Possible involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant activity of berberine chloride
Possible involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant activity of berberine chloride
复制标题
DOI：
10.1016/j.ejphar.2007.05.002
复制
发表时间：
2007-08-13
影响因子：
5
通讯作者：
Dhir, Ashish
中科院分区：
文献类型：
--
作者：
Kulkarni, Shrinivas K.;Dhir, Ashish
小檗碱是从小檗中分离的异喹啉生物碱，小檗是广泛用于印度和中国医学系统的主要草药。小檗碱具有广泛的生物活性，包括抗真菌、抗菌、抗炎等作用，并具有一定的中枢神经系统活性。本研究旨在探讨其抗抑郁活性及其可能的作用机制。此外，L-精氨酸-一氧化氮（NO）-环磷酸鸟苷（cGMP）信号通路参与盐酸小檗碱的抗抑郁作用进行了研究。在强迫游泳和悬尾试验中评估抗抑郁活性。在六分钟的测试期间记录总不动期。小檗碱（5-20 mg/kg，i. p.）在两次测试中都减少了不动期。小檗碱（5 mg/kg，i. p.）与其他抗抑郁药联合给药，可增强亚有效剂量丙咪嗪（2 mg/kg，i. p.）的抗不动作用，地昔帕明（5 mg/kg，i. p.），反苯环丙胺（4 mg/kg，i. p.），氟西汀（5 mg/kg，i. p.），文拉法辛（2 mg/kg，i. p.）或安非他酮（10 mg/kg，i. p.）在强迫游泳试验中。然而，小檗碱并没有改变米安色林（32 mg/kg，腹腔注射）的作用或曲唑酮（2 mg/kg，腹膜内），两种非典型抗抑郁药神经化学分析显示小檗碱（5 mg/kg，i. p.）增加小鼠全脑中去甲肾上腺素、血清素或多巴胺的水平。小檗碱（5 mg/kg，i. p.）腹腔注射L-精氨酸（750 mg/kg）可预防小鼠强迫游泳实验中的急性应激反应。[一氧化氮合酶（NOS）的底物]。用7-硝基吲唑（25 mg/kg，i. p.）[神经元型一氧化氮合酶（nNOS）特异性抑制剂]能增强亚有效剂量小檗碱（2 mg/kg，i. p.）的作用。此外，用亚甲蓝（10 mg/kg，i. p.）[一氧化氮合酶（NOS）和可溶性鸟苷酸环化酶（sGC）的直接抑制剂]加强小檗碱（2 mg/kg，i. p.）在强迫游泳测试中。此外，小檗碱（5 mg/kg，i. p.）西地那非（5 mg/kg，i. p.）[磷酸二酯酶5抑制剂]。各种调节剂及其与小檗碱的组合未产生运动活性的任何变化。我们的研究结果表明，黄连素发挥抗抑郁样作用，在各种行为范式的绝望可能通过调节脑生物胺（去甲肾上腺素，5-羟色胺或多巴胺）和进一步，抗抑郁样作用的黄连素在强迫游泳试验涉及的相互作用与L-精氨酸-NO-cGMP途径。(c)2007 Elsevier B. V.保留所有权利。
Berberine is an isoquinoline alkaloid isolated from Berberis aristata, a major herb widely used in Indian and Chinese systems of medicine. Berberine possessed a wide range of biological activity including antidiarrheal, antimicrobial, anti-inflammatory effects and some central nervous system activity as well. The present study was designed to explore the antidepressant activity and its possible mechanism of action. Further, the involvement Of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of berberine chloride was investigated. The antidepressant activity was assessed in forced-swim and tail-suspension tests. Total immobility period was recorded during a six-min test. Berberine (5-20 mg/kg, i.p.) produced a reduction in immobility period in both the tests. When berberine (5 mg/kg, i.p.) was co-administered with other antidepressant drugs, it enhanced the anti-immobility effect of subeffective doses of imipramine (2 mg/kg, i.p.), desipramine (5 mg/kg, i.p.), tranylcypromine (4 mg/kg, i.p.), fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.) in forced-swim test. However, berberine did not modify the effects of mianserine (32 mg/kg, i.p.) or trazodone (2 mg/kg, i.p.), the two atypical antidepressant drugs. The neurochemical analysis revealed that berberine (5 mg/kg, i.p.) increased the levels of norepinephrine, serotonin or dopamine in the mouse whole brain. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced-swim test was prevented by pretreatment with L-arginine (750 mg/kg, i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg, i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of berberine (2 mg/kg, i.p.). In addition, treatment of mice with methylene blue (10 mg/kg, i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of berberine (2 mg/kg, i.p.) in the forced-swim test. Furthermore, the reduction in the immobility period elicited by berberine (5 mg/kg, i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg, i.p.) [phosphodiesterase 5 inhibitor]. The various modulators and their combination with berberine did not produce any changes in locomotor activity. Our findings demonstrated that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin or dopamine) and further, the antidepressant-like effect of berberine in the forced-swim test involved an interaction with the L-arginine-NO-cGMP pathway. (c) 2007 Elsevier B.V. All rights reserved.