CAJ | 학술논문

目的：研究5-羟色胺1A受体(5-HT1A)部分激动和5-羟色胺(5-HT)重摄取抑制双靶标抗抑郁候选新药YL-0919的抗抑郁作用及对树突复杂性的影响。方法每天从10种刺激中随机选1~2种连续4周建立大鼠慢性应激抑郁模型,每天应激前1 h 分别ig 给予氟西汀10 mg·kg－1, YL-09190.625,1.25和2.5 mg·kg－1。应激结束后第2天行开场实验观察水平运动和垂直运动,第4天行蔗糖饮水实验检测蔗糖偏嗜度,第5天行新奇抑制摄食实验检测摄食潜伏期；第6天取脑,高尔基染色法观察海马齿状回锥体神经元树突长度、分支数以及树突棘密度。结果慢性应激模型组大鼠水平运动和垂直运动显著降低,蔗糖偏嗜度显著降低,新奇抑制摄食潜伏期时间显著延长( P<0.01)。给予YL-09192.5 mg·kg－1或氟西汀10 mg·kg－1可显著逆转上述抑郁样行为改变；高尔基染色结果显示,与应激模型组比较,YL-09191.25和2.5 mg·kg－1或氟西汀10 mg·kg－1组海马齿状回锥体细胞树突长度分别显著增加24.3％,64.7％和76.0％( P<0.01),分支数分别显著增加38.0％,118.2％和109.1％( P<0.01),YL-09192.5 mg·kg－1或氟西汀10 mg·kg－1组树突棘密度分别显著增加20.5％和21.4％( P<0.05)。给予 YL-0919可显著增强树突复杂性。结论YL-0919的抗抑郁作用与保护海马齿状回锥体神经元树突结构可塑性,增强树突复杂性有关。
목적：연구5-간색알1A수체(5-HT1A)부분격동화5-간색알(5-HT)중섭취억제쌍파표항억욱후선신약YL-0919적항억욱작용급대수돌복잡성적영향。방법매천종10충자격중수궤선1~2충련속4주건립대서만성응격억욱모형,매천응격전1 h 분별ig 급여불서정10 mg·kg－1, YL-09190.625,1.25화2.5 mg·kg－1。응격결속후제2천행개장실험관찰수평운동화수직운동,제4천행자당음수실험검측자당편기도,제5천행신기억제섭식실험검측섭식잠복기；제6천취뇌,고이기염색법관찰해마치상회추체신경원수돌장도、분지수이급수돌극밀도。결과만성응격모형조대서수평운동화수직운동현저강저,자당편기도현저강저,신기억제섭식잠복기시간현저연장( P<0.01)。급여YL-09192.5 mg·kg－1혹불서정10 mg·kg－1가현저역전상술억욱양행위개변；고이기염색결과현시,여응격모형조비교,YL-09191.25화2.5 mg·kg－1혹불서정10 mg·kg－1조해마치상회추체세포수돌장도분별현저증가24.3％,64.7％화76.0％( P<0.01),분지수분별현저증가38.0％,118.2％화109.1％( P<0.01),YL-09192.5 mg·kg－1혹불서정10 mg·kg－1조수돌극밀도분별현저증가20.5％화21.4％( P<0.05)。급여 YL-0919가현저증강수돌복잡성。결론YL-0919적항억욱작용여보호해마치상회추체신경원수돌결구가소성,증강수돌복잡성유관。
OBJECTlVE To investigate the effect on anti-depression and dendritic complexity of YL-0919, a novel dual-acting antidepressant with 5-HT1A receptor agonist and serotonin reuptake inhibitor properties. METHODS To apply the chronic unpredicted stress (CUS) model in rats, the animals were subjected to 1-2 stressors randomly chosen from 10 different stressors except for control non-stressed group. The vehicle or YL-0919(0.625, 1.25 or 2.5 mg·kg-1) or fluoxetine(10 mg·kg-1) was adminis-tered orally 1 h before the stress procedure. After 4-week stress, the open field test ( OFT ) , sucrose preference test, and novelty-suppressed feeding ( NSF) test were performed to evaluate the changes in behavior. Golgi staining was applied to evaluate the changes in dendritic length, branching points and spine density of the hippocampus pyramidal neurons. RESULTS The locomotor activity and sucrose preference of chronically stressed rats were significantly decreased, but the latency to NSF was increased, while administration of fluoxetine(10 mg·kg-1, ig) and YL-0919(2.5 or 1.25 mg·kg-1, ig) reversed those effects. Golgi staining showed that YL-0919 increased dendritic complexity. After adminis-tration of YL-0919 (2.5 or 1.25 mg·kg-1, ig) and fluoxetine(10 mg·kg-1, ig), the total dendritic length was increased by 24. 3%, 64. 7% and 76. 0%( P<0. 01 ) , respectively, while the number of dendritic branching points was increased by 38.0%, 118.2%and 109.1%( P<0.01) , respectively. After administra-tion of YL-0919( 2.5 mg·kg-1 , ig) and fluoxetine( 10 mg·kg-1 , ig) , dendritic spine density was increased by 20.5% and 21.4%(P<0.05). Chronic treatment with YL-0919 increased dendritic complexity signifi-cantly. CONCLUSlON These results indicate that YL-0919 produces reliable antidepressive effect on the chronically stressed rat models. The dendritic complexity of hippocampus pyramidal neurons contrib-utes to the pathophysiology of depression, and the antidepression-like effect of YL-0919 may be related to the protection of neurons.