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• β(2) - Adrenoceptor and insulin receptor expression in the skeletal muscle of streptozotocin induced diabetic rats: Antagonism by Vitamin D(3) and Curcumin.

  Authors: Serene Xavier, Jayanarayanan Sadanandan, Naijil George, Chiramadathikudiyil Skaria Paulose

  European journal of pharmacology.

  Diabetes mellitus is a heterogeneous disease and nutritional therapy forms a necessary dimension for its long-term management. Traditional medicinal plants and vitamins are the potentially usefulDiabetes mellitus is a heterogeneous disease and nutritional therapy forms a necessary dimension for its long-term management. Traditional medicinal plants and vitamins are the potentially useful natural products for diabetes control. Diabetes causes atrophy and wasting of skeletal muscles resulting in major peripheral damage. The current study was designed to investigate the therapeutic effect of vitamin D(3) and curcumin treatment on β(2) - adrenoceptors, transcription factor CREB, insulin receptors, protein kinase B (Akt) and malate dehydrogenase activity in the skeletal muscle of diabetic rats. Radioreceptor binding assay was done for β(2)-adrenoceptors using specific ligand, [(3)H] propranolol and gene expression studies of β(2)-adrenoceptors, transcription factor CREB, insulin receptors and Akt were also done using specific probes. The results of the β(2)-adrenoceptor assay showed significant increase in binding parameters, receptor number (B(max)) and equilibrium dissociation constant (K(d)) in the diabetic group in comparison to control. Similarly, an up regulation of β(2)-adrenoceptor and CREB gene expression was observed in the diabetic group whereas the insulin receptor expression was down regulated which signifies the increased glycogenolysis, gluconeogenesis and decreased glycogenesis in the muscles. Expression of Akt was found to be up regulated in the diabetic group. Malate dehydrogenase activity was significantly decreased in both cytosolic and mitochondrial fractions of the diabetic group. All these molecular aspects were reversed to near control with vitamin D(3) and curcumin treatment. Our results suggest the rising potential of both vitamin D(3) and curcumin in the management of peripheral complications associated with diabetes.

• Atorvastatin synergizes with IFN-γ in treating human non-small cell lung carcinomas via potent inhibition of RhoA activity.

  Authors: Jie Chen, Jincai Hou, Jingjie Zhang, Yu An, Xiaojie Zhang, Liling Yue, Jicheng Liu, Xuejun Li

  European journal of pharmacology. 682(1-3):161-70.

  Interferon-γ (IFN-γ) has been widely used to treat various malignant tumors including human non-small-cell-lung carcinomas (NSCLCs). However, the tumor-inhibitory effect of IFN-γ displays notInterferon-γ (IFN-γ) has been widely used to treat various malignant tumors including human non-small-cell-lung carcinomas (NSCLCs). However, the tumor-inhibitory effect of IFN-γ displays not satisfactory in NSCLC treatment due to the lack of immunogenicity of NSCLCs. This study demonstrated that inhibition of RhoA activity led to significant inhibition of NSCLC cell growth accompanied by decreased expression of c-myc and cyclin D1 and increased levels of major histocompatibility complex (MHC) class I and peptide transporter protein 1 (TAP1) which are involved in tumor immunity. Combination treatment of atorvastatin and IFN-γ resulted in a synergistic inhibition of NSCLC cell growth both in vitro and in vivo. Though IFN-γ alone exerted minimal inhibitory effect on RhoA activity, additional administration of atorvastatin could result in a significant inhibition of RhoA activity, thus substantially suppressing NSCLC cell growth. Specifically, atorvastatin could induce specific deposition of endogenous IFN-γ in tumors while not in other normal tissues in LLC-harbored mice. In conclusion, atorvastatin can enhance IFN-γ sensitivity in NSCLCs both in vitro and in vivo, probably through induction of a synergistic inhibitory effect on RhoA activity. This study also suggests a potential alternative of combination of atorvastatin and IFN-γ in clinical therapy against NSCLCs.

• The signaling mechanisms mediating the inhibitory effect of TCH-1116 on formyl peptide-stimulated superoxide anion generation in neutrophils.

  Authors: Ya-Ru Tsai, Li-Jiau Huang, Miau-Rong Lee, Yeh-Long Chen, Sheng-Chu Kuo, Cherng-Chyi Tzeng, Mei-Feng Hsu, Jih-Pyang Wang

  European journal of pharmacology. 682(1-3):171-80.

  In fMLP (formyl-Met-Leu-Phe)-stimulated rat neutrophils, a mixture of regioisomers benzo[a]furo[2,3-c]phenazine-10-carboxylic acid and benzo[a]furo[2,3-c]phenazine-11-carboxylic acid (TCH-1116)In fMLP (formyl-Met-Leu-Phe)-stimulated rat neutrophils, a mixture of regioisomers benzo[a]furo[2,3-c]phenazine-10-carboxylic acid and benzo[a]furo[2,3-c]phenazine-11-carboxylic acid (TCH-1116) inhibited O(2)(-) (superoxide anion) generation, which was not mediated by scavenging the generated O(2)(-) or by a cytotoxic effect on neutrophils. TCH-1116 had no effect on the arachidonic acid-induced NADPH oxidase activation in a cell-free system, whereas it effectively attenuated the phosphorylation of Ser residues in p47(phox) and the association between p47(phox) and p22(phox) in fMLP-stimulated neutrophils. The interaction of p47(phox) with PKC (protein kinase C) isoforms (α, βI, βII, δ and ζ) was attenuated by TCH-1116, whereas TCH-1116 did not affect the PKC isoforms membrane translocation, phosphorylation (Ser660) and kinase activity. TCH-1116 effectively attenuated the association between PKB/Akt (protein kinase B) and p47(phox), Akt phosphorylation (Thr308/Ser473) and kinase activities of Akt and human recombinant PDK (3-phosphoinositide-dependent kinase) 1, whereas it had no effect on recruitment of Akt, phospho-PDK1 (Ser241) and p110γ to membrane. Moreover, the interaction of p21-activated kinase (PAK) 1 with p47(phox) and the phosphorylation of PAK1 (Thr423 but not Ser144) were inhibited by TCH-1116, but without affecting the membrane recruitment of PAK1. The cellular cyclic AMP level was not changed by TCH-1116. Taken together, these results suggest that TCH-1116 inhibits fMLP-stimulated O(2)(-) generation in rat neutrophils through the blockade of PKC, Akt and PAK signaling pathways.

• Prevention effects of ND-07, a novel drug candidate with a potent antioxidative action and anti-inflammatory action, in animal models of severe acute pancreatitis.

  Authors: Jin Hwan Lee, Chun San An, Bok Sun Yun, Kum Suk Kang, Young Ae Lee, Sun Mi Won, Byoung Joo Gwag, Sung Ig Cho, Ki-Baik Hahm

  European journal of pharmacology.

  Oxidative stress and inflammation both play major roles in the development of the acute pancreatitis. Currently, a pancreatic enzyme inhibitor with limited efficacy is only clinically available in aOxidative stress and inflammation both play major roles in the development of the acute pancreatitis. Currently, a pancreatic enzyme inhibitor with limited efficacy is only clinically available in a few countries, and antioxidants or non-steroidal anti-inflammatory drugs (NSAIDs) provide only partial tissue protection in acute pancreatitis animal models. Here, we introduce a new drug candidate for treating acute pancreatitis named ND-07 [chemical name: 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid] that exhibits both potent antioxidative and anti-inflammatory activities. In an electron spin resonance (ESR) study, ND-07 almost blocked hydroxyl radical generation as low as 0.05μM and significantly suppressed DNA oxidation and cell death in a lipopolysaccharide (LPS)-stimulated pancreatic cell line. In a cerulein plus LPS-induced acute pancreatitis model, ND-07 pretreatment showed significant tissue protective effects, with reductions of serum amylase and lipase levels and pancreatic wet weights. ND-07 not only diminished the plasma levels of malondialdehyde (MDA) and nitric oxide but also significantly decreased prostaglandin E(2) (PGE(2)) and expression of tumor necrotizing factor-alpha (TNF-α) in the pancreatic tissue. In a severe acute necrotizing pancreatitis model induced by a choline deficient, ethionine-supplemented (CDE) diet, ND-07 dramatically protected the mortality even without any death, providing attenuation of pancreas, lung, and liver damages as well as the reductions in serum levels of lactate dehydrogenase (LDH), amylase and lipase, MDA levels in the plasma and pancreatic tissues, plasma levels of TNF-α, and interleukin-1betaIL-1β. These findings suggest that current dual synergistic action mechanisms of ND-07 might provide a superior protection for acute pancreatitis prevention than conventional drug treatments.

• Temperature-dependent enhancement of the antinociceptive effects of opioids in combination with gabapentin in mice.

  Authors: Harshini Neelakantan, Ellen A Walker

  European journal of pharmacology.

  Prescription opioids and anticonvulsants such as gabapentin are often used as combination therapeutics for chronic as well as acute post-operative pain conditions although the effectiveness of suchPrescription opioids and anticonvulsants such as gabapentin are often used as combination therapeutics for chronic as well as acute post-operative pain conditions although the effectiveness of such combinations may be dependent on the intensity of the pain state. To test the capacity of gabapentin to enhance opioid effectiveness in the presence of different thermal stimulus intensities, morphine, oxycodone and gabapentin were examined alone and in combination for antinociception in Swiss-Webster male mice using a hot-plate set to one of three temperature intensities (48.5°C, 50.5°C, 52.5°C). Morphine and oxycodone produced significant dose- and stimulus intensity-dependent antinociception whereas gabapentin produced only modest antinociception. However, in combination, gabapentin enhanced the effectiveness of sub-antinociceptive doses of morphine and oxycodone and the gabapentin and oxycodone combinations were both dose- and temperature intensity-dependent. These results provide evidence that the effectiveness and magnitude of the interactions between gabapentin and opioids are dependent on the intensity of the pain stimulus in acute thermal pain states.

• Involvement of different types of potassium channels in the antidepressant-like effect of ascorbic acid in the mouse tail suspension test.

  Authors: Morgana Moretti, Josiane Budni, Camille Mertins Ribeiro, Ana Lúcia S Rodrigues

  European journal of pharmacology.

  Considering that the administration of ascorbic acid elicits an antidepressant-effect in mice by a mechanism which involves an interaction with N-methyl-d-aspartate receptors and theConsidering that the administration of ascorbic acid elicits an antidepressant-effect in mice by a mechanism which involves an interaction with N-methyl-d-aspartate receptors and the l-arginine-nitric oxide-cGMP pathway and taking into account that the stimulation of this pathway is associated with the activation of potassium (K(+)) channels, this study investigated the involvement of different types of K(+) channels on the effect of ascorbic acid in the mouse tail suspension test (TST). Intracerebroventricular administration of tetraethylammonium (TEA, a non-specific blocker of K(+) channels, 25pg/site), glibenclamide (an ATP-sensitive K(+) channel blocker, 0.5pg/site), charybdotoxin (a large- and intermediate conductance calcium-activated K(+) channel blocker, 25pg/site) or apamin (a small-conductance calcium-activated K(+) channel blocker, 10pg/site) was able to produce a synergistic effect with a sub-effective dose of ascorbic acid (0.1mg/kg) given orally (p.o.). The antidepressant-like effect of ascorbic acid (1mg/kg, p.o.) in the TST was prevented by the pre-treatment of mice with cromakalim (a K(+) channel opener, 10μg/site, i.c.v.) and minoxidil (10μg/site, i.c.v.). Moreover, cromakalim abolished the synergistic effect elicited by the combined treatment with sub-effective doses of ascorbic acid and 7-nitroindazole. The administration of the K(+) channel modulators alone or in combination with ascorbic acid did not affect the locomotion of mice. Together, our results show that the antidepressant-like effect of ascorbic acid in the TST may involve, at least in part, the modulation of neuronal excitability, via inhibition of K(+) channels.

• Mechanism of relaxation and interaction with nitric oxide of the soluble guanylate cyclase stimulator BAY 41-2272 in mouse gastric fundus and colon.

  Authors: Sarah M R Cosyns, Romain A Lefebvre

  European journal of pharmacology.

  BAY 41-2272 is a heme-dependent nitric oxide-independent soluble guanylate cyclase (sGC) stimulator, but its relaxant effect in vascular, respiratory and urogenital tissue is only partially dependentBAY 41-2272 is a heme-dependent nitric oxide-independent soluble guanylate cyclase (sGC) stimulator, but its relaxant effect in vascular, respiratory and urogenital tissue is only partially dependent on sGC activation. As its mechanism of action has not been studied in the gastrointestinal tract, it was investigated in mouse gastric fundus and colon. Circular smooth muscle strips were mounted in organ baths under nonadrenergic noncholinergic (NANC) conditions for isometric force recording and cGMP levels were determined using an enzyme immunoassay kit. BAY 41-2272 induced concentration-dependent relaxation in both tissues and increased cGMP levels. The sGC inhibitor ODQ totally inhibited this BAY 41-2272-induced increase of cGMP, but only partially reduced the corresponding relaxation. PDE-5 inhibitor sildenafil had no effect on BAY 41-2272-induced responses. The NO synthase inhibitor L-NAME caused a significant decrease in BAY 41-2272-induced responses in colonic strips. Electrical field stimulation in the presence of BAY 41-2272 induced increased NANC relaxation in fundus, while in colon, rebound contraction at the end of the stimulation train was no longer visible. This suggests synergy with endogenously released NO. Responses to BAY 41-2272 were not significantly influenced by apamin, charybdotoxin or ouabain, excluding interaction with small, intermediate and large conductance Ca(2+)-activated K(+) channels and with Na(+)-K(+)-ATPase. Under depletion of intracellular calcium, CaCl(2)-induced contractions were significantly reduced by BAY 41-2272 in an ODQ-insensitive way. The present study demonstrates that BAY 41-2272 exerts its relaxing effect in mouse gastric fundus and colon partially through a cGMP-dependent mechanism and at least one additional cGMP-independent mechanism involving Ca(2+)-entry blockade.

• Inhibitors of 20-hydroxyeicosatetraenoic acid (20-HETE) formation attenuate the natriuretic effect of dopamine.

  Authors: Maria M Federik Fernandez, Daniel Gonzalez, Jan M Williams, Richard J Roman, Susana Nowicki

  European journal of pharmacology.

  Endogenous renal dopamine is a major physiological regulator of renal ion transport; however its intracellular signaling pathways are not thoroughly understood. The present study examined the role ofEndogenous renal dopamine is a major physiological regulator of renal ion transport; however its intracellular signaling pathways are not thoroughly understood. The present study examined the role of 20-hydroxyeicosatetraenoic acid (20-HETE), the major cytochrome P450 (CYP4A) metabolite of arachidonic acid formed in the renal cortex, on the natriuretic response to dopamine in Sprague Dawley rats. Infusion of dopamine (1.5μg/kg/min, i.v.) increased urine flow (1.9 fold over basal), sodium excretion (UNaV, 2.7 fold), fractional sodium excretion (FENa, 3.3 fold) and proximal and distal delivery of sodium by 1.5- and 2-fold respectively. Administration of two inhibitors of the synthesis of 20-HETE, 1-aminobenzotriazole (ABT) and N-hydroxy-N'-(-4-butyl-2-methylphenyl)formamidine (HET0016) reduced the response to dopamine by 65%. Induction of the renal expression of CYP4A enzymes with clofibrate did not alter the response to dopamine. The natriuretic response to dopamine was lower in Dahl salt-sensitive rats in comparison to an SS.BN5 consomic strain in which transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats upregulates the renal expression of CYP4A protein and the production of 20-HETE. Treatment with HET0016 blocked the renal effects of dopamine in SS.BN5 rats. We also examined the influence of 20-HETE in the natriuretic response to acute volume expansion that is in part mediated via the release of endogenous dopamine. The increase in urine flow, UNaV, FENa and distal FENa following volume expansion was markedly reduced in rats treated with ABT. These results suggest that 20-HETE plays at least a permissive role in the natriuretic response to dopamine.

• Minocycline up-regulates the expression of brain-derived neurotrophic factor and nerve growth factor in experimental autoimmune encephalomyelitis.

  Authors: Xiaohong Chen, Lili Ma, Ying Jiang, Shaoqiong Chen, Cansheng Zhu, Mei Liu, Xiaomeng Ma, Dongliang Zhu, Yingying Liu, Fuhua Peng, Qing Wang, Rongbiao Pi

  European journal of pharmacology.

  Previous evidence demonstrated that minocycline could ameliorate clinical severity of experimental autoimmune encephalomyelitis and exhibit several anti-inflammatory and neuroprotective activities.Previous evidence demonstrated that minocycline could ameliorate clinical severity of experimental autoimmune encephalomyelitis and exhibit several anti-inflammatory and neuroprotective activities. However, few studies have been carried out to assess its effects on the expression of neurotrophins in experimental autoimmune encephalomyelitis or multiple sclerosis. Here we investigated the alteration of brain-derived neurotrophic factor and nerve growth factor in the sera, cerebral cortex, and lumbar spinal cord of experimental autoimmune encephalomyelitis C57 BL/6 mice in vivo as well as the splenocytes culture supernatants in vitro after minocycline administration. Our results demonstrated that minocycline could up-regulate the expression of brain-derived neurotrophic factor and nerve growth factor both in peripheral (sera and splenocytes culture supernatants) and target organs (cerebral cortex and lumber spinal cord) of mice with experimental autoimmune encephalomyelitis. These data suggest that up-regulation of neurotrophins in experimental autoimmune encephalomyelitis may be a novel neuroprotective mechanism of minocycline.

• The inhibitory effects of m-nisoldipine on the 5-hydroxytryptamine-induced proliferation of pulmonary artery smooth muscle cells via Ca(2+) antagonism and antioxidant mechanisms.

  Authors: Xueyan Chen, Huanlong Liu, Zhenhua Pan, Qingfeng Miao, Yongjian Zhang

  European journal of pharmacology.

  The excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the development of pulmonary arterial hypertension. Recent studies indicate that Ca(2+) andThe excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the development of pulmonary arterial hypertension. Recent studies indicate that Ca(2+) and reactive oxygen species are critically involved in the process of smooth muscle cell proliferation stimulated by mitogens, such as 5-hydroxytryptamine (5-HT). Because m-nisoldipine, a Ca(2+) channel blocker of the dihydropyridine class, possesses some calcium antagonistic and antioxidant properties, we investigated the effect of m-nisoldipine on PASMC proliferation. The results indicated that m-nisoldipine inhibited 5-HT-induced PASMC proliferation, evaluated by BrdU incorporation and the MTT assay, and this effect was associated with a decreased expression of proliferating cell nuclear antigen (PCNA). Flow cytometry analysis showed that m-nisoldipine blocked 5-HT-induced cell-cycle progression by arresting the cells in the G(0)/G(1) phase. Next, the production of reactive oxygen species and the levels of [Ca(2+)](i) in PASMCs were measured by laser scanning confocal microscopy; m-nisoldipine pretreatment attenuated the [Ca(2+)](i) elevation and the production of reactive oxygen species induced by 5-HT. In addition, m-nisoldipine significantly decreased the 5-HT-induced activation of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) and the subsequent c-fos and c-jun mRNA expression. Meanwhile, results also showed that N-acetylcysteine (a reactive oxygen species scavenger) suppressed the proliferation and the ERK1/2 and JNK activation induced by 5-HT. In summary, this study demonstrated that m-nisoldipine effectively suppressed the 5-HT-induced PASMC proliferation, ERK1/2 and JNK activation and subsequent c-fos and c-jun mRNA expression, all of which might be associated with the Ca(2+) antagonistic and antioxidant properties of m-nisoldipine.

• High glucose increases the expression of proinflammatory cytokines and secretion of TNFα and β-hexosaminidase in human mast cells.

  Authors: Kanji Nagai, Tatsunobu Fukushima, Hideaki Oike, Masuko Kobori

  European journal of pharmacology.

  Epidemiological studies demonstrated that obesity, which is a high-risk factor for development of hyperglycemia-associated metabolic syndromes, is associated with prevalence/incidence of allergicEpidemiological studies demonstrated that obesity, which is a high-risk factor for development of hyperglycemia-associated metabolic syndromes, is associated with prevalence/incidence of allergic diseases. To elucidate the underlying mechanisms of the relationship between hyperglycemia and allergy, we examined the effect of high glucose on the activation of human mast cell lines, HMC-1 and LAD2. HMC-1 and LAD2 cells were cultured in low (5.5mM) and high (25mM)-glucose Dulbecco's modified Eagle's medium (DMEM). High-glucose medium increased the intracellular reactive oxygen species levels in HMC-1 and LAD2 cells after 2days of incubation; in HMC-1 cells, the expression levels of tumor necrosis factor (TNF) α, interleukin (IL)-1β, IL-6, and IL-13 were increased significantly. The β-hexosaminidase release rates were not significantly different between LAD2 cells cultured in both media; however, the intracellular and extracellular activities of β-hexosaminidase in cells were significantly higher in high-glucose than in low-glucose media. High glucose increased the secretion of TNFα by unstimulated HMC-1 cells and IgE crosslinking-stimulated LAD2 cells. High glucose increased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs), which regulate the expression of TNFα and other inflammatory cytokines, in both HMC-1 and LAD2 cells. Thus, high glucose increased the expression of proinflammatory and proallergic cytokines, the secretion of TNFα, and β-hexosaminidase activity in human mast cells. Our result suggests that hyperglycemia promotes the activation of human mast cells associated with allergy and inflammation under unstimulated and stimulated conditions.

• Efficacy and mechanism of hypoxic postconditioning in salvage of ex vivo human rectus abdominis muscle from hypoxia/reoxygenation injury.

  Authors: Andreas Naparus, Homa Ashrafpour, Stefan O P Hofer, Toni Zhong, Ning Huang, Neil J Cahoon, Sandra E McAllister, Peter C Neligan, Trisha Roy, Joan E Lipa, Cho Y Pang

  European journal of pharmacology.

  In reconstructive surgery, skeletal muscle may endure protracted ischemia before reperfusion, which can lead to significant ischemia/reperfusion injury. Ischemic postconditioning induced by briefIn reconstructive surgery, skeletal muscle may endure protracted ischemia before reperfusion, which can lead to significant ischemia/reperfusion injury. Ischemic postconditioning induced by brief cycles of reperfusion/reocclusion at the end of ischemia has been shown to salvage skeletal muscle from ischemia/reperfusion injury in several animal models. However, ischemic postconditioning has not been confirmed in human skeletal muscle. Using an established in vitro human skeletal muscle hypoxic conditioning model, we tested our hypothesis that hypoxic postconditioning salvages ex vivo human skeletal muscle from hypoxia/reoxygenation injury and the mechanism involves inhibition of opening of the mitochondrial permeability transition pore (mPTP) and preservation of ATP synthesis. Muscle strips (~0.5×0.5×15mm) from human rectus abdominis muscle biopsies were cultured in Krebs-Henseleit-HEPES buffer, bubbled with 95%N(2)/5%CO(2) (hypoxia) or 95%O(2)/5%CO(2) (reoxygenation). Samples were subjected to 3h hypoxia/2h reoxygenation. Hypoxic postconditioning was induced by one or two cycles of 5min reoxygenation/5min hypoxia after 3h hypoxia. Muscle injury, viability and ATP synthesis after 2h of reoxygenation were assessed by measuring lactate dehydrogenase (LDH) release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) reduction and ATP content, respectively. Hypoxic postconditioning or treatment with the mPTP-opening inhibitors Cyclosporine A (CsA, 5×10(-6)M) or N-Methyl-4-isoleucine Cyclosporine (NIM811, 5×10(-6)M) 10min before reoxygenation decreased LDH release, increased MTT reduction and increased muscle ATP content (n=7 patients; P<0.05). Conversely, treatment with the mPTP opener Atractyloside (5×10(-6)M) 10min before hypoxic postconditioning abolished its protective effect (n=7 patients; P<0.05). We conclude that hypoxic postconditioning effectively salvages human skeletal muscle from hypoxia/reoxygenation injury by inhibition of mPTP opening and preservation of ATP synthesis during reoxygenation.

• Inhibitory effects of dextrorotatory morphinans on the human 5-HT(3A) receptor expressed in Xenopus oocytes: Involvement of the N-terminal domain of the 5-HT(3A) receptor.

  Authors: Byung-Hwan Lee, Sung-Hee Hwang, Sun-Hye Choi, Tae-Joon Shin, Jiyeon Kang, Hyun-Joong Kim, Hyoung-Chun Kim, Joon-Hee Lee, Seung-Yeol Nah

  European journal of pharmacology.

  We previously developed a series of dextromethorphan (DM, 3-methoxy-17-methylmorphinan) analogs modified at positions 3 and 17 of the morphinan ring system. Recent reports have shown that DMWe previously developed a series of dextromethorphan (DM, 3-methoxy-17-methylmorphinan) analogs modified at positions 3 and 17 of the morphinan ring system. Recent reports have shown that DM attenuates abdominal pain caused by irritable bowel syndrome, and multidrug regimens that include DM prevent nausea/vomiting following cancer surgery. However, little is known regarding the molecular mechanisms underlying the beneficial effects of DM. Here, we investigated the effects of DM, 3 of its analogs (AM, 3-allyloxy-17-methoxymorphian; CM, 3-cyclopropyl-17-methoxymorphinan; and DF, 3-methyl-17-methylmorphinan), and 1 of its metabolites (HM, 3-methoxymorphinan) on the activity of the human 5-HT(3A) receptor channel expressed in Xenopus laevis oocytes, using the 2-microelectrode voltage clamp technique. We found that intra-oocyte injection of human 5-HT(3A) receptor cRNAs elicited an inward current (I(5-HT)) in the presence of 5-HT. Cotreatment with AM, CM, DF, DM, or HM inhibited I(5-HT) in a dose-dependent, voltage-independent, and reversible manner. The IC(50) values for AM, CM, DF, DM, and HM were 24.5±1.4, 21.5±4.2, 132.6±35.8, 181.3±23.5, and 191.3±31.5μM, respectively. The IC(50) values of AM and CM were 7-fold lower than that of DM, and mechanistic analysis revealed that DM, DF, HM, AM, and CM were competitive inhibitors of I(5-HT). Point mutations of Arg241 in the N-terminal, but not amino acids in the pore region, to other amino acid residues attenuated or abolished DM- and DM-analog-induced inhibition of I(5-HT). Together, these results demonstrated that dextrorotatory morphinans might regulate 5-HT(3A) receptor channel activity via interaction with its N-terminal domain.

• A comparison of the effects of the dopamine partial agonists aripiprazole and (-)-3-PPP with quinpirole on stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry in vitro.

  Authors: John J O'Connor, John P Lowry

  European journal of pharmacology.

  The effects of aripiprazole, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique ofThe effects of aripiprazole, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (-)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10μM for aripiprazole. Both compounds were tested against the concentration-response curve for quinpirole's inhibition of stimulated single pulse dopamine release. Aripiprazole and (-)-3-PPP shifted the concentration-response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D(2) ligands remains controversial.

• The rewarding action of acute cocaine is reduced in β-endorphin deficient but not in μ opioid receptor knockout mice.

  Authors: Alexander T Nguyen, Paul Marquez, Abdul Hamid, Brigitte Kieffer, Theodore C Friedman, Kabirullah Lutfy

  European journal of pharmacology.

  We have previously shown that β-endorphin plays a functional role in the rewarding effect of acute cocaine. Considering that β-endorphin has high affinity for the μ opioid receptor, we determined theWe have previously shown that β-endorphin plays a functional role in the rewarding effect of acute cocaine. Considering that β-endorphin has high affinity for the μ opioid receptor, we determined the role of this receptor in the rewarding action of acute cocaine. For comparison, we assessed the role of the μ opioid receptor in the rewarding effect of acute morphine. We also examined the effect of intracerebroventricular (i.c.v.) administration of β-funaltrexamine (β-FNA), an irreversible μ opioid receptor antagonist, on the rewarding action of acute cocaine as well as that of morphine. Using the conditioned place preference (CPP) paradigm as an animal model of reward, we first assessed the rewarding action of cocaine in mice lacking β-endorphin or the μ opioid receptor and their respective wild-type littermates/controls. Mice were tested for preconditioning place preference on day 1, conditioned once daily with saline/cocaine (30mg/kg, i.p.) or cocaine/saline on days 2 and 3, and then tested for postconditioning place preference on day 4. We next studied the rewarding action of acute morphine in μ knockout mice and their wild-type controls. The CPP was induced by single alternate-day saline/morphine (10mg/kg, s.c.) or morphine/saline conditioning. We finally determined the effect of β-FNA on CPP induced by cocaine or morphine in wild-type mice, in which mice were treated with saline or β-FNA (9ug/3μl; i.c.v.) a day prior to the preconditioning test day. Our results revealed that morphine induced a robust CPP in wild-type mice but not in mice lacking the μ opioid receptor or in wild-type mice treated with β-FNA. In contrast, cocaine induced CPP in μ knockout mice as well as in wild-type mice treated with β-FNA. On the other hand, cocaine failed to induce CPP in mice lacking β-endorphin. These results illustrate that β-endorphin is essential for the rewarding action of acute cocaine, but the μ opioid receptor may not mediate the regulatory action of endogenous β-endorphin.

• Cationic derivative of dextran reverses anticoagulant activity of unfractionated heparin in animal models of arterial and venous thrombosis.

  Authors: Bartlomiej Kalaska, Emilia Sokolowska, Kamil Kaminski, Krzysztof Szczubialka, Karol Kramkowski, Andrzej Mogielnicki, Maria Nowakowska, Wlodzimierz Buczko

  European journal of pharmacology.

  Heparin is a natural polymer widely used in medicine especially during the treatment of cardiovascular diseases since it is a potent blood anticoagulant. In case of emergency, e.g., massiveHeparin is a natural polymer widely used in medicine especially during the treatment of cardiovascular diseases since it is a potent blood anticoagulant. In case of emergency, e.g., massive hemorrhage, the anticoagulant activity of heparin has to be quickly stopped by the administration of a heparin reversing agent. Currently protamine sulfate, an allergenic protein, is used for this purpose. We are reporting the studies on a new polymeric substance, a cationic dextran derivative, which is able to form complexes with heparin. Dextran is a blood compatible polymer which is also frequently applied in medicine. By substituting dextran with glycidyltrimethylammonium chloride a cationic polymer was obtained that in vitro binds to heparin with an efficiency similar to that of protamine. To investigate the influence of modified dextran on the reversal of conventional heparin we used the models of experimental arterial thrombosis induced by electrical stimulation and chemically induced venous thrombosis. A decrease in bleeding time and activated partial thromboplastin time after administration of the cationic dextran to heparinized rats was found. Moreover, other routinely measured blood parameters are significantly affected. Modified dextran, in contrast to protamine sulfate, significantly increases red blood cell counts, hemoglobin level and hematocrit value. The data we obtained show that the modified dextran may reduce anticoagulative heparin activity both under in vivo and in vitro conditions. Further clinical studies are needed to estimate whether modified dextran could replace protamine sulfate, especially in dialyzed patients with the end-stage renal disease associated with anemia.

• Open-channel blockade is less effective on GluN3B than GluN3A subunit-containing NMDA receptors.

  Authors: David W McClymont, John Harris, Ian R Mellor

  European journal of pharmacology.

  The GluN3 subunits of the N-methyl-d-aspartate (NMDA) receptor are known to reduce its Ca(2+) permeability and Mg(2+) sensitivity, however, little is known about their effects on other channelThe GluN3 subunits of the N-methyl-d-aspartate (NMDA) receptor are known to reduce its Ca(2+) permeability and Mg(2+) sensitivity, however, little is known about their effects on other channel blockers. cRNAs for rat NMDA receptor subunits were injected into Xenopus oocytes and responses to NMDA and glycine were recorded using two electrode voltage clamp. Channel block of receptors containing GluN1-1a/2A, GluN1-1a/2A/3A or GluN1-1a/2A/3B subunits was characterised using Mg(2+), memantine, MK-801, philanthotoxin-343 and methoctramine. IC(50) values for Mg(2+) and memantine increased when receptors contained GluN3A subunits and were further increased when they contained GluN3B, e.g. IC(50)s at -75mV for block of GluN1-1a/2A, GluN1-1a/2A/3A and GluN1-1a/2A/3B receptors respectively were 4.2, 22.4 and 40.1μM for Mg(2+), and 2.5, 7.5 and 17.5μM for memantine. Blocking activity was found to be fully or partially restored when G or R (at the N and N +1 sites respectively) were mutated to N in GluN3A. Thus, the changes cannot be attributed to the loss of the N or N +1 sites alone, but rather involve both sites or residues elsewhere. Block by MK-801 and philanthotoxin-343 was also reduced by GluN3A, most strongly at -100mV but not at -50mV, and by GluN3B at all V(h). Methoctramine was the least sensitive to introduction of GluN3 subunits suggesting a minimal interaction with the N and N +1 sites. We conclude that GluN3B-containing receptors provide increased resistance to channel block compared to GluN3A-containing receptors and this must be due to differences outside the deep pore region (N site and deeper).

• Cyclooxygenase-2 prostaglandins mediate anandamide-inhibitory action on nitric oxide synthase activity in the receptive rat uterus.

  Authors: Micaela S Sordelli, Jimena S Beltrame, Maximiliano Cella, Ana M Franchi, Maria Laura Ribeiro

  European journal of pharmacology.

  Anandamide, an endocannabinoid, prostaglandins derived from cyclooxygenase-2 and nitric oxide synthesized by nitric oxide synthase (NOS), are relevant mediators of embryo implantation. We adopted aAnandamide, an endocannabinoid, prostaglandins derived from cyclooxygenase-2 and nitric oxide synthesized by nitric oxide synthase (NOS), are relevant mediators of embryo implantation. We adopted a pharmacological approach to investigate if anandamide modulated NOS activity in the receptive rat uterus and if prostaglandins mediated this effect. As we were interested in studying the changes that occur at the maternal side of the fetal-maternal interface, we worked with uteri obtained from pseudopregnant rats. Females were sacrificed on day 5 of pseudopregnancy, the day in which implantation would occur, and the uterus was obtained. Anandamide (2ng/kg, i.p.) inhibited NOS activity (P<0.001) and increased the levels of prostaglandin E(2) (P<0.001) and prostaglandin F(2α) (P<0.01). These effects were mediated via cannabinoid receptor type 2, as the pre-treatment with SR144528 (10mg/kg, i.p.), a selective cannabinoid receptor type 2 antagonist, completely reverted anandamide effect on NOS activity and prostaglandin levels. The pre-treatment with a non-selective cyclooxygenase inhibitor (indomethacin 2.5mg/kg, i.p.) or with selective cyclooxygenase-2 inhibitors (meloxicam 4mg/kg, celecoxib 3mg/kg, i.p.) reverted anandamide inhibition on NOS, suggesting that prostaglandins are derived from cyclooxygenase-2 mediated anandamide effect. Thus, anandamide levels seemed to modulate NOS activity, fundamental for implantation, via cannabinoid receptor type 2 receptors, in the receptive uterus. This modulation depends on the production of cyclooxygenase-2 derivatives. These data establish cannabinoid receptors and cyclooxygenase enzymes as an interesting target for the treatment of implantation deficiencies.

• Omentin plays an anti-inflammatory role through inhibition of TNF-α-induced superoxide production in vascular smooth muscle cells.

  Authors: Kyosuke Kazama, Tatsuya Usui, Muneyoshi Okada, Yukio Hara, Hideyuki Yamawaki

  European journal of pharmacology.

  Omentin is a recently identified adipocytokine and its effect in vasculature is largely unknown. Here we examined the effects of omentin on smooth muscle cells (SMCs) inflammatory states. WesternOmentin is a recently identified adipocytokine and its effect in vasculature is largely unknown. Here we examined the effects of omentin on smooth muscle cells (SMCs) inflammatory states. Western blotting was performed to analyze inflammatory signal transduction in cultured SMCs. Phosphorylation of nuclear factor-κB (NF-κB), p38 and JNK, and expression of vascular cell adhesion molecule (VCAM)-1 and cyclooxygenase-2 were not induced by omentin (50-300ng/ml, 20min or 24h). On the other hand, tumor necrosis factor-α (TNF-α (10ng/ml, 20min)-induced phosphorylation of p38 and JNK was significantly inhibited by omentin pretreatment in a concentration-dependent manner (50-300ng/ml, 30min). TNF-α (24h)-induced expression of VCAM-1 was also significantly inhibited by omentin pretreatment in a concentration-dependent manner. Both inhibitor of p38 (SB203580) and JNK (SP600125) significantly inhibited TNF-α-induced VCAM-1 expression. Omentin (300ng/ml, 30min) inhibited TNF-α (1h)-induced nicotinamide adenine dinucleotide phosphate oxidase activity as determined by lucigenin assay. An antioxidant drug, N-acetyl-l-cysteine significantly inhibited TNF-α-induced phosphorylation of p38 and JNK. Furthermore, omentin (300ng/ml, 30min) significantly inhibited TNF-α (24h)-induced monocytic cells adhesion to SMCs. In rat isolated thoracic aorta, omentin (300ng/ml, 30min) inhibited TNF-α (24h)-induced VCAM-1 expression. The present results demonstrate for the first time that omentin plays an anti-inflammatory role by preventing the TNF-α-induced VCAM-1 expression in SMCs. It is suggested that omentin inhibits TNF-α-induced VCAM-1 expression via preventing the activation of p38 and JNK at least in part through inhibition of superoxide production.

• Neurogenic airway microvascular leakage induced by toluene inhalation in rats.

  Authors: Tatsuo Sakamoto, Michihiro Kamijima, Mio Miyake

  European journal of pharmacology.

  Toluene is a representative airborne occupational and domestic pollutant that causes eye and respiratory tract irritation. We investigated whether a single inhalation of toluene elicits microvascularToluene is a representative airborne occupational and domestic pollutant that causes eye and respiratory tract irritation. We investigated whether a single inhalation of toluene elicits microvascular leakage in the rat airway. We also evaluated the effects of CP-99,994, a tachykinin NK(1) receptor antagonist, and ketotifen, a histamine H1 receptor antagonist with mast cell-stabilizing properties, on the airway response. The content of Evans blue dye that extravasated into the tissues was measured as an index of plasma leakage. Toluene (18-450ppm, 10min) concentration-dependently induced dye leakage into the trachea and main bronchi of anesthetized and mechanically ventilated rats. Toluene at concentrations of ≥50 and ≥30ppm caused significant responses in the trachea and main bronchi, respectively, which both peaked after exposure to 135ppm toluene for 10min. This response was abolished by CP-99,994 (5mg/kg i.v.), but not by ketotifen (1mg/kg i.v.). Nebulized phosphoramidon (1mM, 1min), a neutral endopeptidase 24.11 inhibitor, significantly enhanced the response induced by toluene (135ppm, 10min) compared with nebulized 0.9% saline (1min). These results show that toluene can rapidly increase airway plasma leakage that is predominantly mediated by tachykinins endogenously released from airway sensory nerves. However, mast cell activation might not be important in this airway response.

• The analgesic activity of biphalin and its analog AM 94 in rats.

  Authors: Sheila Leone, Annalisa Chiavaroli, Giustino Orlando, Adriano Mollica, Chiara Di Nisio, Luigi Brunetti, Michele Vacca

  European journal of pharmacology.

  Biphalin is an opioid linear octapeptide, which displays a broad affinity for all opioid receptors (μ, δ and κ), as well as exceptionally high antinociceptive activity. AM 94 is a biphalin analog andBiphalin is an opioid linear octapeptide, which displays a broad affinity for all opioid receptors (μ, δ and κ), as well as exceptionally high antinociceptive activity. AM 94 is a biphalin analog and a selective agonist at μ and δ opioid receptors. This study investigated the antinociceptive profile of AM 94. All antinociception evaluations were made in adult male rats using the hot-plate test. AM 94 proved to induce greater and longer antinociception compared to biphalin following intracebroventricular (1nmol/kg) and intravenous administration (1200nmol/kg) as evaluated by % maximum possible effect (M.P.E.), when administered intracerebroventricularly and intravenously and sustained analgesia up to 210min. The antinociceptive activities of biphalin and AM 94 were antagonized by naloxone (10mg/kg intraperitoneally). Our data suggest that AM 94 could be regarded as a novel pharmacologically active opioid compound for eliciting potent and sustained analgesia after central and peripheral administration.

• Two mechanistically distinct effects of dihydropyridine nifedipine on Ca(V)1.2 L-type Ca(2+) channels revealed by Timothy syndrome mutation.

  Authors: Xiaona Sheng, Tsutomu Nakada, Motohiro Kobayashi, Toshihide Kashihara, Toshihide Shibazaki, Miwa Horiuchi-Hirose, Simmon Gomi, Masamichi Hirose, Toshifumi Aoyama, Mitsuhiko Yamada

  European journal of pharmacology.

  Dihydropyridine Ca(2+) channel antagonists (DHPs) block Ca(V)1.2 L-type Ca(2+) channels (LTCCs) by stabilizing their voltage-dependent inactivation (VDI); however, it is still not clear how DHPsDihydropyridine Ca(2+) channel antagonists (DHPs) block Ca(V)1.2 L-type Ca(2+) channels (LTCCs) by stabilizing their voltage-dependent inactivation (VDI); however, it is still not clear how DHPs allosterically interact with the kinetically distinct (fast and slow) VDI. Thus, we analyzed the effect of a prototypical DHP, nifedipine on LTCCs with or without the Timothy syndrome mutation that resides in the I-II linker (L(I)-(II)) of Ca(V)1.2 subunits and impairs VDI. Whole-cell Ba(2+) currents mediated by rabbit Ca(V)1.2 with or without the Timothy mutation (G436R) (analogous to the human G406R mutation) were analyzed in the presence and absence of nifedipine. In the absence of nifedipine, the mutation significantly impaired fast closed- and open-state VDI (CSI and OSI) at -40 and 0mV, respectively, but did not affect channels' kinetics at -100mV. Nifedipine equipotently blocked these channels at -80mV. In wild-type LTCCs, nifedipine promoted fast CSI and OSI at -40 and 0mV and promoted or stabilized slow CSI at -40 and -100mV, respectively. In LTCCs with the mutation, nifedipine resumed the impaired fast CSI and OSI at -40 and 0mV, respectively, and had the same effect on slow CSI as in wild-type LTCCs. Therefore, nifedipine has two mechanistically distinct effects on LTCCs: the promotion of fast CSI/OSI caused by L(I-II) at potentials positive to the sub-threshold potential and the promotion or stabilization of slow CSI caused by different mechanisms at potentials negative to the sub-threshold potential.

• Cathepsin E induces itch-related response through the production of endothelin-1 in mice.

  Authors: Tsugunobu Andoh, Tetsuro Yoshida, Jung-Bum Lee, Yasushi Kuraishi

  European journal of pharmacology.

  This study investigated the pruritogenic potency of cathepsin E, an aspartic protease, and its mechanisms in mice. An intradermal injection of cathepsin E to the rostral back elicited scratching, anThis study investigated the pruritogenic potency of cathepsin E, an aspartic protease, and its mechanisms in mice. An intradermal injection of cathepsin E to the rostral back elicited scratching, an itch-associated response, of the injection site. This action was inhibited by the aspartic protease inhibitor pepstatin A, the endothelin ET(A) receptor antagonist BQ-123, and the opioid receptor antagonists naltrexone and naloxone, but not by the H(1) histamine receptor antagonist terfenadine, the proteinase-activated receptor-2 antagonist FSLLRY-NH(2), or mast cell deficiency. Pepstatin A inhibited scratching induced by intradermal injection of the mast-cell degranulator compound 48/80, but not by tryptase, a mast-cell mediator. An intradermal injection of cathepsin E increased endothelin-1 levels in the skin at the injection site. Preproendothelin-1 mRNA was present in primary cultures of keratinocytes, and immunohistochemistry using an antibody recognizing endothelin-1 and big-endothelin-1 revealed immunoreactivity in the epidermis, especially in the prickle and granular cell layers, but not in the basal cell layer. These results suggest that cathepsin E is an endogenous itch inducer, and that its action is mediated at least in part by the production of endothelin-1 in the epidermis.

• Ginsenoside Rb(1) inhibits the carotid neointimal hyperplasia induced by balloon injury in rats via suppressing the phenotype modulation of vascular smooth muscle cells.

  Authors: Shu Zhang, Jiang Deng, Yang Gao, Dan-Li Yang, Qi-Hai Gong, Xie-Nan Huang

  European journal of pharmacology.

  This study aims to investigate the effects of ginsenoside Rb(1) on vascular intimal hyperplasia in rats and explore the mechanisms. The rat vascular neointimal hyperplasia model was made by rubbingThis study aims to investigate the effects of ginsenoside Rb(1) on vascular intimal hyperplasia in rats and explore the mechanisms. The rat vascular neointimal hyperplasia model was made by rubbing the endothelia of carotid artery with a balloon and Rb(1) (10 and 30mg/kg/day) was given the day after surgery for 14 consecutive days. The neointimal hyperplasia level and the degree of vascular smooth muscle cells (VSMCs) proliferation were evaluated by histopathology and by calculating the proliferating cell nuclear antigen (PCNA) positive expression percentage; protein expressions of PCNA, phosphorylation extracellular signal-regulated kinase 1/2 (pERK1/2), smooth muscle α-actin (SM α-actin), and the mRNA expressions of proto-oncogene c-myc, SM α-actin, SM-emb (embryonic smooth muscle myosin heavy chain) and p38 MAPK were detected by immunohistochemistry and Real Time RT-PCR, respectively. Compared with the endothelia rubbing model group, Rb(1) 10 and 30mg/kg/day medication significantly ameliorated the neointimal hyperplasia (P<0.05), and decreased the positive expression percentage of PCNA(P<0.05). Rb(1) medication also significantly decreased the elevated protein expression of pERK1/2 and the mRNA expression of c-myc(P<0.05), and tended to reduce the expression of p38 MAPK mRNA. Endothelial rubbing increased the SM-emb mRNA expression, but decreased the expression of SM α-actin mRNA which was reversed by Rb(1) (P<0.05). The results indicate that Rb(1) inhibits the vascular neointimal hyperplasia induced by balloon-injury in rats via suppressing the VSMC proliferation, which may be involved in part the inhibition of pERK1/2 protein and related to its inhibition on VSMC phenotype modulation.

• Inhibition of cystathionine gamma-lyase and the biosynthesis of endogenous hydrogen sulphide ameliorate gentamicin-induced nephrotoxicity.

  Authors: Van P Dam, Jennifer L Scott, Anthony Ross, Robert T Kinobe

  European journal of pharmacology.

  Clinical use of gentamicin over prolonged periods is limited because of dose- and time-dependent nephrotoxicity. Primarily, lysosomal phospholipidosis, intracellular oxidative stress and heightenedClinical use of gentamicin over prolonged periods is limited because of dose- and time-dependent nephrotoxicity. Primarily, lysosomal phospholipidosis, intracellular oxidative stress and heightened inflammation have been implicated. Hydrogen sulphide is an endogenously produced signal transduction molecule with strong anti-inflammatory, anti-apoptotic and cytoprotective properties. In several models of inflammatory disease however, tissue damage has been associated with increased activity of cystathionine gamma-lyase, biosynthesis of hydrogen sulphide and activation of leukocytes. The aim of this study was to determine effects of inhibiting hydrogen sulphide biosynthesis by DL-propargyl glycine (an irreversible inhibitor of cystathionine gamma-lyase) on inflammation, necrosis and renal function, following treatment with gentamicin in rats. Adult female Sprague-Dawley rats were divided into six groups and treated with; physiological saline, sodium hydrosulphide, DL-propargyl glycine, gentamicin, a combination of gentamicin and sodium hydrosulphide, or gentamicin and DL-propargyl glycine respectively. Gentamicin-induced histopathological changes including inflammatory cell infiltration and tubular necrosis were attenuated by co-administering gentamicin with DL-propargyl glycine (P<0.05 compared to saline controls and P<0.05 compared to gentamicin only). Similarly, DL-propargyl glycine caused a significant reduction (P<0.05) in lipid peroxidation, production of superoxide and the activation of tumour necrosis factor-alpha in gentamicin-treated animals. These data show that protective effects of DL-propargyl glycine might be related at least in part, to the reduced inflammatory responses observed in animals treated with both gentamicin and DL-propargyl glycine. Thus, enzyme systems involved in hydrogen sulphide biosynthesis may offer a viable therapeutic target in alleviating the nephrotoxic effects of gentamicin.

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