Abstract:
BACKGROUND AND PURPOSE:SU4312, a potent and selective inhibitor of VEGF receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion (MPP(+) )-induced neurotoxicity and further explored the underlying mechanisms. EXPERIMENTAL APPROACH:MPP(+) -treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms. KEY RESULTS:SU4312 unexpectedly prevented MPP(+) -induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC(50) value of 19.0 μM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS. CONCLUSIONS AND IMPLICATION:SU4312 exhibited neuroprotection against MPP(+) at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Cui W,Zhang Z,Li W,Hu S,Mak S,Zhang H,Han R,Yuan S,Li S,Sa F,Xu D,Lin Z,Zuo Z,Rong J,Ma ED,Choi TC,Lee SM,Han Ydoi
10.1111/bph.12004subject
Has Abstractpub_date
2013-03-01 00:00:00pages
1201-14issue
5eissn
0007-1188issn
1476-5381journal_volume
168pub_type
杂志文章abstract:BACKGROUND AND PURPOSE:This paper is intended to assist pharmacologists to make the most of statistical analysis and in avoid common errors. APPROACH:A scenario is presented where an experimenter performed an experiment to test the effects of two drugs on cultured cells. Analysis of the results, expressed as percentag...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707372
更新日期:2007-10-01 00:00:00
abstract::1. Vascular endothelial and smooth muscle cells generate nitric oxide (NO) via different nitric oxide synthase (NOS) isozymes. Activation of the endothelial constitutive NOS (ecNOS) contributes to the maintenance of cardiovascular homeostasis, whereas expression of the endotoxin- and cytokine-inducible pathway (iNOS) ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15510.x
更新日期:1996-07-01 00:00:00
abstract::1. When injected intraperitoneally into mice in doses larger than those used clinically, all the amino derivatives of bisphosphonates (aminoBPs) tested induce a variety of inflammatory reactions such as induction of histidine decarboxylase (HDC, the histamine-forming enzyme), hypertrophy of the spleen, atrophy of the ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702367
更新日期:1999-02-01 00:00:00
abstract:BACKGROUND AND PURPOSE:N-docosahexaenoylethanolamine (DHEA) is the ethanolamine conjugate of the long-chain polyunsaturated n-3 fatty acid docosahexaenoic (DHA; 22: 6n-3). Its concentration in animal tissues and human plasma increases when diets rich in fish or krill oil are consumed. DHEA displays anti-inflammatory pr...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12747
更新日期:2015-01-01 00:00:00
abstract::1. The use of pharmacological inhibitors of nitric oxide (NO) synthesis to treat patients with septic shock is limited by the observation that they cause a fall in cardiac output in some subjects. The aim of this work was to investigate this fall and to test whether it was reversible by subsequent administration of ni...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb13089.x
更新日期:1994-06-01 00:00:00
abstract::1. LP-805, 8-tert-butyl-6,7-dihydropyrrolo-[3,2-e]-5-methylpyrazolo- [1,5a]-pyrimidine-3-carbonitrile, is a newly synthesized potent vasodilator. To investigate the cellular mechanisms of vasorelaxation induced by LP-805, we simultaneously determined the effects of LP-805 on cytosolic Ca2+ concentrations ([Ca2+]i) and...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17121.x
更新日期:1994-12-01 00:00:00
abstract:BACKGROUND:Macrophage elastase (MMP-12) is involved in the inflammatory process of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate in mice the effect of MMP-12 inhibition on the inflammatory process induced by cigarette smoke (CS) or by lipopolysaccharide (LPS) exposure of the air...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/bjp.2008.180
更新日期:2008-07-01 00:00:00
abstract::The action of 'selective' agonists and antagonists at muscarinic receptors mediating ileal contractions, and the rate and force of atrial contractions has been assessed. The effect of nicotinic receptor stimulation, catecholamine release and acetylcholinesterase (AChE) action on muscarinic activity has also been asses...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb09446.x
更新日期:1985-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:N-arachidonyl dopamine (NADA) has been identified as a putative endocannabinoid, but there is little information about which signalling pathways it activates. The purpose of this study was to identify the signalling pathways activated by NADA in vitro. EXPERIMENTAL APPROACH:Human or rat cannabin...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13341
更新日期:2016-01-01 00:00:00
abstract::1. This study was done to characterize the influence of calcium channel blockade on renin secretion and renin gene expression in normal rats and rats with renovascular hypertension. To this end we studied the effects of the 1,4-dihydropyridine derivative, amlodipine, on plasma renin activity and renal renin m-RNA leve...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15735.x
更新日期:1996-10-01 00:00:00
abstract::1. The alpha 2-adrenoceptor agonists TL99 (2-(N N-dimethyl)amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene) and UK14304 (5-bromo-6-[2-imidazoline-2-yl-aminol]-quinoxaline), in concentrations that are less than 1% of those producing vasoconstriction, enhance vasoconstrictor responses to noradrenaline and phenylephrin...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1989.tb14635.x
更新日期:1989-11-01 00:00:00
abstract::1 The effects of piribedil on contractile responses and noradrenaline release evoked by sympathetic nerve stimulation have been studied in the isolated kidney of the rabbit. These effects were compared to those of apomorphine.2 Electrical stimulation (2, 5 and 10 Hz) of sympathetic renal nerves produced frequency-depe...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb10965.x
更新日期:1980-01-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Recombinant human erythropoietin (rHuEPO) is currently the mainstay of renal anaemia treatment. Recently, rHuEPO has been shown to provide pleiotrophic tissue protection in various pathological conditions. However, the benefits of rHuEPO beyond anaemia treatment are limited because it increases r...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2012.02123.x
更新日期:2013-01-01 00:00:00
abstract::1. Plasma exudation and blood flow changes induced by intradermal injection of prostaglandins E2 (PGE2), I2 (PG12), D2 (PGD2) and F2 alpha (PGF2 alpha) were measured in rabbit dorsal skin by the use of [131I]-albumin and 133Xe. 2. Little plasma exudation was produced by any of the prostaglandins when injected alone. 3...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1979.tb07860.x
更新日期:1979-03-01 00:00:00
abstract::1 The isolated perfused ear of the rabbit connected to the body only by its nerve, was used to investigate the influence of prostaglandin F2alpha on the algesic effect of bradykinin and acetylcholine. 2 Bradykinin and acetylcholine, following intra-arterial injection into the isolated perfused ear elicited a dose-rela...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb08390.x
更新日期:1977-03-01 00:00:00
abstract:BACKGROUND AND PURPOSE:ARL 67156, 6-N,N-Diethyl-D-beta-gamma-dibromomethylene adenosine triphosphate, originally named FPL 67156, is the only commercially available inhibitor of ecto-ATPases. Since the first report on this molecule, various ectonucleotidases responsible for the hydrolysis of ATP at the cell surface hav...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707361
更新日期:2007-09-01 00:00:00
abstract::1. Exogenous adenosine triphosphate (ATP) stimulated the short circuit current (SCC) in primary monolayer cultures of rat epididymal cells when added to the apical but not to the basolateral side of the monolayers. Half-maximal stimulation was achieved at 5 x 10(-8) M ATP. 2. The increase in SCC induced by ATP was dep...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11770.x
更新日期:1988-12-01 00:00:00
abstract::1. By use of the whole-cell configuration of the patch-clamp technique, membrane currents induced by cyclopiazonic acid (CPA; an inhibitor of the sarcoplasmic reticulum (SR) calcium-ATPase) were investigated in single smooth muscle cells freshly dispersed from the mouse anococcygeus. Voltage-dependent calcium currents...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1996.tb15228.x
更新日期:1996-02-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans. EXPERIMENTAL...
journal_title:British journal of pharmacology
pub_type: 杂志文章,meta分析
doi:10.1111/bph.13218
更新日期:2015-09-01 00:00:00
abstract::The consumption of green tea (Camellia sinensis) has been shown to have many physiological and pharmacological health benefits. In the past two decades several studies have reported that epigallocatechin-3-gallate (EGCG), the main constituent of green tea, has anti-infective properties. Antiviral activities of EGCG wi...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
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更新日期:2013-03-01 00:00:00
abstract::1. Endothelial cells, under given circumstances, can initiate contraction (constriction) of the vascular smooth muscle cells that surround them. Such endothelium-dependent, acute increases in contractile tone can be due to the withdrawal of the production of nitric oxide, to the production of vasoconstrictor peptides ...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/sj.bjp.0706042
更新日期:2005-02-01 00:00:00
abstract::1. The effects of some chloride channel antagonists were studied on the calcium-activated chloride current (ICl(Ca)) in smooth muscle cells from the rabbit portal vein with the perforated patch technique. 2. 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulphonic acid (SITS) and 4,4'-diisothiocyanato-stilbene-2,2'-disu...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb14891.x
更新日期:1994-04-01 00:00:00
abstract::1. Acetylcholine mustard (N-2-chloroethyl-N-methyl-2-acetoxyethylamine), a potent muscarinic agonist, binds virtually irreversibly to muscarinic receptors in longitudinal muscle strips from guinea-pig small intesting, as shown by the inhibition of the binding of E13-H]-propylbenzilycholine mustard ([3-H-PrBCM), an aff...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1975.tb07372.x
更新日期:1975-03-01 00:00:00
abstract::1. The effects of acetylcholine (ACh) on membrane potential, relaxation and cyclic GMP levels were compared to the NO donor L-nitrosocysteine (Cys-NO) in segments of guinea-pig coronary artery. 2. ACh and Cys-NO produced concentration-dependent relaxations of muscles contracted with the H1 receptor agonist, 2-(2-amino...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb14851.x
更新日期:1994-04-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Asthenozoospermia is a leading cause of male infertility, but development of pharmacological agents to improve sperm motility is hindered by the lack of effective screening platforms and knowledge of suitable molecular targets. We have demonstrated that a high-throughput screening (HTS) strategy ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.14814
更新日期:2019-12-01 00:00:00
abstract::The S-S reducing agent, dithiothreitol (DTT) altered the properties of nicotinic receptors in rat superior cervical ganglia such that (i) carbachol became less active as a depolarizing agent and (ii) bromo-acetylcholine produced an irreversible depolarization. The latter was temporarily annulled by hexamethonium (whic...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1976.tb06968.x
更新日期:1976-01-01 00:00:00
abstract::1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb14775.x
更新日期:1994-02-01 00:00:00
abstract::1--Responses (relaxation) to the beta-adrenoceptor agonists, isoprenaline, fenoterol or noradrenaline, were obtained on cat tracheal preparations contracted with a submaximal concentration of carbachol (0.5 microM). 2--The relative potencies of isoprenaline: fenoterol: noradrenaline were 100:8.1:10.7. From this, it wa...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1983.tb09406.x
更新日期:1983-02-01 00:00:00
abstract::1. The present study was designed to characterize the positive inotropic response to DPI 201-106 in isolated papillary muscle strips obtained from heart failure patients undergoing surgery. 2. The positive inotropic responses to isoprenaline and milrinone and cardiac beta-adrenoceptor density were also determined. 3. ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1989.tb16892.x
更新日期:1989-09-01 00:00:00
abstract::1. Microvascular permeability in the mesentery and consequent leakage of protein into the peritoneum of spontaneously hypertensive rats (SHR) and normotensive rats (NTR) was measured in vivo by the extravasation of Evans blue dye. 2. In sensitized NTR, challenge with antigen produced extensive increases in dye extrava...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701875
更新日期:1998-06-01 00:00:00