐stimulated right atria, left atria, right ventricles and left ventricular papillary muscles from reserpine‐treated rats were used as a measure of their inverse agonist activities.
β1AR antagonists acebutolol, atenolol and metoprolol, β2AR antagonist ICI‐181,551 and nonselective βAR antagonists alprenolol, nadolol, propranolol and timolol produced negative inotropic effects, which were most marked on the right atria.
The nonselective βAR antagonist pindolol did not exhibit inverse agonist activity but inhibited the negative inotropic activities of ICI‐118,551, atenolol and propranolol.
The negative inotropic effects of lidocaine, nifedipine and pentobarbitone were similar on all the four myocardial preparations.
The positive inotropic efficacy of salbutamol on right and left atria but not on right ventricles and papillary muscles was comparable to that of isoprenaline. The antagonist activity of ICI‐118,551 against isoprenaline was greater on right atria than on other cardiac regions.
β1AR proteins were expressed in all regions of the heart but of β2AR were primarily localized in the right atrium.
It is concluded that β2AR play a greater role in right atria than in other cardiac regions and almost all βAR antagonists behave as inverse agonists.

British Journal of Pharmacology (1999) 127, 895–902; doi:10.1038/sj.bjp.0702616