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Protective effects of iptakalim,a novel ATP-sensitive potassium channel opener,on global cerebral ischemia-evoked insult in gerbils

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Acta Pharmacologica Sinica 2006年第6期27卷 665-672页

作者： Hua CHEN~(2,4)Yong YANG~(2,4)Hong-hong YAO~2 Xing-chun TANG~2 Jian-hua DING~2 Hai WANG~3 Gang HU~(2,5)2 Laboratory of Neuropharmacology,department of Anatomy,Histology and pharmacology,Nanjing Medical University,Nanjing 210029,China 3 department of Cardiovascular pharmacology,Beijing Institute of pharmacology and Toxicology,Beijing 100850,China department of Anatomy Laboratory of Neuropharmacology Histology and Pharmacology Nanjing Medical University Nanjing China department of Cardiovascular pharmacology Beijing Institute of Pharmacology and Toxicology Beijing China

Aim:To investigate the protective role of iptakalim,a novel ATP sensitive potas-sium channel opener,on global cerebral ischemia-evoked insult in gerbils andglutamate-induced PC 12 cell injury.Methods:Global cerebral ischemia was in-duced by occluding the bilateral common carotid arteries in gerbils for 5 min.Theopen field maze and T-maze were employed to investigate the experimental thera-peutic value of iptakalim on ischemic brain insult（n=8）.The pyramidal cells in thehippocampal CA1 regions were counted to assess the protective effects ofiptakalim.Glutamate released from the gerbil hippocampus and PC12 cells weredetermined by HPLC.Intracellular calcium was measured by Fluo-3 AM with ABio-Rad Radiance 2100TM confocal system in conjunction with a Nikon TE300microscope.Astrocyte glutamate uptake measurements were determined by liq-uid scintillation counting.Results:Iptakalim（0.5-4.0 mg/kg per day,ip）couldreduce the high locomotor activity evoked by ischemia and improve global cere-bral ischemia-induced working memory impairments.Histological studies revealedthat iptakalim could increase the survival neuron in the hippocampus CA1 zone ina dose-dependent manner.Moreover,iptakalim could reverse ischemia-evokedincreases of glutamate in the hippocampus of gerbils.In an in vitro study,iptakalimprotected PC12 cells against glutamate-induced excitotoxicity,reduced the[Ca2+]iincreases,and enhanced the glutamate uptake activity of primary culturedastrocytes.Conclusions:Iptakalim plays a key role in preventing global cerebralischemia-evoked insults in gerbils and glutamate-induced PC12 cell injury by anti-excitotoxicity.Iptakalim might be a promising novel candidate for the preventionand/or treatment of stroke.

关键词： ATP-sensitive potassium channel opener iptakalim global cerebral ischemia neuroprotection excitotoxicity

Induction of systemic lupus erythematosus syndrome in BALB/c mice by immunization with active chromatin

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Acta Pharmacologica Sinica 2004年第6期25卷 105-109页

作者： Hong LI, Yun-yi ZHANG, Ya-nan SUN, Xi-yi HUANG, Yong-feng JIA, Duan LI2 department of pharmacology, Schoolof Pharmacy, Fudan University, Shanghai 200032, China department of pharmacology School of Pharmacy Fudan University 上海 200032 department of pharmacology School of Pharmacy Fudan University Shanghai 200032

AIM: To establish an animal model for systemic lupus erythematosus (SLE)-like syndrome in mice. METHODS: BALB/c mice were immunized with active chromatin isolated from ConA-actived syngeneic spleno-lymphocytes. Plasma samples of mice were tested by enzyme-linked immunosorbent assays (ELISA) for the presence of IgG anti-dsDNA, -ssDNA, and anti-histone antibodies. Tumor necrosis factor-α (TNF-α) in serum was measured by ELISA. Spleno-lymphocyte proliferation assays and the levels of interferon-γ (IFN-γ) in supernatants were tested respectively. Proteinuria was measured. Kidneys were examined by direct immunohistochemical method and light microscopy. RESULTS: Anti-ds DNA, ssDNA, and histone antibodies were induced in active chromatin-immu- nized mice, the proliferation response of splenocytes to ConA and LPS were reduced, levels of interferon-γ in supernatants and TNF-α in serum were lowered. Lupus nephritis was assessed by the presence of Ig deposits, glomerular pathology and proteinuria. CONCLUSION: The active chromatin-induced SLE-like mouse model was similar to idiopathic SLE in human.

关键词： systemic lupus erythematosus chromatin autoantibody tumor necrosis factor interferon type II B-lymphocytes T-lymphocytes female enzyme-linked immunosorbent assay

Construction and Co-expression of Bicistronic Plasmid Encoding Human WEE1 and Stem Cell Factor

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Acta Biochimica et Biophysica Sinica 2005年第2期37卷 107-112页

作者： Ping LEI Wen-Han LI Wen-Jun LIAO Bing YU Hui-Fen ZHU Jing-Fang SHAO Guan-Xin SHEN Laboratory of Molecular and Immuno-pharmacology,department of Immunology and department of pharmacology,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China Laboratory of Molecular and Immuno-pharmacology Department of Immunology and Department of Pharmacology Tongji Medical College Huazhong University of Science and TechnologyWuhan 430030 China

To protect the hematopoietic stem cells(HSCs)from apoptosis induced by chemotherapy andpromote HSC proliferation,bi-functional gene delivery systems are increasingly investigated in gene therapy.In the present study,we constructed a bicistronic vector,pWISG,expressing the anti-apoptotic proteinhuman WEE1(WEE1Hu)and the fusion protein of the proliferation-stimulating stem cell factor(SCF)andenhanced green fluorescent protein(EGFP)separately with internal ribosome entry site(IRES).We firstexamined

关键词： internal ribosome entry site (IRES) human WEE1 (WEE1Hu) stem cell factor (SCF)

Influence of Trace Amount of Calponin on Smooth Muscle Myosin in Different States

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Acta Biochimica et Biophysica Sinica 2004年第8期36卷 529-536页

作者： Jing-Xian YANG, Xiao-Hua FENG, Ying ZHANG, and Yuan LIN department of pharmacology, Dalian Medical University, Dalian 116027, China department of pharmacology Dalian Medical UniversityDalian 116027 China

Calponin (CaP), a thin filament-associated protein, is thought to be involved in modulating smooth muscle contractile activity, but the role and mechanism keep unknown. In this study, trace amount of calponin (TAC) was found to obviously influence myosin in different states in Ca2+-independent manner, suggesting a high efficient interaction between TAC and myosin. In this assay, the lowest ratio of CaP vs. myosin was 1:10,000, with the concentration of CaP 10,000-fold lower than that used previously. Myosin phosphorylation, myosin Mg2+-ATPase activity and protein binding activity were detected to determine the effects of TAC on the myosin in different states. The amount of precipitated myosin that bound to TAC was used as the index to determine the interaction between myosin and TAC in binding assay. Our data showed that in the absence of actin, TAC significantly increased the precipitation of unphosphorylated myosin, Ca2+- dependently or independently phosphorylated myosin by MLCK, and stimulated the Mg2+-ATPase activities of these myosins slightly but significantly. However, no obvious change of precipitation of myosin phospho- rylated by PKA was observed, indicating the relatively selective effect of TAC. In the presence of actin, the increase of myosin precipitations was abolished, and no obvious change of actin precipitations and actin- activated myosin Mg2+-ATPase activities were observed implicating the high efficiency of TAC on myosin being present in the absence of actin. Although we can not give conclusive comments to our results, we propose that the high efficiency of TAC-myosin interaction is present when actin is dissociated from myosin, even if CaP/myosin ratio is very low; this high efficient interaction can be abolished by actin. However, why and how TAC can possess such a high efficiency to influence myosin and how the physiological significance of the high efficiency of TAC is in regulating the interaction between myosin and actin remain to be investigated.

关键词： trace amount of calponin protein binding phosphorylation myosin Mg2+-ATPase

MicroRNAs as potential biomarkers for diagnosis of attention deficit hyperactivity disorder

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Neural Regeneration Research 2024年第3期19卷 557-562页

作者： Bridget Martinez Philip V.Peplow department of pharmacology University of Nevada-RenoRenoUSA department of Medicine University of Nevada-RenoRenoUSA department of Anatomy University of OtagoDunedinNew Zealand

Inappropriate levels of hyperactivity,impulsivity,and inattention characterize attention deficit hyperactivity disorder,a common childhood-onset neuropsychiatric disorder.The cognitive function and learning ability of children with attention deficit hyperactivity disorder are affected,and these symptoms may persist to adulthood if they are not treated.The diagnosis of attention deficit hyperactivity disorder is only based on symptoms and objective tests for attention deficit hyperactivity disorder are missing.Treatments for attention deficit hyperactivity disorder in children include medications,behavior therapy,counseling,and education services which can relieve many of the symptoms of attention deficit hyperactivity disorder but cannot cure it.There is a need for a molecular biomarker to distinguish attention deficit hyperactivity disorder from healthy subjects and other neurological conditions,which would allow for an earlier and more accurate diagnosis and appropriate treatment to be initiated.Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of attention deficit hyperactivity disorder.The recent studies reviewed had performed microRNA profiling in whole blood,white blood cells,blood plasma,and blood serum of children with attention deficit hyperactivity disorder.A large number of microRNAs were dysregulated when compared to healthy controls and with some overlap between individual studies.From the studies that had included a validation set of patients and controls,potential candidate biomarkers for attention deficit hyperactivity disorder in children could be miR-140-3p,let-7g-5p,-30e-5p,-223-3p,-142-5p,-486-5p,-151a-3p,-151a-5p,and-126-5p in total white blood cells,and miR-4516,-6090,-4763-3p,-4281,-4466,-101-3p,-130a-3p,-138-5p,-195-5p,and-106b-5p in blood serum.Further studies are warranted with children and adults with attention deficit hyperactivity disorder,and consideration should be given to utilizing rat

关键词： adults attention deficit hyperactivity disorder biomarkers blood plasma blood serum children microRNA total white blood cells whole blood

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Endogenous histamine inhibits the development of morphine-induced conditioned place preference

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Acta Pharmacologica Sinica 2007年第1期28卷 10-18页

作者： Ying-xia GONG~2 Min LV~(2,3) Yong-ping ZHU~2 Yuan-yuan ZHU~2 Er-qing WEI~2 Hong SHI~3 Qun-li ZENG~2 Zhong CHEN~(2,4)2 department of pharmacology and Neurobiology,School of Medicine,Zhejiang University,Hangzhou 310031,China 3 department of pharmacology,Zhejiang Academy of Medical Sciences,Hangzhou 310031,China department of pharmacology and Neurobiology School of Medicine Zhejiang University Hangzhou China department of pharmacology Zhejiang Academy of Medical Sciences Hangzhou China

Aim:The conditioned place preference(CPP)paradigm was used to investigatethe effects of endogenous histamine on the processes leading to morphine-induced reward-seeking behavior in Sprague-Dawley rats.Methods:The modelof CPP was used to assess the rewarding effect of morphine.The levels of histamine,glutamate,γ-aminobutyric acid(GABA),dopamine(DA)and 3,4-dihydroxyphenyl-acetic acid(DOPAC)in rat brains were measured with high-performance liquidchromatography.Immunohistochemistry technique was used to observe themorphological changes of neurons.Results:Intraperitoneal injection of mor-phine(2,5 or 10 mg/kg)induced the development of CPP in a dose-dependentmanner.In addition,morphine administrations(10 mg/kg)decreased the hista-mine content and reduced the number and size of histaminergic neurons in thetuberomammillary nucleus(TM),as well as markedly increasing the DOPAC/DAratios in the ventral tegmental area(VTA)and nucleus accumbens(NAc).Intra-peritoneal injection of histidine(50,100 or 200 mg/kg)dose-dependently inhibitedthe development of morphine-induced CPP.Bilateral lesions of the TM,whichdecreased the histamine levels in the VTA and NAc,potentiated the developmentof CPP induced by morphine(1 mg/kg,a dose that produced no appreciable effectwhen given alone)and increased the DOPAC/DA ratios in the VTA and NAc,butdid not change the glutamate or GABA levels in these nuclei.Histidine reversedthe effects of the TM lesions.Conclusion:These results indicate that endog-enous histamine plays a role in inhibiting the development of morphine-inducedreward-seeking behavior,and the inhibition may involve the modulation of dopa-minergic activity.

关键词： conditioned place preference histamine morphine rat tuberomammillary nucleus

Effects of nine antihypertensive drugs on blood pressure variability in sinoaortic-denervated rats

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Acta Pharmacologica Sinica 2006年第8期27卷 1013-1017页

作者： Jin Wang~(2,3) Fu-ming SHEN~2 Mm-wei WANG~3 Ding-feng SU~(2,4) ~2 department of pharmacology,Second Military Medical University,Shanghai 200433 ~3department of" pharmacology,Shenyang Pharmaceutical University,Shenyang 110016,China department of pharmacology Second Military Medical University Shanghai China department of pharmacology Shenyang Pharmaceutical University Shenyang China

Aim:The present work was designed to investigate the effects of nine commonlyused antibypertensive drugs on blood pressure(BP)and blood pressure variabil-ity(BPV)in conscious sinoaortic-denervated(SAD)rats.Methods:Seventy-twoSAD rats were randomly divided into nine groups.They were respectively givennifedipine 3 mg/kg,nitrendipine 5 mg/kg,amlodipine 1mg/kg,clonidine 10 μg/kg,prazosin 0.5 mg/kg,atenolol 20 mg/kg,telmisartan 20 mg/kg,hydrochlorothiazide40 mg/kg or captopril 50 mg/kg.The drugs were given via a catheter previouslyimplanted into the stomach.BP was recorded for 5 h from 1 h before drug admin-istration to 4 h after drug administration in conscious,freely moving rats.Results:It was found that all these nine drugs significantly decreased BP in SAD rats.Sixof these drugs(nifedipine,nitrendipine,amlodipine,clonidine,prazosin andatenolol)significantly decreased BPV in SAD rats,but the remaining three drugsdid not.Clonidine and atenolol increased the heart period and the others did not.No drugs affected the heart period variability.Conclusion:Among nine antihy-pertensive drugs from different classes,calcium antagonists and sympatheticinhibitors decreased BPV in SAD rats.

关键词： antihypertensive drugs blood pressure blood pressure variability sinoaortic denervation

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Acta Pharmacologica Sinica 2003年第12期24卷 91-95页

作者： LIU Hui-Chen, JIN Shu-Min, WANG Yong-Li department of pharmacology, Hebei Medical University, Shijiazhuang 050017, China department of pharmacology Hebei Medical University Shijiazhuang 050017

AIM: To compare the pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (M1), in male and female rats. METHODS: Following a single oral dose of 10 mg/kg trans-T hydrochloride to rats, (+)-trans-T, (-)-trans-T, (+)-M1, and (-)-M1 in plasma were determined by a high performance capillary electrophoresis method. RESULTS: The females showed higher plasma concentrations of (+)-trans-T, (-)-trans-T, and (+)-M1 than the males. The enantiomers of trans-T were absorbed and eliminated more slowly in the females than in the males. (+)-M1 was eliminated more slowly in the females than in the males. All pharmacokinetic parameters but Tmaxof the two enantiomers of trans-T were significantly different in both sex rats. The (+)/(-)-enantiomeric ratios of the pharmacokinetic parameters for trans-T in the males were similar to those in the females. The values of Cmax, AUC0-∞of the two enantiomers of M1 were significantly different in both sex rat

关键词： tramadol pharmacokinetics sex factors

Role of N-formyl peptide receptor 2 in germinal matrix hemorrhage:an intrinsic review of a hematoma resolving pathway

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Neural Regeneration Research 2024年第2期19卷 350-354页

作者： Jerry Flores Jiping Tang department of Physiology&pharmacology Loma Linda University School of MedicineLoma LindaCAUSA

Germinal matrix hemorrhage is one of the leading causes of morbidity,mortality,and acquired infantile hydrocephalus in preterm infants in the United States,with little progress made in its clinical management.Blood clots have been shown to elicit secondary brain injury after germinal matrix hemorrhage,by disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage causing post-hemorrhagic hydrocephalus development.Current evidence suggests that rapid hematoma resolution is necessary to improve neurological outcomes after hemorrhagic stroke.Various articles have demonstrated the beneficial effects of stimulating the polarization of microglia cells into the M2 phenotype,as it has been suggested that they play an essential role in the rapid phagocytosis of the blood clot after hemorrhagic models of stroke.N-formyl peptide receptor 2(FPR2),a G-protein-coupled receptor,has been shown to be neuroprotective after stroke.FPR2 activation has been associated with the upregulation of phagocytic macrophage clearance,yet its mechanism has not been fully explored.Recent literature suggests that FPR2 may play a role in the stimulation of scavenger receptor CD36.Scavenger receptor CD36 plays a vital role in microglia phagocytic blood clot clearance after germinal matrix hemorrhage.FPR2 has been shown to phosphorylate extracellular-signal-regulated kinase 1/2(ERK1/2),which then promotes the transcription of the dual-specificity protein phosphatase 1(DUSP1)gene.In this review,we present an intrinsic outline of the main components involved in FPR2 stimulation and hematoma resolution after germinal matrix hemorrhage.

关键词： AnxA1 FPR2 GMH hematoma resolution hemorrhagic stroke M1 M2 microglia polarization microglia phagocytosis

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