百事乐加味方对脑卒中后抑郁模型大鼠海马-前额叶皮层神经细胞凋亡蛋白的影响
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摘要
目的观察百事乐加味方对脑卒中后抑郁(PSD)大鼠神经功能、形态学及海马(HP)、前额叶皮层(PFC)组织Bax、Bcl-2、Caspase-3蛋白表达的影响,从神经细胞凋亡方面探讨百事乐加味方防治PSD作用机制。方法采用MCAO+CUMS+孤养法复合因素建立PSD模型。分组前进行行为学评分,随机分为假手术组、抑郁组、卒中组、PSD组、阳性药组和百事乐加味方高、低剂量组,各给药组给予相应药物,连续28 d。采用HE和Nissl染色观察HP、PFC组织形态学;采用免疫组化检测大鼠HP、PFC组织Bax、Bcl-2、Caspase-3蛋白表达。结果对神经功能缺损评分的影响:与PSD组大鼠比较,百事乐加味方高、低剂量组第21、28日神经功能缺损评分显著改善(P<0.05,P<0.01);对HP、PFC组织形态学的影响:与PSD组比较,百事乐加味方高、低剂量组大鼠病变明显改善。对凋亡蛋白的影响:百事乐加味方高剂量组大鼠HP、PFC组织Bax、Caspase-3蛋白表达显著降低,Bcl-2蛋白表达显著升高,Bcl-2/Bax比值显著增大(P<0.01);百事乐加味方低剂量组大鼠HP、PFC组织Bcl-2蛋白表达显著升高,Caspase-3蛋白表达显著降低,HP组织Bax蛋白表达显著降低,Bcl-2/Bax比值显著增大(P<0.05,P<0.01)。结论百事乐加味方通过调控凋亡蛋白表达,抑制细胞凋亡,减少神经病变,改善神经功能,从而发挥治疗作用,是其抗PSD主要作用机制之一。
Objective To study the effects of modified Baishile Decoction on the neurological deficit score and the expression levels of Bax, Bcl-2 and Caspase-3 in hippocampal prefrontal cortical circuit in post-stroke depression(PSD) rats; To explore the preventive and therapeutic mechanism of modified Baishile Decoction for PSD from neuronal apoptosis. Methods The PSD rat model was established by the method of middle cerebral artery occlusion), combining with chronic unpredictable mild stress and solitary nourishment. The behavioral scores were evaluated before division. The rats were randomly divided into sham-operation group, depression group, stroke group, PSD group, positive medicine group and modified Baishile high-, medium-and low-dosage groups. Each administration group was given relevant medicine for 28 d. The morphological changes of hippocampus and prefrontal cortex were observed by HE staining and Nissl staining. Immunohistochemical method was used to detect the expressions of Bax, Bcl-2 and Caspase-3 in hippocampus and prefrontal cortex of PSD rats. Results Effects on neurological impairment score: compared with PSD group, the scores of neurological impairment on the 21 th and 28 th day in modified Baishile high-and low-dosage groups significantly improve(P<0.05,P<0.01). Effects on morphological changes of neurons in hippocampus and prefrontal cortex: compared with PSD group, lesion was obviously improved in modified Baishile high-and low-dosage groups. Effects on apoptosis protein of Bax, Bcl-2 and Caspase-3 in hippocampus and prefrontal cortex: the expressions of Bax and Caspase-3 protein in hippocampus and prefrontal cortex of modified Baishile high-dosage group significantly decreased, the expression of Bcl-2 protein significantly increased, and Bcl-2/Bax significantly increased(P<0.01). In modified Baishile low-dosage group, the expression of Bcl-2 significantly increased, Caspase-3 protein significantly decreased in hippocampus and prefrontal cortex, the expression of Bax protein significantly decreased in hippocampus, and Bcl-2/Bax significantly increased(P<0.01, P<0.05). Conclusion Modified Baishile Decoction can exert therapeutic effects by regulating the expression of apoptotic proteins, inhibiting apoptosis, reducing neuropathy, and improving neurological function, which is its one of the main mechanisms of anti-PSD effect.
Objective To study the effects of modified Baishile Decoction on the neurological deficit score and the expression levels of Bax, Bcl-2 and Caspase-3 in hippocampal prefrontal cortical circuit in post-stroke depression(PSD) rats; To explore the preventive and therapeutic mechanism of modified Baishile Decoction for PSD from neuronal apoptosis. Methods The PSD rat model was established by the method of middle cerebral artery occlusion), combining with chronic unpredictable mild stress and solitary nourishment. The behavioral scores were evaluated before division. The rats were randomly divided into sham-operation group, depression group, stroke group, PSD group, positive medicine group and modified Baishile high-, medium-and low-dosage groups. Each administration group was given relevant medicine for 28 d. The morphological changes of hippocampus and prefrontal cortex were observed by HE staining and Nissl staining. Immunohistochemical method was used to detect the expressions of Bax, Bcl-2 and Caspase-3 in hippocampus and prefrontal cortex of PSD rats. Results Effects on neurological impairment score: compared with PSD group, the scores of neurological impairment on the 21 th and 28 th day in modified Baishile high-and low-dosage groups significantly improve(P<0.05,P<0.01). Effects on morphological changes of neurons in hippocampus and prefrontal cortex: compared with PSD group, lesion was obviously improved in modified Baishile high-and low-dosage groups. Effects on apoptosis protein of Bax, Bcl-2 and Caspase-3 in hippocampus and prefrontal cortex: the expressions of Bax and Caspase-3 protein in hippocampus and prefrontal cortex of modified Baishile high-dosage group significantly decreased, the expression of Bcl-2 protein significantly increased, and Bcl-2/Bax significantly increased(P<0.01). In modified Baishile low-dosage group, the expression of Bcl-2 significantly increased, Caspase-3 protein significantly decreased in hippocampus and prefrontal cortex, the expression of Bax protein significantly decreased in hippocampus, and Bcl-2/Bax significantly increased(P<0.01, P<0.05). Conclusion Modified Baishile Decoction can exert therapeutic effects by regulating the expression of apoptotic proteins, inhibiting apoptosis, reducing neuropathy, and improving neurological function, which is its one of the main mechanisms of anti-PSD effect.
引文
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[13]BONNEAU B,PRUDENT J,Popqeorgiev N,et al.Non-aptotic roles of Bcl-2 family:the calcium connection[J].Biochim Biophys Acta,2013,1833(7):1755-1765.
[14]孙贤辉,梁华兵,周爽,等.姜黄素减轻过氧化氢诱导皮层神经细胞凋亡的JAK信号通路机制研究[J].临床和实验医学杂志,2018,17(14):1489-1493.
[15]董海影,张静艳,柏青杨,等.柴胡皂苷A对抑郁模型大鼠海马神经细胞凋亡的保护作用[J].中国老年学杂志,2015,35(7):1935-1937.
[16]孙斯琪,李琳,储利胜,等.川芎嗪预处理骨髓间充质干细胞移植对脑缺血大鼠神经细胞凋亡的影响[J].中华中医药杂志,2017,32(3):1259-1262.
[2]刘林,刘羽,廖亮英,等.百事乐加味方抗抑郁作用的实验研究[J].中华中医药学刊,2016,34(2):317-319.
[3]SUN R,SONG Y,LI S,et al.Levo-tetrahydropalmatine attenuates neuron apoptosis induced by cerebral ischemia-reperfusion injury:Involvement of c-Abl activation[J].J Mol Neurosci,2018,65(3):391-399.
[4]程瑞凤,华冰,景晶,等.甘草总黄酮抗大鼠应激抑郁行为作用及对海马脑区神经细胞凋亡调控相关蛋白表达的影响[J].中药药理与临床,2014,30(2):69-72.
[5]戢运建,况娥.脑卒中后抑郁患者血清TSH含量与神经递质、神经营养状态及神经细胞凋亡的关系[J].海南医学院学报,2017,23(9):1276-1283.
[6]樊蔚虹,姚建平,赵文景.柴胡疏肝散对卒中后抑郁大鼠海马组织Bcl-2,Bax蛋白表达的影响[J].中国实验方剂学杂志,2011,17(3):181-183.
[7]HUANG X,MAO Y S,LI C,et al.Venlafaxine inhibits apoptosis of hippocampal neurons by up-regulating brain-derived neurotrophic factor in a rat depression model[J].Pharmazie,2014,69(12):909-916.
[8]邓海峰,孙缦利,陈浩,等.毛蕊花糖苷对抑郁症大鼠行为学和前额叶皮层内质网应激的影响[J].中国病理生理杂志,2018,34(1):101-106.
[9]刘林,杨蕙,刘羽,等.百事乐加味方对卒中后抑郁大鼠海马-前额叶皮层环路形态及BDNF影响的实验研究[J].中华中医药杂志,2016,31(4):1398-1401.
[10]CZEH B,VARDYA I,VARGA Z.Long-term stress disrupts the structural and functional integrity of GABAergic neuronal networks in the medial prefrontal cortex of rats[J].Front Cell Neurosci,2018,12:148.
[11]LICZNERSKI P,DUMAN R S.Remodeling of axo-spinous synapses in the pathoph ysiology and treatment of depression[J].Neuroscience,2013,251:33-50.
[12]PAN J,LIU H,ZHOU J,et al.Ipsilateral hippocmpal proteomics reveals mitochondrial antioxidative stress impairment incortical-lesioned chronicmild stressed rats[J].Curr Mol Med,2014,14(9):1186-1196.
[13]BONNEAU B,PRUDENT J,Popqeorgiev N,et al.Non-aptotic roles of Bcl-2 family:the calcium connection[J].Biochim Biophys Acta,2013,1833(7):1755-1765.
[14]孙贤辉,梁华兵,周爽,等.姜黄素减轻过氧化氢诱导皮层神经细胞凋亡的JAK信号通路机制研究[J].临床和实验医学杂志,2018,17(14):1489-1493.
[15]董海影,张静艳,柏青杨,等.柴胡皂苷A对抑郁模型大鼠海马神经细胞凋亡的保护作用[J].中国老年学杂志,2015,35(7):1935-1937.
[16]孙斯琪,李琳,储利胜,等.川芎嗪预处理骨髓间充质干细胞移植对脑缺血大鼠神经细胞凋亡的影响[J].中华中医药杂志,2017,32(3):1259-1262.