二苯乙烯酰胺衍生物类化合物促进大鼠海马神经发生的适合剂量研究
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摘要
本研究拟探究二苯乙烯酰胺衍生物类化合物WS69与WS74促进大鼠成年海马神经发生的最佳浓度范围。以成年大鼠为实验对象,每个化合物设置了三个剂量梯度(5mg/Kg,0.5mg/Kg,0.05mg/Kg),以28天腹腔注射的方式将两种化合物对大鼠分别给药,并在给药后通过免疫荧光实验确定不同剂量的化合物给药对大鼠海马神经发生的影响情况。结果显示,在进行BrdU标记后的第一天,相比对照组,WS69和WS74的三个剂量给药均显著地增加了大鼠海马齿状回区的BrdU阳性细胞数目,但WS74的高剂量组的增加效果反而低于中剂量组与低剂量组。在进行BrdU标记的28d后,相比对照组,WS69和WS74的三个剂量给药均显著地增加了大鼠海马齿状回区的BrdU-NeuN共阳性细胞数目。其中,两种化合物的低剂量和中剂量给药增加程度较大。体外神经干细胞培养试验结果显示,相比对照组,WS69的低剂量药物处理相比中剂量组和高剂量组更显著的增加了神经球的直径,WS74化合物的低中高剂量药物处理都能够显著的增加神经球的直径。综合体内体外实验结果可以得出,低剂量给药可以更好的发挥两种化合物的促进神经发生活性,表明这两种化合物具有较高的药用潜力,本研究或为药物促进神经发生的相关研究提供新思路。
The aim of this study is to discover the optimal concentration range for stilbene amide derivative compounds WS69 and WS74 to exert their activities in promoting rat hippocampal neurogenesis. The test subjects of this study was adult rat.Three dose gradients of this two compounds(5 mg/Kg, 0.5 mg/Kg, 0.05 mg/Kg) were administered to the rats through a 28-day intraperitoneal injection, then the influences of the different doses of compound administration on hippocampal neurogenesis were valued through the immunofluorescence experiments. The results showed that, in the first day after BrdU labeling, all three doses of both WS69 and WS74 can significantly increase the number of BrdU positive cell in rat hippocampal dentate gyrus,however in WS74, the effect of high dose group is lower than the middle dose group and the low dose group. 28 d after BrdU labeling, all three doses of the two compounds significantly increase the number of BrdU-NeuN co-positive cells in dentate gyrus, low dose administration of the two compounds have a better effect than high dose administration. The results of in vitro neural stem cell culture experiments showed that compared to medium and high dose groups, the low dose administration of WS69 more significantly increased the diameter of the newly formed neurosphere. All of the low, medium and high doses of WS74 compounds can significantly increase the diameter of the neurosphere. From the results of in vitro and in vivo experiments we can conclude that for both compounds, low-dose administration had the better neurogenic-promoting activity, indicating that these two compounds have high medicinal potential. This study may provide new ideas for researches related to the drug promoting of neurogenesis.
The aim of this study is to discover the optimal concentration range for stilbene amide derivative compounds WS69 and WS74 to exert their activities in promoting rat hippocampal neurogenesis. The test subjects of this study was adult rat.Three dose gradients of this two compounds(5 mg/Kg, 0.5 mg/Kg, 0.05 mg/Kg) were administered to the rats through a 28-day intraperitoneal injection, then the influences of the different doses of compound administration on hippocampal neurogenesis were valued through the immunofluorescence experiments. The results showed that, in the first day after BrdU labeling, all three doses of both WS69 and WS74 can significantly increase the number of BrdU positive cell in rat hippocampal dentate gyrus,however in WS74, the effect of high dose group is lower than the middle dose group and the low dose group. 28 d after BrdU labeling, all three doses of the two compounds significantly increase the number of BrdU-NeuN co-positive cells in dentate gyrus, low dose administration of the two compounds have a better effect than high dose administration. The results of in vitro neural stem cell culture experiments showed that compared to medium and high dose groups, the low dose administration of WS69 more significantly increased the diameter of the newly formed neurosphere. All of the low, medium and high doses of WS74 compounds can significantly increase the diameter of the neurosphere. From the results of in vitro and in vivo experiments we can conclude that for both compounds, low-dose administration had the better neurogenic-promoting activity, indicating that these two compounds have high medicinal potential. This study may provide new ideas for researches related to the drug promoting of neurogenesis.
引文
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[17]Witte A V,Kerti L,Margulies D S,et al.Effects of Resveratrol on Memory Performance,Hippocampa Functional Connectivity,and Glucose Metabolism in Healthy Older Adults[J].Journal of Neuroscience2014,34(23):7862-7870.
[2]Drew M,Hen R.Adult Hippocampal Neurogenesis as Target for the Treatment of Depression[J].CNS&Neurological Disorders-Drug Targets,2007,6(3):205-218.
[3]Ehninger D,Kempermann G.Neurogenesis in the adult hippocampus[J].Cell&Tissue Research,2008331(1):243-250.
[4]Braun S M G,Jessberger S.Adult neurogenesis:mechanisms and functional significance[J]Development,2014,141(10):1983-1986.
[5]Zhao C,Deng W,Gage F H.Mechanisms and Functional Implications of Adult Neurogenesis[J]Cell,2008,132(4):0-660.
[6]刘加强,童卫.海马神经发生障碍与阿尔兹海默病发病机制[J].神经解剖学杂志,2014,30(2):244-248.
[7]Costa V,Lugert S,Jagasia R.Role of adul hippocampal neurogenesis in cognition in physiology and disease:pharmacological targets and biomarkers[J].Handb Exp Pharmacol,2015,228:99-155.
[8]Liang J H,Yang L,Wu S,et al.Discovery of efficient stimulators for adult hippocampa neurogenesis based on scaffolds in dragon\"s blood[J]European Journal of Medicinal Chemistry,2017,136:382-392.
[9]Sahay A,Scobie K N,Hill A S,et al.Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation[J].Nature,2011472(7344):466-470.
[10]Mao J,Huang S,Liu S,et al.A herbal medicine for Alzheimer\"s disease and its active constituents promote neural progenitor proliferation[J].Aging Cell,2015,14(5):784-796.
[11]郭洪波,邹飞.大鼠海马神经干细胞的分离、培养及鉴定[J].南方医科大学学报,2004,24(10):1143-1146.
[12]白连琴,刘娜,李腾腾.新生鼠和胎鼠海马神经干细胞分离和培养方法的比较[J].神经解剖学杂志,2015(4):481-486.
[13]Monte-Silva K,Kuo M F,Thirugnanasambandam N,et al.Dose-Dependent Inverted U-Shaped Effect of Dopamine(D2-Like)Receptor Activation on Focal and Nonfocal Plasticity in Humans[J].Journal of Neuroscience,2009,29(19):6124-6131.
[14]Kempermann G,Jessberger S,Steiner B,et al Milestones of neuronal development in the adult hippocampus[J].Trends in Neurosciences,200427(8):0-452.
[15]Jensen J B,Parmar M.Strengths and limitations of the neurosphere culture system[J].Molecular Neurobiology,2006,34(3):153-161.
[16]Rogers J F,Nafziger A N,Bertino JSPharmacogenetics affects dosing,efficacy,and toxicity of cytochrome P450-metabolized drugs[J]American Journal of Medicine,2002,113(9):0-750.
[17]Witte A V,Kerti L,Margulies D S,et al.Effects of Resveratrol on Memory Performance,Hippocampa Functional Connectivity,and Glucose Metabolism in Healthy Older Adults[J].Journal of Neuroscience2014,34(23):7862-7870.
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