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Acta pharmacologica Sinica
Science Press
Acta pharmacologica Sinica

Science Press

月刊

1671-4083

Acta pharmacologica Sinica/Journal Acta pharmacologica SinicaSCIISTPAHCI
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    Beneficial effects of melatonin in experimental models of Alzheimer disease

    Yong CHENGZheng FENGQing-zhu ZHANGJun-tian ZHANG...
    p.129-139页
    查看更多>>摘要：Alzheimer's disease (AD), a progressive degenerative disorder, is characterized by the presence of amyloid deposits, neurofibrillary tangles and neuron loss. Emerging evidence indicates that antioxidants could be useful either for the prevention or treatment of AD. It has been shown that melatonin is a potent antioxi-dant and free radical scavenger. Additionally, melatonin stimulates several antioxidative enzymes and improves mitochondrial energy metabolism. These findings led us to study amyloid precursor protein transgenic mice, ovariectomized rats, and pheochromocytoma and astroglioma cell lines, to observe whether melatonin had any effect on Alzheimer's symptoms or pathological changes. We found that melatonin had many beneficial effects in experimental models of AD, including improvement of cognitive function, anti-oxidative injury, anti-apoptosis, inhibition of β-amyloid (Aβ) deposition and Aβ fiber formation. Several groups have shown that melatonin has an inhibitory effect on tau protein hyperphosphorylation. These actions may potentially slow down or stop the progression of dementia.
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    Recent trends in drug abuse in China

    Yu-xia FANGYan-bo WANGJie SHIZhi-min LIU...
    p.140-144页
    查看更多>>摘要：Drug abuse has spread quickly since reemerging as a national problem in China in the late 1980s. The number of registered drug abusers increased from 70 000 in 1990 to more than one million by the end of 2004. In addition to opioids, abuse of "new" types of drugs including 3,4-methylenedioxymethamphetamine (MDMA) and ketamine has spread since 1997. Illicit drug trafficking and production have swept most of southern China, and throughout the country drug abuse has caused many problems for both abusers and the community. One major drug-related problem is the spread of HIV, which has caused major social and economic damage in China. In response, the Chinese government has begun an anti-drug campaign, including legislative measures to control drug abuse. However, changing the public's attitudes toward drug abusers and breaking the link between drug use and HIV spread are equally important.
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    Neuroprotective effects of stearic acid against toxicity of oxygen/glucose deprivation or glutamate on rat cortical or hippocampal slices

    Ze-jian WANGGuang-mei LIWen-lu TANGMing YIN...
    p.145-150页
    查看更多>>摘要：Aim: To observe the effects of stearic acid, a long-chain saturated fatty acid consisting of 18 carbon atoms, on brain (cortical or hippocampal) slices insulted by oxygen-glucose deprivation (OGD), glutamate or sodium azide (NaN_3) in vitro. Methods: The activities of hippocampal slices were monitored by population spikes recorded in the CA1 region. In vitro injury models of brain slice were induced by 10 min of OGD, 1 mmol/L glutamate or 10 mmol/L NaN_3. After 30 min of pre-incubation with stearic acid (3-30 μmol/L), brain slices (cortical or hippocampal) were subjected to OGD, glutamate or NaN_3, and the tissue activities were evaluated by using the 2,3,5-triphenyltetrazolium chloride method. MK886 [5 mmol/L; a noncompetitive inhibitor of proliferator-activated receptor (PPAR-α)] or BADGE (bisphenol A diglycidyl ether; 100 μmol/L; an antagonist of PPAR-γ) were tested for their effects on the neuroprotection afforded by stearic acid. Results: Viability of brain slices was not changed significantly after direct incubation with stearic acid. OGD, glutamate and NaN_3 injury significantly decreased the viability of brain slices. Stearic acid (3-30 μmol/L) dose-dependently protected brain slices from OGD and glutamate injury but not from NaN_3 injury, and its neuroprotective effect was completely abolished by BADGE. Conclusion: Stearic acid can protect brain slices (cortical or hippocampal) against injury induced by OGD or glutamate. Its neuroprotective effect may be mainly mediated by the activation of PPAR-γ.
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    High density lipoprotein 3 inhibits oxidized low density lipoprotein- induced apoptosis via promoting cholesterol efflux in RAW264.7 cells

    Pei JIANGPeng-ke YANJian-xiong CHENBing-yang ZHU...
    p.151-157页
    查看更多>>摘要：Aim: To investigate the protective effect of high density lipoprotein 3 (HDL_3) on oxidized low density lipoprotein (ox-LDL)-induced apoptosis in RAW264.7 cells. Methods: RAW264.7 cells were exposed to 50 mg/L ox-LDL for various durations up to 48 h, and apoptosis was detected using Hoechst 33258 staining and flow cytometric analysis. Total cholesterol levels were detected by high performance liquid chromatography, cholesterol efflux was determined by Tritium labeling, and the cellular lipid droplets were assayed by oil red O staining. Results: Treatment with 50 mg/L ox-LDL for 12, 24, and 48 h increased the apoptotic rate of RAW264. 7 cells in a time-dependent manner. The peak apoptotic rate (47.7%) was observed after 48 h incubation. HDL_3 at various concentrations (50 mg/L, 100 mg/L, and 200 mg/L) inhibited the ox-LDL (50 mg/L for 48 h)-mediated apoptosis that was accompanied by an increased rate of intracellular cholesterol efflux, and decreased total cholesterol levels in cells in a concentration-dependent manner. Blockage of cholesterol efflux by brefeldin decreased the protective effect of HDL_3 on ox-LDL-induced apoptosis. Increase of the cholesterol efflux effected by another cholesterol acceptor, β-cyclodextrin, led to a dramatic decrease in the apoptotic rate of cells. Conclusion: HDL_3 antagonizes ox-LDL-induced apoptosis in RAW264.7 cells, through reducing the accumulation of toxic cholesterol.
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    Role of norepinephrine in development of short-term myocardial hibernation

    Zuo-lin FUYi-bai FENGHong-xiaXUXin-ping ZHANG...
    p.158-164页
    查看更多>>摘要：Aim: To investigate the role of norepinephrine in the development of short-term myocardial hibernation. Methods: Hearts were removed from rats and set up as isometrically beating or short-term hibernation models. The hearts were perfused with modified Krebs-Henseleit buffer under a controlled perfusion pressure. The myocardial ultrastructure was examined, and the content of ATP, phosphocreatine, and glycogen in myocardium, the extent of myocyte apoptosis, and the amount of Bcl-2 and Bax products were determined after 120-min ischemia assessed by TUNEL and immunocytochemistry. Results: There was no significant difference between the reserpinized hearts and the NS control group with respect to heart function, myocardial ultrastructure, ATP, phosphocreatine, or glycogen content, myocyte apoptosis, or amount of Bax or Bcl-2 products. However, relative to the normal saline group, in the norepinephrine-treated hearts, heart function, and myocardial ultrastructure deteriorated significantly, apoptosis and amount of Bax product increased significantly, and the ATP, phosphocreatine, and glycogen content decreased significantly, as did the amount of Bcl-2 product. Conclusion: Myocardial norepinephrine does not contribute to the development of short-term hibernation, but that exogenous NE can induce progressive decreases in coronary flow and cardiac performance, which might result from the increases in apoptosis and necrosis. Norepinephrine may be an important factor in the deterioration of myocardial structure and function during hibernation, and that anti-adrenergic treatment may be helpful for the development and sustainment of short-term myocardial hibernation.
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    Ouabain at pathological concentrations might induce damage in human vascular endothelial cells

    Yan-ping RENRuo-wen HUANGZhuo-ren LUE
    p.165-172页
    查看更多>>摘要：Aim: To examine the time- and dose-dependent effects of ouabain on human umbilical vein endothelial cells (HUVEC) in vivo, and the changes in aortic endot-helium and the different expression levels of Kv4.2 in vitro. Methods: The proliferation of HUVEC and cell death were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, the incorporation of [~3H]TdR, trypan blue staining, and lactate dehydrogenase (LDH) release. The response of endothelial cells to ouabain was explored with a complementary DNA microarray and a candidate gene was found. "Ouabain-sensitive" hypertensive rats were established by chronic administration of ouabain. Changes in the aortic endothe-lium were observed by electron microscopy, and the expression level of Kv4.2 in different animals was studied by using real-time quantitative reverse transcrip-tion-polymerase chain reaction (RT-PCR). Results: Ouabain stimulated the proliferation of HUVEC at physiological concentrations (0.3-0.9 nmol/L). Ouabain at pathological concentrations (0.9-1.8 nmol/L) inhibited proliferation and induced cell death. mRNA profile analysis indicated that 340 genes were differentially expressed after ouabain treatment: 145 were upregulated, of which 6 were upregulated significantly, including KCND2 (encoding the potassium voltage-gated channel shal-related subfamily member 2). The upregulated genes were mainly related to cell metabolism and transcription. In ouabain-sensitive hypertensive rats, the aortic endothelium was damaged and Kv4.2 (coded by KCND2) was over-expressed. Conclusion: The physiological role of ouabain in HUVEC might involve the control of growth and metabolism. Ouabain at pathological concentrations might affect the structure and function of the vascular endothelium by modification of expression of the KCND2 gene, and participate vascular remodeling in hypertension.
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    Effects of neutral sulfate berberine on LPS-induced cardiomyocyte TNF-α secretion, abnormal calcium cycling, and cardiac dysfunction in rats

    Jing YANGHua-dong WANGDa-xiang LUYan-ping WANG...
    p.173-178页
    查看更多>>摘要：Aim: To evaluate the effect of neutral sulfate berberine on cardiac function, tumor necrosis factor α (TNF-α) release, and intracellular calcium concentration ([Ca~(2+)]_i) in cardiomyocytes exposed to lipopolysaccharide (LPS). Methods: Primary cultured rat cardiomyocytes were prepared from ventricles of 3-4-day old Sprague-Dawley rats. TNF-α concentrations in cell-conditioned media were measured by using a Quantikine enzyme-linked immunosorbent assay kit, and cardiomyocyte [Ca~(2+)]_i was measured by using Fura-2/AM. The isolated rat hearts were perfused in the Langendorff mode. Results: LPS at doses of 1,5,10, and 20 μg/mL markedly stimulated TNF-α secretion from cardiomyocytes, and neutral sulfate berberine inhibited LPS-induced TNF-α production. Intracellular calcium concentration was significantly decreased after LPS stimulation for 1 h, and increased 2 h after LPS treatment. Pretreatment with neutral sulfate berberine reversed the LPS-induced [Ca~(2+)]_i alterations, although neutral sulfate berberine did not inhibit a rapid increase in cardiomyocyte [Ca~(2+)]_i induced by LPS. Perfusion of isolated hearts with LPS (100 μg/mL) for 20 min resulted in significantly impaired cardiac performance at 120 min after LPS challenge: the maximal rate of left ventricular pressure rise and fall (±dp/dt_(max)) decreased compared with the control. In contrast, ±dp/dt_(max) at 120 min in hearts perfused with neutral sulfate berberine (1 μmol/L) for 10 min followed by 20 min LPS (100 μg/mL) was greater than the corresponding value in the LPS group. Conclusion: Neutral sulfate berberine inhibits LPS-stimulated myocardial TNF-α production, impairs calcium cycling, and improves LPS-induced contractile dysfunction in intact heart.
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    Effect of resveratrol on L-type calcium current in rat ventricular myocytes

    Li-ping ZHANGJing-xiang YINZheng LIUYi ZHANG...
    p.179-183页
    查看更多>>摘要：Aim: To study the effect of resveratrol on L-type calcium current (Ⅰ_(Ca-L)) in isolated rat ventricular myocytes and the mechanisms underlying these effects. Methods: Ⅰ_(Ca-L) was examined in isolated single rat ventricular myocytes by using the whole cell patch-clamp recording technique. Results: Resveratrol (10-40 μmol/L) reduced the peak amplitude of Ⅰ_(Ca-L) and shifted the current-voltage (Ⅰ-Ⅴ) curve upwards in a concentration-dependent manner. Resveratrol (10, 20, 40 μmol/L) decreased the peak amplitude of Ⅰ_(Ca-L) from -14.2±1.5 pA/pF to -10.5±1.5 pA/pF (P < 0.05), -7.5±2.4 pA/pF (P < 0.01), and -5.2±1.2 pA/pF (P < 0.01), respectively. Resveratrol (40 μmol/L) shifted the steady-state activation curve of Ⅰ_(Ca-L) to the right and changed the half-activation potential (V_(0.5)) from -19.4±0.4 mV to -15.4±1.9 mV (P < 0.05). Resveratrol at a concentration of 40 μmol/L did not affect the steady-state inactivation curve of Ⅰ_(Ca-L), but did markedly shift the time-dependent recovery curve of Ⅰ_(Ca-L) to the right, and slow down the recovery of Ⅰ_(Ca-L) from inactivation. Sodium orthovanadate (Na_3VO_4; 1 mmol/L), a potent inhibitor of tyrosine phosphatase, significantly inhibited the effects of resveratrol (P < 0.01). Conclusion: Resveratrol inhibited Ⅰ_(Ca-L) mainly by inhibiting the activation of L-type calcium channels and slowing down the recovery of L-type calcium channels from inactivation. This inhibitory effect of resveratrol was mediated by the inhibition of protein tyrosine kinase in rat ventricular myocytes.
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    Thrombin-like enzymes from venom gland of Deinagkistrodon acutus: cDNA cloning, mechanism of diversity and phylogenetic tree construction

    Xiang-dong ZHAHe-sheng HUANGLi-zhi ZHOUJing LIU...
    p.184-192页
    查看更多>>摘要：Aim: To clone cDNAs of thrombin-like enzymes (TLEs) from venom gland of Deinagkistrodon acutus and analyze the mechanisms by which their structural diversity arose. Methods: Reverse transcription-polymerase chain reaction and gene cloning techniques were used, and the cloned sequences were analyzed by using bioinformatics tools. Results: Novel cDNAs of snake venom TLEs were cloned. The possibilities of post-transcriptional recombination and horizontal gene transfer are discussed. A phylogenetic tree was constructed. Conclusion: The cDNAs of snake venom TLEs exhibit great diversification. There are several types of structural variations. These variations may be attributable to certain mechanisms including recombination.
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    MI-QSAR models for prediction of corneal permeability of organic compounds

    Cheng CHENJie YANG
    p.193-204页
    查看更多>>摘要：Aim: To derive a theoretical model for the prediction of corneal permeability of miscellaneous organic compounds in drug design. Methods: A training set of 28 structurally diverse compounds was used to build up the membrane-interaction quantitative structure-activity relationship (MI-QSAR) models. Intermolecular and intramolecular solute descriptors were computed using molecular mechanics, molecular dynamics simulations and quantum chemistry. The QSAR models were optimized using multidimensional linear regression fitting and a stepwise method. A test set of 8 compounds was evaluated using the models as part of a validation process. Results: Significant MI-QSAR models (R=0.976,S=0.1301, F=70.957) of corneal permeability of organic compounds were constructed. Corneal permeability was found to depend upon the sum of net atomic charges of hydrogen atoms attached to the heteroatoms (N, O), the sum of the absolute values of the net atomic charges of oxygen and nitrogen atoms, the principal moment of inertia (X), the Connolly accessible area and the conformational flexibility of the solute-membrane complex. Conclusion: The MI-QSAR models indicated that the corneal permeability of organic molecules was not only influenced by the organic solutes themselves, but also related to the properties of the solute-membrane complex, that is, the interactions of the molecule with the phospholipid-rich regions of cellular membranes.
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