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The Neuroprotective Effect of Acetyl Ferulaic Isosorbide and Ginsenoside-Rd

Author: YuanLiBang
Tutor: XiongLiZe;DongHaiLong
School: Fourth Military Medical University
Course: Anesthesiology
Keywords: The acetylation ferulic single isosorbide dinitrate Apoptosis Ginsenoside Rd Synergistic effect Cerebral ischemia -reperfusion injury
CLC: R965
Type: Master's thesis
Year: 2010
Downloads: 41
Quote: 0
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Background ischemic cerebrovascular disease is one of the most serious diseases of human death and disability, despite a large number of researchers in this field tireless research, but in addition to thrombolytic therapy, also do not have any kind of treatment measures and the drug is clinically proven efficacy reliable. Very short time window of thrombolytic therapy is currently looking for an exact and effective neuroprotective agents become more urgent task. The laboratory long-term commitment to finding and screening cerebral protective effects of drugs and measures. Cerebral ischemia-reperfusion injury is caused by a series of harmful cascade reaction involving multiple pathological processes, previous studies have demonstrated the clinical efficacy of neuroprotective agents for a single link are inaccurate, and therefore neuroprotective agents in combination or more targets of drug studies to become a new way of brain protection research. Radical damage has been important pathological aspects of ischemic brain damage. In the research of new drug targets, drugs for free radical damage is likely to become a new drug candidate for brain protection. Radicals into oxygen free radicals (OFR) and nitrogen radicals (NFR). Oxygen free radicals including superoxide anion (· O2-), hydrogen peroxide (H2O2) and hydroxyl radical (· HO). The nitrogen radicals major endogenous nitric oxide (NO), nitrogen dioxide (NO2) and generated by the reaction of NO · O2-peroxynitrite (peroxynitrite, ONOO ˉ). Endogenous NO in cerebral ischemia and reperfusion injury depends on the type of NO synthesis of nitric oxide synthase (NOS), although endothelial nitric oxide synthase (eNOS) synthesis in the ischemic early making within the neurotoxic effects of a small amount of NO may play a neuroprotective effect, but by neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) in the process of reperfusion mass produced NO play a negative effect derived NO in ischemic brain damage. Latest research suggests that exogenous NO inhibits c - jun N end kinase 3 (JNK3) phosphorylation caused neuronal apoptosis mediated by endogenous NO have a protective effect, the addition of exogenous NO also promote angiogenesis and neuronal differentiation play a neuroprotective effect. Similarly, a large number of studies have confirmed cerebral ischemia and reperfusion process explosive release of oxygen free radicals in cerebral ischemia reperfusion injury plays a multiple of the harmful effects of oxygen free radical scavenger by scavenging oxygen free radicals play a neuroprotective role . Research and development of new drugs against free radicals are oxygen free radicals and nitrogen radicals both split off. Avoiding disadvantages righting suppressing evil philosophy previously oxygen free radical scavenger ferulic acid (FA Fig. 1A) and exogenous NO donor mononitrate isosorbide esters (ISMN, Figure 1B) which The two drugs were designed and synthesized acetyl ferulic acid can scavenge oxygen free radicals and the release of exogenous NO dual target drug isosorbide mononitrate (acetyl ferulaic isosorbide, AFI, Figure 2), the purpose of this study is to study brain protective effect and to explore the mechanisms. Countries of a new class of drugs, traditional Chinese medicine monomer ginsenoside Rd (Gs-Rd) for the treatment of ischemic cerebrovascular disease ongoing phase III clinical study. Blood traditional Chinese medicine monomer tetramethylpyrazine puerarin have been numerous studies have confirmed cerebral protective effects, whether ginsenoside Rd with ligustrazine and puerarin combined to play a more powerful role in brain protection is worth further study. This study is divided into two parts, experiment a clear of OFR and exogenous NO release dual-target drugs: study in vivo - acetyl ferulic acid esters (AFI) isosorbide cerebral ischemia-reperfusion injury protective effect, and to explore its mechanism of inhibition of neuronal apoptosis. Experiment II: To explore the Herbal Monomer the ginsenoside Rd puerarin and (or) of tetramethylpyrazine joint application of the cerebral protective effects. Experiment protective effect against focal cerebral ischemia-reperfusion injury in Research Methods 1 AFI AFI AFI's brain protective effect and mechanism research purposes of the protective effects and mechanisms of cerebral ischemia-reperfusion injury 60 SD rats randomly divided into six groups: control (control) group, acetyl ferulic single isosorbide dinitrate (AFI) group, isosorbide mononitrate (ISMN) group, sodium ferulate (SF) group, sodium ferulate acetyl single isosorbide dinitrate (SF ISMN) group, edaravone (edavarone) group. Animals in each group preparation right MCAO model, each dose group were in reperfusion 10min before intraperitoneal injection of the appropriate drug control group was given the corresponding volume of solvent (1ml, 20% acetone). 72h after reperfusion nerve function scores, and the animals were sacrificed, and the brain rows 2,3,5 - triphenyltetrazolium chloride wow (TIC) staining to measure the volume of cerebral infarction. 2 AFI cerebral protective effect of the dose-effect relationship of 40 SD rats were randomly divided into four groups: control group, group AFI 1mg/kg group, AFI 3mg/kg group, AFI 9mg/kg. Animals in each group preparation right MCAO model, are in reperfusion before 10min to give the appropriate dose of AFI (1,3,9 mg / kg) or solvent. 72h after reperfusion nerve function scores, and the animals were sacrificed, and the brain rows 2,3,5 - triphenyltetrazolium chloride wow (TIC) staining to measure the volume of cerebral infarction. 3 AFI caspase-3 activity after cerebral ischemia-reperfusion injury in 24 SD rats were randomly divided into sham group, the control group and the group of AFI, prepared right MCAO model animals in each group (sham group does not bolt line The rest of the operations of the other two groups), both before reperfusion 10min give AFI 3mg/kg or solvent, 24 h after reperfusion animals were sacrificed, were taken penumbra cortex and striatum line determination of caspase-3 activity. 4 AFI neuronal apoptosis 36 SD rats were randomly divided into sham group, the control group, and the AFI group, animals in each group preparation right MCAO model were before reperfusion 10min AFI 3mg/kg or solvent , respectively, after reperfusion 4h and 24h the left ventricle perfusion-fixed, paraffin-embedded sections, TUNEL staining (n = 6) animals, take high magnification in the corresponding parts of the four horizons line TUNEL-positive neurons count, calculated The mean and standard deviation. Results 1 neurological function scores and infarct volume was measured 72 hours after reperfusion, compared to the control group, the AFI group, SF group, SF ISMN group, the edaravone group of nerve function learning were improved (P lt; 0.05), which edaravone group The most obvious improvement (P lt; 0.001), the AFI followed by group (P lt; 0.01), while the ISMN group compared with the control group no statistically significant difference. 72 hours after reperfusion, compared to the control group, the AFI group, SF group, SF ISMN group, edaravone group infarction accommodate percentage were significantly reduced (P lt; 0.05), the minimum edaravone group infarction volume (P lt; 0.001), AFI group, followed by (P lt; 0.01), and the ISMN group compared with the control group no significant difference. 2 dose-response relationship 72 hours after reperfusion, the AFI the 3mg/kg group and AFI 9mg/kg of group can improve neurological function score was (P lt; 0.05), to reduce the infarct volume (P lt; 0.05), AFI 1mg/kg group nerve function scores and infarct volume percentage of the control group, there was no significant statistical difference. 3 AFI caspase-3 activity after cerebral ischemia-reperfusion injury. 24 hours after reperfusion, want more than that in the control group, AFI can significantly reduce the penumbra of the cortex and striatum caspase-3 activity (P lt; 0.01). 4 AFI neuronal apoptosis compared to the control group, 4h, AFI can significantly reduce reperfusion the penumbra cortex and striatum number of TUNEL-positive neurons (P lt; 0.05), 24h after reperfusion. reduce more significantly (P lt; 0.01). Conclusions the AFI can improve neurological function in the rat brain after ischemia-reperfusion injury and reduce infarct volume, further research found that by reducing the activity of caspase-3, play a neuroprotective effect of reducing neuronal apoptosis. Experiment two Gs-Rd its joint medication brain protection effect research purposes to explore ginsenoside Rd ginseng soap glucoside Rd tetramethylpyrazine and (or) puerarin joint application whether to have brain protection effect and compare separate use ginsenoside Rd and joint medication ' whether the protective effect of differences between. 50 male Sprague-Dawley rats were randomly divided into five groups (n = 10). Each dose group separately by setting the time and dose or in combination with intraperitoneal injection of the appropriate drug control group was given the corresponding volume of solvent (20% propylene glycol 1 ml). Each set of rows focal cerebral ischemia after 2 hours to restore perfusion to 72h. In reperfusion nerve function score (NBS) 72h, 72h score taken after brain line TTC (2, 3, 5 - triphenyl tetrazolium) staining calculate the percentage of infarct volume. Results used alone ginsenoside Rd Ginsenoside Rd rats with focal cerebral ischemia-reperfusion injury, neurological score (P lt; 0.05) can significantly improve joint with of tetramethylpyrazine and (or) puerarin reduce cerebral infarction volume (P lt; 0.05), compared to each dose group were not statistically different. Conclusion separate ginsenoside Rd and ginsenoside Rd brain protective effect the of tetramethylpyrazine and (or) puerarin joint use, but the combined treatment group did not show a strong synergistic protective effect of administered alone.

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