bluuebunny/crossref_metadata_2025 huggingface dataset:
Depletion of Copper and Manganese in Brain after MPTP Treatment of Mice
Authors: Ríos Camilo , Alvarez‐Vega Rocío , Rojas Patricia
Published: March 2009

Abstract: The mechanism of action of MPTP, a parkinsonism‐inducing drug has been related to trace metals as a result of the observed potentiation of the neurotoxic action of the drug when diethyldithiocarbamate is concurrently administered. Diethyldithiocarbamate is a well‐known chelator of trace metals, particularly copper. In the present study we analyzed the concentrations of copper and manganese in four brain regions of mice treated with neurotoxic doses of MPTP, in order to further substantiate the relationship between trace metals of MPTP‐induced neurotoxicity. Male Swiss albino mice were administered with MPTP (30 mg/kg) for either three or five days. Seven days after the last MPTP administration, they were sacrified and the content of manganese and copper in the following regions was determined by graphite furnace atomic absorption spectrophotometry: cortex, cerebellum, midbrain and corpus striatum. Results indicate a significant depletion of manganese in corpus striatum (19.5% versus control) in the mice treated with MPTP for 5 days. Copper was also found to be decreased in corpus striatum (17.3% in mice treated for 3 days and 51.3% in mice treated for 5 days). Midbrain copper was depleted by 42.9% in the group of mice treated for 5 days with MPTP. Results indicate that MPTP induced a diminution of both copper and manganese in corpus striatum, suggesting that this alteration could be related to MPTP mechanism of action.
Mechanism of Cisplatin Ototoxicity: Antioxidant System
Authors: Ravi Radhika , Somani Satu M. , Rybak Leonard P.
Published: March 2009

Abstract: The dose and duration limiting toxic effects of cisplatin are ototoxicity and nephrotoxicity. While several studies have attempted to shed some light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investigation was undertaken to delineate the potential mechanisms underlying cisplatin ototoxicity. The role of glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde levels, and antioxidant enzyme activities [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplatin. Male Wistar rats were treated with various doses of cisplatin. Pretreatment auditory brain stem evoked responses (ABR) were performed and then post‐treatment ABRs and endocochlear potentials were also performed after three days. Acute cochlear toxicity (ototoxicity) was evidenced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin‐treated rats as compared to control animals. The rats were sacrified and cochleae isolated. The GSH, GSSG and malondialdehyde levels, and antioxidant enzyme activities were determined. Cisplatin ototoxicity correlated with a decrease in cochlear GSH [0.45±0.012 nmol/mg] after cisplatin administration compared to 0.95±012 nmol/mg in control cochleae (P<0.05). Superoxide dismutase, catalase activities and malondialehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH‐peroxidase and GSH reductase activity significantly decreased after cisplatin administration. Alterations in the activity of antioxidant enzymes, an increase in malondialdehyde levels, and depletion of cochlear GSH suggest a role for reactive oxygen species mediated damage of the cochlea in cisplatin toxicity. These biochemical changes were accompanied by the elevation of ABR threshold that appears to correlate well with alterations in antioxidant systems which could be the cause of cisplatin ototoxicity.
Cytochrome P4502E1 Inhibition by Propylene Glycol Prevents Acetaminophen (Paracetamol) Hepatotoxicity in Mice without Cytochrome P4501A2 Inhibition
Authors: Thomsen Mikael S. , Loft Steffen , Roberts Dean W. , Poulsen Henrik E.
Published: March 2009

Abstract:Acetaminophen hepatotoxicity is associated with its biotransformation to the reactive metabolite N‐acetyl‐p‐benzoquinone imine that binds to protein. Two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated as primarily responsible for the bioactivation. To determine the relative contributions of these P450's, overnight fasted male NMRI mice were pretreated with 10 ml of 50% v/w propylene glycol/kg or fluvoxamine (10 mg/kg) at–80 and–20 min. relative to acetaminophen dosing to inhibit CYP2E1 and CYP1A2, respectively. Mice were sacrificed at 0.5 or 4 hr after a hepatotoxic dose of acetaminophen (300 mg/kg). Propylene glycol or propylene glycol plus fluvoxamine, but not fluvoxamine alone protected against acetaminophen hepatotoxicity as indicated by abolished increase in serum alanine aminotransferase activity, less depletion of hepatic glutathione and lower livenbody weight ratios. Propylene glycol inhibited the activity of CYP2E1 as indicated by 84% reduction in the clearance of 3 mg/kg dose of chlorzoxazone, whereas fluvoxamine inhibited the activity of CYP1A2 as indicated by 40% reduction in the clearance of a 10 mg/kg dose of caffeine. For this animal model, the data are consistent with the notion that hepatotoxicity is associated with bioactivation of acetaminophen by CYP2E1 but not by CYP1A2.
Effects of Ethanol on Recombinant Rat GABAAReceptors: [35S]t‐Butylbicyclophosphorothionate ([35S]TBPS) Binding Study
Authors: Korpi Esa R. , Herb A. , Lüddens H.
Published: March 2009

Abstract:To determine the roles of the alternatively spliced short and long forms of the γ2 subunit in the effect of ethanol on the GABAAreceptor function, picrotoxin‐sensitive [35S]t‐butylbicyclophosphorothionate ([35S]TBPS) binding was studied in recombinant rat α1β2γ2 and α6β2γ2 receptors expressed in human embryonic kidney 293 cells. Ethanol (10–500 mM) in the absence of added GABA had only minor effects on [35S]TBPS binding irrespective of the γ2 splice variant, its effects being greater in α6β2γ2 than in α1β2γ2 receptors. Ethanol (100 mM) decreased the binding in all four subunit combinations at various concentrations of GABA, again an effect independent of the γ2 variant. The two γ2 variants had different effects on GABA modulation of the binding, with the long γ2 variant decreasing the efficiency of GABA inhibition in α6β2γ2 receptors and enhancing the biphasic GABA stimulation and inhibition in α1β2γ2 receptors. The findings confirm the importance of the α subunits in the allosteric interactions between the convulsant binding site and other effector sites, which can be modified only to a minor extent by the type of the γ2 splice variant.
Furosemide Elicits Immediate Sympathoexcitation via a Renal Mechanism Independent of Angiotensin II
Authors: Petersen Jørgen S. , DiBona Gerald F.
Published: March 2009

Abstract:This investigation aimed at examing the hypothesis that furosemide elicits renal sympathoexcitation through stimulation of renal renin release, which in turn produces increased plasma angiotensin II levels, causing centrally mediated sympathoexcitation. In addition, direct central nervous actions of furosemide on central control of mean arterial pressure, heart rate, and efferent renal sympathetic nerve activity were examined. Furosemide (300 mg/kg intravenously) was administered to four groups of rats: (1) control; (2) nephrectomized; (3) with intravenous losartan blockade (10 μmol/kg); and (4) with intracerebroventricular losartan blockade (10 nmol). In a fifth group of rats, furosemide was administered intracerebroventricularly (0, 2.5, 25 or 250 μg). To eliminate reflex control of mean arterial pressure, heart rate and efferent renal sympathetic nerve activity, all experiments were performed in rats with sinoaortic denervation and bilateral vagotomy. Experiments were performed during Saffan anaesthesia (0.9% alphaxalone/0.3% alphadolone), and rats were paralyzed with pancuronium and artifically ventilated. Furosemide produced an immediate 40% increase in efferent renal sympathetic nerve activity while the furosemide vehicle, 2 vol.% ethanolamine, did not affect efferent renal sympathetic nerve activity. The furosemide‐induced increase in efferent renal sympathetic nerve activity was abolished in rats with bilateral nephrectomy but it was not affected by intravenous or intracerebroventricular losartan blockade. Intracerebroventricular angiotensin II produced an increase in mean arterial pressure and efferent renal sympathetic nerve activity whereas intravenous angiotensin II produced a pressor response in absence of increased efferent renal sympathetic nerve activity. Losartan effectively blocked responses to intravenous or intracerebroventricular angiotensin II. Intracerebroventricular administration of furosemide produced no changes in mean arterial pressure, heart rate or efferent renal sympathetic nerve activity. It is concluded that intravenous administration of furosemide elicits an immediate increase in efferent renal sympathetic nerve activity via a renal mechanism independent of angiotensin II. Intracerebroventricular furosemide has no effect on central nervous control of mean arterial pressure, heart rate or efferent renal sympathetic nerve activity.
Pharmacokinetics, Metabolism and Toxicity of the Plant‐Derived Photoxin α‐Terthienyl
Authors: Marles R. , Durst T. , Kobaisy M. , Soucy‐Breau C. , Abou‐Zaid M. , Arnason J. T. , Kacew S. , Kanjanapothi D. , Rujjanawate C. , Meckes M. , Lozoya X.
Published: March 2009

Abstract: The plant‐derived insecticide, α‐terthienyl was prepared by synthesis as 3′,4′‐di[14C]‐α‐terthienyl for pharmacokinetic and metabolism studies. When administered orally to rats at a single dose of 50 mg/kg, excretion of the labelled material was maximal one day after administration and declined to no measurable quantities by day 4. Two metabolites [1,4‐di(2′‐thienyl)1,4‐butadione and 2‐2′‐bithiophene‐5‐carboxylic acid] and trace quantities of the parent material were isolated from the urine and chemically identified. These represent the first metabolites of α‐terthienyl identified. In pilot acute and subacute trials, unlabelled α‐terthienyl was non‐toxic when administered orally to rats as the “ready to use” formulation (0.1% active ingredient). The pure compound had an LD50 of 110 mg/kg when administered intraperitoneally to rats. The results suggest that there is considerable separation with respect to mosquito larvae and non‐target mammal sensitivity.
Hepatocellular Regeneration: Key to Thioacetamide Autoprotection
Authors: Mangipudy Raja S. , Chanda Sanjay , Mehendale Harihara M.
Published: March 2009

Abstract:Low doses of thioacetamide stimulate cell division and tissue repair in the liver. The objective of this study was to develop an autoprotection model for thioacetamide and investigate if a low dose of thioacetamide (50 mg/kg orally) protects against lethality of a subsequently administered lethal dose (400 mg/kg orally) of the same compound. The extent of cell division was investigated to test if autoprotection results from augmented tissue repair and recovery from injury rather than decreased injury itself. After a single administration of the protective dose of thioacetamide, hepatocellular nuclear DNA synthesis as measured by3H‐thymidine incorporation into hepatocellular nuclear DNA peaked at 36 hr indicating maximum level of S‐phase stimulation. Pretreatment with the antimitotic colchicine abolished autoprotection and this was associated with a significantly decreased3H‐thymidine incorporation. Preadministration of the protective dose of thioacetamide did not result in an altered infliction of injury from the subsequently administered lethal dose. Colchicine intervention in the autoprotected group resulted in injury that followed a pattern similar to the group that received the high dose alone, ultimately resulting in animal death. These findings suggest that cell division stimulated by the protective low dose of thioacetamide is the critical mechanism in thioacetamide autoprotection.
Prolonged Oral Treatment with Two Monoesters of meso‐2,3‐Dimercaptosuccinic Acid for Depleting Inorganic Mercury Retention in Suckling Rats
Authors: Kostial Krista , Blanuša Maja , Piasek Martina , Jones Mark M. , Singh Pramod K.
Published: March 2009

Abstract: Two monoesters of meso‐2,3‐dimercaptosuccinic acid (DMSA), monoisoamyl meso‐2,3‐dimercaptosuccinate (Mi‐ADMS) and mono‐n‐hexyl meso‐2,3‐dimercaptosuccinate (Mn‐HDMS) were compared to DMSA in their efficiency to mobilize 203Hg in mercury‐laden suckling rats. Seven‐day‐old pups were given 203Hg (18.5 kBq) with a dose of 0.5 mg Hg/kg/day as HgCl2 for five days. Seven days after the beginning of Hg loading a ten‐day oral treatment with DMSA, Mi‐ADMS, or Mn‐HDMS was administered at a dose of 0.25 mmol/kg/day. At the end of experiment, radioactivity was measured in the whole body, liver, both kidneys, and brain. Monoesters of DMSA were superior to DMSA in decreasing body and organ Hg retention. The highest reduction in comparison to controls in groups treated with DMSA, Mi‐ADMS, or Mn‐HDMS occurred in the kidneys (48%, 97%, and 96%), followed by reduction in the liver (24%, 84%, and 83%), and in the brain (8%, 23%, and 23%, respectively). For both, Mi‐ADMS and Mn‐HDMS, the reductions in the whole body and organs were significantly greater than in controls or DMSA‐treated rats. No difference between the efficiency of the two DMSA‐monoesters was found.
Different Postnatal Development of Convulsions and Lethality Induced by Strychnine in Rats
Authors: Kubová Hana , Mareš Pavel
Published: March 2009

Abstract:The convulsant action of strychnine was studied in 310 male albino rats, aged 3 to 25 days. Doses of 0.25–4 mg/kg were administered intraperitoneally and the animals were observed for 30 min. Generalized tonic‐clonic seizures involving also tonic hindlimb extension occurred in all age groups. The convulsant effects of strychnine increased from day 3 to day 18, and decreased again from day 25, as indicated by the incidence and latencies of seizures. Lethal effects did not occur before day 12. Hyperactivity was seen as the first sign of strychnine action in rats during the first week of life, automatisms predominating in 18‐day‐old animals. Electroencephalographic study in 30 rat pups with implanted electrodes demonstrated an extremely poor electro‐clinical correlation.
[3H]Dexamethasone Binding Activity in Liver Microsomes is Modulated Differently by 17 α‐Alkylated Androgens and Testosteronein vivo
Authors: Fernández Leandro , Boada Luis D. , Luzardo Octavio P. , Zumbado Manuel , López Antonio , Díaz‐Chico Bonifacio N. , Chirino Ricardo
Published: March 2009

Abstract:Rat liver microsomes contain a single class of steroid binding sites, capable of binding various glucocorticoids and progesterone. In a previous article, we have described thein vitrointeraction of several androgens with this binding site. Unlike natural androgens, the 17 α‐alkyl derivatives stanozolol and danazol were capable of interacting with this binding site through a negative allosteric pattern. Now, the effects these steroids exert on the microsomal [3H]dexamethasone binding site have been studiedin vivo.The administration of a single dose of stanozolol to rats provoked a significant reduction in the microsomal [3H]dexamethasone binding capacity. This effect was maximal two hr after stanozolol administration and persisted for six hr. The restoration of the [3H]dexamethasone binding level after stanozolol administration was dependent on protein synthesis, since it was blocked by the concomitant administration of cycloheximide. None of the other androgens tested (danazol, methyltestosterone, fluxymesterone, and testosterone propionate) was capable of provoking a similar effect when administered 2 or 24 hr prior to sacrifice. In rats treated for seven days with a daily dose of diverse androgens and sacrificed 24 hr after the last treatment, none of the 17 α‐alkyl androgens assayed provoked significant changes in the microsomal [3H]dexamethasone binding level, although stanozolol, danazol, and methyltestosterone provoked a significant increase in glucocorticoid receptor concentration. In contrast, the administration of testosterone propionate provoked a 50% reduction in the [3H]dexamethasone binding level without causing changes in the glucocorticoid receptor concentration. These results provide new evidence on the existence of different effects on the liver of 17 α‐alkyl androgens, compared to the effects produced by natural androgens.
Altered cAMP Response after Isoprenaline Stimulation of Mononuclear Leucocytes from Insulin‐Dependent Diabetic Patients with Hypoglycaemia Unawareness
Authors: Trovik Thor S. , Vaartun Aase , Sager Georg
Published: March 2009

Abstract:Loss of adrenergic hypoglycaemic symptoms is the most distinctive feature in insulin‐dependent diabetes mellitus (IDDM) patients with hypoglycaemia unawareness. Previous reports fromin vivostudies show reduced heart rate responsiveness both to adrenergic agonists and antagonists in these patients. This study was carried out to investigate whether the reduced adrenergic sensitivity in IDDM patients with hypoglycaemia unawareness (IDDM‐unaware) also could be demonstrated as reduced increase in cAMP production in mononuclear leucocytes induced by isoprenaline stimulation, or reduced inhibition by ICI‐118551 (a selective β2‐adrenergic receptor blocker) of isoprenaline induced cAMP production. We found that the slope of the concentration‐response curves of isoprenaline/cAMP and the maximal cAMP concentrations obtained after isoprenaline stimulation were reduced in IDDM‐unaware compared to control and IDDM patients with normal hypoglycaemia awareness (IDDM‐aware). We did not find any significant differences in the response to ICI‐118551 between control, IDDM‐aware and IDDM‐unaware. This study supports the reports of reduced sensitivity of adrenergic agonists as a part of the pathophysiological changes in hypoglycaemia unawareness, but we have not been able to confirm the reports of an association between hypoglycaemia unawareness and reduced effect of adrenergic antagonists.
Cassia Senna Inhibits Mutagenic Activities of Benzo[a]‐pyrene, Aflatoxin B1, Shamma and Methyl Methanesulfonate
Authors: Al‐Dakan Ahmed A. , Al‐Tuffail Mohammed , Hannan Mohammed A.
Published: March 2009

Abstract: Ethanol extract of Senokot tablets (Cassia senna concentrate used as vegetable laxative), was found to be non‐mutagenic while it inhibited the mutagenicity of benzo[a]pyrene, shamma, aflatoxin B1 and methyl methanesulfonate in the Ames histidine reversion assay using the Salmonella typhimurium tester strain TA98. While the Senokot extract completely inhibited the mutagenicity of promutagens (i.e. metabolic activation dependent) like benzo[a]pyrene and shamma, it reduced the mutagenic activity of the direct acting mutagen methyl methanesulfonate by only 58%. The mutagen aflatoxin B1 showed a 25‐fold increase in the number of histidine revertants per plate at low concentrations (1.0–4.0 μg/plate) in the presence of metabolic activation system while at high concentrations (10.0–30.0 μg/plate) it proved to be weakly mutagenic (with a 5‐fold increase in the number of histidine revertants/plate) without metabolic activation. The Senokot extract completely inhibited the mutagenic effect of low concentrations of aflatoxin B1 in the presence of metabolic activation but not that resulting from higher concentrations without metabolic activation. The results obtained with benzo[a]pyrene, shamma and aflatoxin B1 indicated that the antimutagenic effects of Senokot extract could be largely due to an interaction with the metabolic process involved in the activation of procarcinogens. However, the results obtained with methyl methanesulfonate suggested that factors in Senokot may also interact with direct mutagens to produce some antimutagenic effects. An ethanol extract of crude senna leaves found to be weakly mutagenic also inhibited (though less than Senokot) the mutagenic effect of benzo[a]pyrene suggesting that the antimutagenic principle is present in the complex plant material itself.
Purinergic Inhibition of Neurotransmitter Release in the Central Nervous System
Authors: Ribeiro J. A.
Published: March 2009

Abstract:Neurotransmitter release and the role of adenosine in its regulation has been investigated for more than twenty years, and it is now widely accepted that adenosine tonically inhibits the release of excitatory neurotransmitters. This effect of adenosine is operated by an A1adenosine receptor. Since activation of this receptor could inhibit Ca2+conductance, increase K+conductance, inhibit adenylate cyclase or phospholipase C, it is not clear if there is only one mechanism or several mechanisms operated by adenosine to inhibit neurotransmitter release, and in that case, what is the relative importance of each mechanism. The mechanism by which adenosine inhibits evoked synchronous transmitter release might be different from that used by the nucleoside to inhibit spontaneous asynchronous release. In some systems adenosine triphosphateper seacts like adenosine and inhibits neurotransmitter release. However, in most cases the inhibitory effect of this adenine nucleotide depends upon its hydrolysis into adenosine by a cascade of ectoenzymes, the last step being mediated by ecto‐5′‐nucleotidase.
Role of Calcium Fluxes in the Action of Glucagon on Cytosolic Glutathione S‐Transferase Activity in Rat Liver Slices *
Authors: Monti Juan A. , Carnovale Cristina E. , Scapini Celina , Favre Cristián , Carrillo María C.
Published: March 2009

Abstract: In a previous study we demonstrated that the administration of 20 μg/kg b.wt. of glucagon to rats caused a significant diminution of hepatic cytosolic glutathione S‐transferase (GST) activity. This inhibition was non‐competitive and reversible. We suggested that the effect would be mediated by cytosolic effectors. The present work was performed to characterize the mechanism involved in this inhibition. Liver tissue slices (170 to 200 mg) were incubated during different periods of time (0, 5, 10, 15, 20 and 30 min.) with several concentrations of glucagon (10‐5M, 10‐8M and 10‐10M), dibutiryl cyclic AMP (10‐4M, 10‐6M and 10‐9M), divalent cation ionophore A23187 (10‐4M, 10‐6M and 10‐9M) or vasopressin (10‐7M, 5×10‐7M and 10‐8M). The incubation was done with or without calcium in the medium. In all cases the cytosolic GST activity were determined in liver slices. The percentage of inhibition of GST activity was directly related to the increase of concentration of the test substances. An inhibition between 40% to 45% after 10 min. of incubation with the highest concentrations was observed (except vasopressin which caused 10% of inhibition). 10‐10M glucagon did not produce a decrease of GST activity. The inhibition disappeared in calcium‐free incubated slices, but direct relationship between plasma‐membrane calcium influx and inhibition of GST activity (r=0.950, P<0.001, n=24) could be obtained. By using calmodulin antagonists, we conclude that the inhibition process of the enzyme was mediated by calmodulin. In summary, we propose that plasma‐membrane calcium influx induced by high concentrations of glucagon activates calmodulin, which promotes a modification (actually a methylation, according to other authors) on GST, thereby causing a decrease in its activity.
Inhibition of Alloxan‐Induced Hyperglycaemia in Mice by the Pyridoindole Stobadine
Authors: Stefek Milan , Trnkova Zuzana
Published: March 2009

Abstract:Alloxan‐induced hyperglycaemia was used as a model of free radical pathology to test the antioxidant activity of the pyridoindole drug, stobadine, in the intact mouse. Stobadine was injected intraperitoneally in a dose range 7.5–60 mg/kg prior to intravenous injection of alloxan (50 mg/kg), and blood glucose concentration 72 hr after alloxan administration was used as an index of alloxan toxicity. Stobadine efficiently suppressed the alloxan‐induced hyperglycaemia in a dose‐dependent manner. This protection against the diabetogenic effect of alloxan is consistent with the high efficacy of stobadine to scavenge hydroxyl radicals.
Antinociception and Side Effects of L‐and D‐Dipalmitoylphosphatidyl Choline Liposome‐Encapsulated Alfentanil after Spinal Delivery in Rats*
Authors: Isackson Joel , Wallace Marks S. , Ho Rodney J. Y. , Shen Danny D. , Yaksh Tony L.
Published: March 2009

Abstract:We have obseerved that spinal liposome administration in the rat resulted in an allodynia evoked by light touch. We later determined that liposomes composed of D‐isomer phospholipids were essentially non‐toxic. This study examines the effects of alfentanil encapsulated in liposomes made from the natural L‐isomer and synthetic D‐isomer of dipalmitoyl phosphatidyl choline on antinociception, side effects, and algogenic behaviour. Both unilamellar and multilamellar liposomes were studied. Rats prepared with chronic intrathecal catheters received intrathecal injections of alfentanil (5 or 50 μg) in saline or encapsulated in liposomes composed of either L‐ or D‐isomers of dipalmitoyl phosphatidyl choline (DPPC) in unilamellar or multilamellar liposome formulations. Antinociception was measured using the hot plate test (52.5°). Side effects were measured by catalepsy, corneal responses, pinna response, righting reflex, and paw step. Allodynia was measured by lightly stroking the animal's back. Intrathecal alfentanil in saline or in the liposomes produced a dose‐dependent increased latency in the hot plate response. Encapsulation of alfentanil in the liposomes produced a significant decrease in the loss of corneal, paw step and righting reflex and a slight decrease in catalepsy and loss of the pinna response. There was no significant difference between liposome preparations in preventing side effects. L‐multilamellar‐DPPC produced allodynia in 100% of the animals whereas significantly less allodynia was observed with the other preparations. This study indicates that liposomal preparations can significantly enhance the therapeutic ratio of a lipid soluble opioid after spinal delivery. However, the choice of lipids for the formulation of liposomes intended for spinal drug delivery must be considered since the L‐isomer and larger lipid load of multilamellar liposomes have a direct spinal effect leading to alledynia. Previous studies have in fact shown that spinal lysolecithin can yield focal demyelination.
Synthesis of Dopamine and 5‐HT in Anatomical Regions of the Rat's Brain is Unaffected by Sustained Infusion of Amperozide
Authors: Adell Albert , Myers Robert D.
Published: March 2009

Abstract:The 5‐HT2Aantagonist, amperozide, is considered to be a potentially useful drug for the treatment of substance abuse. The effects of this drug on the Sprague‐Dawley rat were examined on the synthesis of dopamine and serotonin (5‐HT) as well as on the intakes of food and water and the level of body weight. Amperozide was delivered subcutaneously by osmotic minipump in doses of 2.5 mg/kg or 5.0 mg/kg per day for 7 days. After injection of 100 mg/kg NSD‐1015, each brain was dissected post mortem into midbrain, pons, hypothalamus, septum, nucleus accumbens, striatum, frontal cortex and the hippocampus. Neither concentration of amperozide altered the synthesis of dopamine or 5‐HT, as measured in terms of the formation of 1–3,4‐dihydroxyphenylalanine (L‐DOPA) and 5‐hydroxytryptophan (5‐HTP), respectively, in any of the 8 brain regions analyzed. Both doses of amperozide reduced food intake by 20% within 24 hr after implantation of the pumps, but feeding resumed postoperatively at the control level within 48 hr. Amperozide affected neither the intake of water nor the level of body weight. The lack of effect on the synthesis of dopamine and 5‐HT and the absence of side effects on the intakes of food and water suggest that amperozide may be a specific agent for suppressing alcohol drinking.
Activators of Sodium, Calcium and Potassium Channels Modulate the Cardiac Effects of Quinidinein vitro
Authors: Brasch Helmut
Published: March 2009

Abstract:Quinidine (25.5 μmol/l) reduced the beating frequency of isolated right guinea‐pig atria, caused a negative inotropic effect in papillary muscles and slightly raised the contractile force of left atria. The functional refractory period of both tissues was prolonged. A 20% increase of the extracellular sodium concentration did not reverse the effects of quinidine. The Na‐channel activator BDF 9148 (1 μmol/l) and the Ca‐channel agonist Bay‐K‐8644 (0.5 μmol/l) further increased the contractile force and caused an additional prolongation of the functional refractory period in quinidine‐pretreated atria. Only Bay‐K‐8644 was able to reverse the negative inotropic effect of quinidine in papillary muscles. The influence of Bay‐K‐8644 on the contractile force in quinidine‐pretreated muscles was not attenuated by lemacalim (3 μmol/l), an activator of ATP‐dependent potassium channels, but the duration of the functional refractory period was significantly reduced. These results suggest that a combination of a calcium channel activator and a potassium channel opener might be able to improve the treatment of quinidine intoxications.
Cytotoxic Effects of Four Antibiotics on Endothelial Cells
Authors: Lanbeck Peter , Paulsen Otto
Published: March 2009

Abstract: Intravenous administration of antibiotics often causes local pain and thrombophlebitis at the site of injection. An in vitro model that could predict these effects would be of great value. In this study the effects of four antibiotics, benzylpenicillin, cefuroxime, dicloxacillin and erythromycin, have been evaluated on three types of endothelial cells in culture. The cell types employed were primary culture from human umbilical vein, primary culture from bovine aorta, and the cell line EA‐hy 926, a hybride endothelial cell. These cells were exposed to antibiotics for 24 hr and subsequently toxic effects on cells were evaluated by three different assays. Benzylpenicillin was atoxic in all types of cells and in all assays, in contrast to the other antibiotics. The other three antibiotics exerted dose dependent toxic effects in all investigated cells when DNA‐synthesis and total cell protein were used as toxicity assays but the results varied between the cell types. There were no significant differences between the effects of cefuroxime, dicloxacillin and erythromycin on bovine endothelial cells. In the other cell types, however, there were significant differences between some drugs but the outcome depended on the cell type. It is concluded that it is possible to show differences between the effect of antibiotics on endothelial cells, but the result depends on the cell type employed.
Biochemical Changes and Morphological Alterations of Liver and Kidney in Hamsters after Administration of the HMG‐Coenzyme A Reductase Inhibitor, Simvastatin: Prevention and Reversibility by Mevalonate *
Authors: Oms Philippe , Assie Nathalie , Bruniquel Françoise , Degryse Anne‐Dominique , van Haverbeke Georges , Delhon André
Published: March 2009

Abstract:The present study analyses the effects of simvastatin, a specific inhibitor of the 3‐hydroxy‐3‐methylglutarylcoenzyme A (HMG‐CoA reductase) in male Syrian hamsters fed a standard diet or a diet supplemented with 0.12% cholesterol and 20% coconut oil. In hamsters fed the standard diet, gastric administration of simvastatin (10 mg/kg/day) during 12 days was found to be lethal and to have hepatotoxic and nephrotoxic effects. This toxicity was exacerbated in hamsters fed a hyperlipidaemic diet and was preceded by a progressive anorexia and loss of body weight. Marked elevations in serum aspartate and alanine aminotransferase activities were associated with the organ lesions. All elevated biochemical changes and morphological alterations were prevented or reversed by coadministration of mevalonate, the product of the HMG‐CoA reductase. It is suggested that the dramatic effect of simvastatin could result from depletion of a non‐sterol metabolite of mevalonate in spite of a lack of protective effects of farnesol and geranylgeraniol in the following study. The toxicity of simvastatin could indeed result from the low basal activity of HMG‐CoA reductase in hamster liver coupled with a prolonged inhibition of mevalonate synthesis.
Gastric Mucosal Damage Accompanying Changes in Mucin Induced by Histamine in Rats
Authors: Ohara Susumu , Tsurui Mituji , Watanabe Tomoe , Ichikawa Takafumi , Hotta Kyoko
Published: March 2009

Abstract: The present study was carried out to clarify the mechanism of histamine‐induced gastric mucosal damage in rats. Following an injection of histamine (80 mg/kg), pH dropped within 30 min. and then recovered control value (pH=4–5) 4 hr later. The decrease in mucosal mucin content and the appearance of haemorrhagic erosions followed the drop in pH. The recovery of mucosal mucin content preceded the healing of haemorrhagic erosions and pH recovery to the control level. Histamine also caused qualitative changes in corpus mucins. These qualitative changes induced by histamine were eliminated at 7 hr following the administration of histamine. It appears from the present results that increase in HCl and decrease in mucins induced by histamine bring about gastric damage.
Protective Effects of Antioxidants Against Uraemia‐Induced Lipid Peroxidation and Glutathione Depletion in Humans
Authors: Hassan M. Q. , Hussain S. A. , Zaki M. A. , Alsharif N. Z. , Stohs S. J.
Published: March 2009

Abstract: The effects of uraemias and antioxidant therapy for 40 days with vitamin A, vitamin C and vitamin E on blood and erythrocyte sulfhydryl (glutathione, GSH) content and on erythrocyte glutathione‐S transferase (GST), glutathione reductase (GSR) and glutathione peroxidase activities were studied in six uraemic patients maintained on haemodialysis. In addition, the effect of antioxidant therapy on erythrocyte lipid peroxidation was determined, and erythrocyte haemoglobin content was measured. Uraemic patients in dialysis exhibited significant decreases in blood and erythrocyte GSH content as well as significant decreases in the activities of GST, GSR and GSH‐peroxidase relative to control subjects. Furthermore, the uraemic patients had elevated erythrocyte malondialdehyde levels. Blood and erythrocyte GSH content from uraemic patients was significantly elevated after 20 days of antioxidant treatment and remained elevated thereafter throughout the remaining 20 days of the study (130% and 173%, respectively). Antioxidant therapy also produced significant increases in GSR and GSH‐peroxidase activities after 20 days of treatment which remained relatively constant thereafter. No significant change in GST activity was observed. Erythrocyte malondialdehyde levels, as an index of oxidative tissue damage, exhibited a significant decrease (70%) in the patients after 40 days of antioxidant therapy. A gradual increase in erythrocyte haemoglobin content was observed following treatment of the uraemic subjects (45% at day 40). The results suggest that antioxidant therapy may protect against oxidative stress associated with uraemia.
The Effects of Phenobarbital Pretreatment on the Metabolism and Toxicity of Paraoxon in the Mouse
Authors: Vitarius James A. , O'Shaughnessy Jacqueline A. , Sultatos Lester G.
Published: March 2009

AbstractThe effects of induction of various forms of cytochromes P450 by chemicals like phenobarbital on the hepatic oxidative desulfuration and acute toxicity of the phosphorothioate insecticide parathion have been well‐characterized. However, the effects of these chemicals on the metabolism and acute toxicity of the active metabolite paraoxon are less understood. In the present study, daily pretreatment of mice with phenobarbital (intraperitoneally 75 mg/kg) for up to eight days resulted in a transient increase in hepatic microsomal A‐esterase activity, with a corresponding transient decrease in serum A‐esterase activity (A‐esterase was defined as hydrolysis of paraoxon which could be inhibited by EDTA). These alterations could be accounted for by a temporary decrease in the rate of secretion of A‐esterase from liver. However, the same pretreatment resulted in a sustained protective effect against the acute toxicity of paraoxon. These data suggest that alterations in A‐esterase activity as a result of phenobarbital pretreatment cannot account for the observed antagonism of the acute toxicity of paraoxon. Furthermore, these data demonstrate that the protective effect of phenobarbital pretreatment on phosphorothioate insecticides like parathion cannot be attributed exclusively to alterations in oxidative desulfuration of these compounds.
Uptake and Transport of Manganese in Primary and Secondary Olfactory Neurones in Pike
Authors: Tjälve Hans , Mejàre Camilla , Borg‐Neczak Kathleen
Published: March 2009

Abstract γ‐spectrometry and autoradiography were used to examine the axoplasmic flow of manganese in the olfactory nerves and to study the uptake of the metal in the brain after application of 54Mn2+ in the olfactory chambers of pikes. The results show that the 54Mn2+ is taken up in the olfactory receptor cells and is transported at a constant rate along the primary olfactory neurones into the brain. The maximal velocity for the transported 54Mn2+ was 2.90±0.21 mm/hr (mean±S.E.) at 10°, which was the temperature used in the experiments. The 54Mn2+ accumulated in the entire olfactory bulbs, although most marked in central and caudal parts. The metal was also seen to migrate into large areas of the telencephalon, apparently mainly via the secondary olfactory axons present in the medial olfactory tract. A transfer along fibres of the medial olfactory tract probably also explains the labelling which was seen in the diencephalon down to the hypothalamus. The results also showed that there is a pathway connecting the two olfactory bulbs of the pike and that this can carry the metal. Our data further showed a marked accumulation of 54Mn2+ in the meningeal epithelium and in the contents of the meningeal sacs surrounding the olfactory bulbs. It appears from our study that manganese has the ability to pass the synaptic junctions between the primary and the secondary olfactory neurones in the olfactory bulbs and to migrate along secondary olfactory pathways into the telencephalon and the diencephalon. Manganese is a neurotoxic metal which in man can induce an extrapyramidal motor system dysfunction associated with occupational inhalation of manganese‐containing dusts or fumes. We propose on basis of our results that the neurotoxicity of inhaled manganese may be related to an uptake of the metal into the brain via the olfactory neurones. The manganese can thereby circumvent the blood‐brain barrier and gain direct access to the central nervous system.
Failure of Calcium Antagonistic Agents to Prevent Hepatotoxicity Induced by Diclofenac
Authors: Schmitz G. , Lepper H. , Estler C.‐J.
Published: March 2009

AbstractDiclofenac (0.5–2 mM) dose‐ and time‐dependently reduces the viability of isolated hepatocytes. This effect cannot be counteracted by the calcium channel blockers diltiazem (0.05–0.1 mM) and verapamil (0.05–0.5 mM), the calmodulin antagonist calmidazolium (0.01 mM) or Quin 2‐AM (0.1 mM), an intracellular calcium chelating agent. On the contrary, verapamil even accentuates the toxic effects of diclofenac. It is concluded from these results, that diclofenac causes cell damage by other mechanisms than calcium overload.
Xanthine Oxidase Mediates Paraquat‐Induced Toxicity on Cultured Endothelial Cell
Authors: Sakai Megumi , Yamagami Kazunobu , Kitazawa Yasuhide , Takeyama Naoshi , Tanaka Takaya
Published: March 2009

Abstract The role of xanthine oxidase in paraquat toxicity was investigated using cultured bovine pulmonary artery endothelial cells. Exposure to paraquat 0.1 mM was done for 24 hr with or without tungsten pretreatment and in the presence or absence of xanthine oxidase inhibitors. Exposure to paraquat significantly increased O2− production and relative xanthine oxidase activity (xanthine oxidase activity divided by total xanthine dehydrogenase plus xanthine oxidase) while depressing cell growth. In contrast, tungsten and allopurinol inhibited the increase of xanthine oxidase activity and decreased O2− release. Cell injury was assessed by leakage of lactate dehydrogenase and by fluorescein diacetate staining; it was found that oxidase inhibitors (both allopurinol and tungsten) reduced paraquat cytotoxicity. Thus the toxicity of paraquat was at least partly due to intracellular O2− production mediated by xanthine oxidase and the subsequent formation of other free radicals.
Relation between Cyclic GMP Generation and Cerebrovascular Reactivity: Modulation by NPY and α‐Trinositol
Authors: You Junping , Zhang Weihe , Jansen‐Olesen Inger , Edvinsson Lars
Published: March 2009

AbstractIt is considered that cyclic guanosine monophosphate (cGMP) plays a pivotal role in mediating the relaxation of vascular and nonvascular smooth muscles. cGMP steady state levels are regulated by guanylyl cyclase, cGMP phosphodiesterases and its flux from cells. The present study examines the possible relation between cerebrovascular vasodilator agents and generation of cGMP in guinea pig cerebral vessels. Acetylcholine, substance P, nitroglycerine and sodium nitroprusside significantly increased the generation of cGMP. The application of acetylcholine, substance P, nitroglycerine and sodium nitroprusside elicited concentration‐dependent relaxation of basilar artery segments. Neuropeptide Y increased the generation of cGMP by 2%–46% of control levels (at 10−7‐10−6M of neuropeptide Y; *P<0.05). In addition, neuropeptide Y (10−6M) induced a transient relaxation of the precontracted guinea pig basilar arteries with endothelium. This transient relaxation was blocked by nitro‐L‐arginine (10−4M). α‐Trinositol does not alter the formation of cGMP nor the neuropeptide Y‐induced relaxation. In the presence of α‐trinositol neuropeptide Y (10−7‐10−6M) did not significantly elevate the production of cGMP as compared with controls. The rise in cGMP induced by acetylcholine, substance P and nitroglycerine was slightly increased by the addition of neuropeptide Y (3×10−7M). Acetylcholine and substance P induced an endothelium‐dependent relaxation of the precontracted guinea pig basilar arteries, while sodium nitroprusside and nitroglycerine induced an endothelium‐independent relaxation. Acetylcholine, substance P and nitroglycerine induced concentration‐dependent relaxations of basilar artery, respectively. The relaxation elicited by acetylcholine or substance P, but not nitroglycerine, was markedly attenuated by neuropeptide Y (3×10−7M). This inhibitory effect of NPY on vasomotor responses was completely reversed by α‐trinositol (10−6M).
Does Ibuprofen Affect Bilirubin‐Albumin Binding in Newborn Infant Serum?
Authors: Cooper‐Peel Celeste , Brodersen Rolf , Robertson Alex
Published: March 2009

Abstract:Intravenous ibuprofen is being studied in sick, premature infants for the prevention of intraventricular haemorrhage and closure of the ductus arteriosus. We tested the effect of ibuprofen on bilirubin‐albumin binding in adult and newborn infant serum by measuring the free ibuprofen concentration in the presence of bilirubin (reverse displacement method). At clinically appropriate ibuprofen concentrations the free fraction of bilirubin is increased by a factor of 4. Ibuprofen may increase the risk of bilirubin encephalopathy when used in sick, premature infants.
Pharmacological Analysis of Local Anaesthetic Tolycaine‐Induced Convulsions by Modification of Monoamines in Rat Brain
Authors: Satoh Takayuki , Sawaki Kohei , Kawaguchi Mitsuru
Published: March 2009

Abstract:The effects of a local anaesthetic, tolycaine, on brain monoamine levels were investigated during the convulsive process in rats. The influence of central monoamine modifications on tolycaine‐induced convulsions was also examined. Tolycaine (140 mg/kg, intraperitoneally) produced a significant elevation of noradrenaline and 5‐hydroxytryptamine levels in all brain regions in the convulsive state from the levels in the non‐convulsive state. Their levels returned to normal during the postconvulsive state. Dopamine levels were depleted in the cerebral cortex, the striatum, and the ponsmedulla oblongata during the convulsive process and increased in the cerebellum. Pretreatment with α‐methyl‐p‐tyrosine, which depletes brain catecholamine, suppresses the tolycaine‐induced convulsions, as shown by a decrease in the incidence; L‐3,4‐dihydroxyphenylalanine and bis‐(1‐methyl‐4‐homopiperazinyl‐thiocarbonyl)‐disulfide, which increase brain catecholamine, intensified the convulsions, as shown by shortening of the latency and increase in the mortality. Antagonists of β‐adrenergic and dopamine receptors, such as propranolol, chlorpromazine and pimozide, markedly suppressed the convulsions, but an antagonist of α‐adrenergic receptor, phenoxybenzamine, had no effect. Furthermore, 5‐hydroxytryptophan, which increases brain 5‐hydroxytryptamine, suppressed the convulsions, and DL‐p‐chlorophenylalanine, which depletes brain 5‐hydroxytryptamine, intensified them. Antagonists of 5‐hydroxytryptamine receptor, methysergide and methiothepin, suppressed the convulsions. These results suggest that brain noradrenaline and 5‐hydroxytryptamine are major regulators in the tolycaine‐induced convulsive process and that central catecholaminergic neurones act in a stimulatory way on the tolycaine‐induced convulsions, while serotonergic neurones act suppressively.
Hypotensive and Vasorelaxing Activities of a Lectin from the Edible Mushroom Tricholoma mongolicum
Authors: Wang H. X. , Ooi V. E. C. , Ng T. B. , Chiu K. W. , Chang S. T.
Published: March 2009

Abstract:A lectin, which exerted a hypotensive action in rats after intravenous injection via the jugular vein, was isolated from the mycelia of the edible mushroomTricholoma mongolicum.The lectin possessed a molecular weight of 37 K and its hypotensive activity was dose‐dependent. Administration of the lectin at a dose of 10 mg/kg body weight caused a mean arterial blood pressure reduction of 95.3±7.4 mmHg. The lectin's hypotensive action was not mediated via autonomic ganglion transmission, α‐adrenoceptors, β‐adrenoceptors, cholinergic receptors, histaminergic receptors, nor the renin‐angiotensin system, but it was probably mediated through vasorelaxation via adenosine A2 receptors and/or nitric oxide production.
Effect of Cholecystokinin‐B/Gastrin Receptor Blockade on Gastric Acid Secretion in Conscious Rats
Authors: Ding Xi‐Qin , Håkanson Rolf
Published: March 2009

Abstract:Gastrin, histamine and acetylcholine are physiological stimuli of gastric acid secretion. The cholecystokinin‐B/gastrin receptor antagonists YM022 and RP73870 were used to study the effect of gastrin receptor blockade on acid secretion. Gastrin, histamine, insulin or bethanechol were administered to conscious gastric fistula rats with or without the concomitant intravenous infusion of YM022 or RP73870. Other rats were subjected to pylorus ligation. YM022 and RP73870 inhibited the gastrin‐induced acid secretion in a dose‐ and time‐ dependent manner; maximal inhibition was observed at a dose of 0.3 μmol·kg−1· hr−1for both YM022 and RP73870, the ID50values being 0.02 μmol · kg−1· hr−1and 0.05 μmol · kg−1· hr−1for YM022 and RP73870, respectively. At a dose of 0.3 μmol · kg−1· hr−1YM022 and RP73870 failed to inhibit basal and histamine‐, bethanechol‐, and insulin‐evoked secretion. They also failed to affect the secretion evoked by infusion of a cocktail of maximally effective doses of gastrin‐17, histamine and bethanechol. YM022 and RP73870, finally, were without effect on the acid response to pylorus ligation. We suggest that endogenous gastrin in the conscious rat does not contribute to the basal acid secretion and does not participate in the acid response to histamine or to vagus stimulation.