文章摘要
螺环哌嗪盐化合物DXL-A-24对慢性疼痛-抑郁共病大鼠行为学及抗氧化能力的影响
Effects of spiropiperazine compounds DXL-A-24 on behavior and antioxidant capacity of chronic pain and depression comorbidities rats
  
DOI：10.12089/jca.2025.08.012
中文关键词: 疼痛-抑郁共病  螺环哌嗪铵盐化合物DXL-A-24  行为学  苏木精-伊红染色  蛋白免疫印迹  Nrf2/ARE通路
英文关键词: Pain and depression comorbidity  Spiropiperazine quaternary ammonium compound DXL-A-24  Behavioristics  Hematoxylin-eosin staining  Western blot  The Nrf2/ARE pathway
基金项目:山东省泰山产业领军人才工程（tscy20200332）
作者单位E-mail
刘冬光 276006, 山东省临沂市, 鲁南制药集团股份有限公司新药药理中心  
徐燕 276006, 山东省临沂市, 鲁南制药集团股份有限公司新药药理中心  
赵文学 276006, 山东省临沂市, 鲁南制药集团股份有限公司新药药理中心 zwx940108@163.com 
姚茹 276006, 山东省临沂市, 鲁南制药集团股份有限公司新药药理中心  
孟雪 276006, 山东省临沂市, 鲁南制药集团股份有限公司新药药理中心  
姚景春 276006, 山东省临沂市, 鲁南制药集团股份有限公司新药药理中心  
姚庆强 山东新时代药业有限公司科研部  
刘忠 276006, 山东省临沂市, 鲁南制药集团股份有限公司新药药理中心  
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中文摘要:
      
目的： 观察DXL-A-24对利血平诱导疼痛-抑郁共病大鼠行为学及抗氧化能力的影响。
方法：选择雄性SPF级SD大鼠50只，6～8周龄，体重180～220 g。取10只大鼠作为对照组（C组），其余大鼠通过腹腔注射利血平诱导建立疼痛-抑郁共病模型。成功建模大鼠随机分为四组：模型组（V组）、DXL-A-24低剂量2 mg/kg组（L组）、DXL-A-24中剂量4 mg/kg组（M组）和DXL-A-24高剂量8 mg/kg组（H组），每组10只。建模后，L组、M组和H组每天灌胃给药，连续给药4周；C组和V组每天灌胃等剂量的溶媒。五组灌胃体积均为10 ml/kg。建模第7天、给药第7、14、21、28天检测体重，并在给药结束后采用旷场实验评估进入中央次数、进入中央时间、中央区域运动距离及运动总距离；采用强迫游泳实验评估不动时间及不动次数；采用新颖抑制摄食实验评估首次摄食潜伏期；采用痛阈测定实验评估热缩足阈值；采用ELISA法检测5-羟色胺（5-HT）、N-甲基-D-天冬氨酸（NMDA）、丙二醛（MDA）、过氧化氢酶（CAT）、超氧化物歧化酶（SOD）、单胺氧化酶A（MAO-A）、单胺氧化酶B（MAO-B）含量；采用HE染色评估海马CA1区病理变化；采用Western blot法检测海马CA1区核因子E2相关因子2（Nrf2）、超氧化物歧化酶（SOD1）、血红素加氧酶1（HO-1）及醌氧化还原酶1（NQO1）蛋白相对表达量。
结果：与C组比较，V组造模第7天体重明显减小（P<0.05），进入中央次数明显减少，进入中央时间、中央区域运动距离、运动总距离、热缩足时间明显缩短，不动时间明显延长，不动次数明显增多（P<0.05），海马CA1区BDNF、5-HT、SOD、CAT含量明显降低（P<0.05），NMDA、MDA、MAO-A、MAO-B含量明显升高（P<0.05），海马CA1区神经元细胞排列松散，细胞层次紊乱，神经元细胞数及神经元轴突数明显减少（P<0.05），海马CA1区Nrf2蛋白在细胞核中表达量明显降低，在胞浆中表达量明显升高（P<0.05），且胞浆中SOD1、HO-1及NQO-1蛋白表达量明显降低（P<0.05）。与V组比较，M组和H组给药第14、21、28天体重明显增加（P<0.05），不动次数明显减少，热缩足时间明显延长（P<0.05），海马CA1区BDNF、5-HT、SOD、CAT含量明显升高（P<0.05）、NMDA含量及MDA、MAO-A、MAO-B含量明显降低（P<0.05），海马CA1区神经元细胞数及神经元轴突数明显增多（P<0.05），神经元细胞排列有序，海马CA1区Nrf2蛋白在细胞核中表达量明显升高，海马CA1区SOD1、HO-1及NQO-1蛋白在胞浆中表达量明显升高（P<0.05）。
结论：DXL-A-24对慢性疼痛-抑郁共病大鼠具有一定的治疗作用，其作用机制可能是通过激活Nrf2基因，启动Nrf2/ARE信号通路，激活其下游SOD1、HO-1及NQO-1等抗氧化酶的表达，发挥抗氧化、抗炎功效，从而改善疼痛、抑郁症状。
英文摘要:
      
Objective: To observe the effects of DLX-A-24 on the behavior and antioxidant capacity of rats with pain-depression comorbidity induced by reserpine.
Methods: Fifty male SPF-grade SD rats, aged 6-8 weeks, weighing 180-220 g were selected. Ten rats were taken as the control group (group C), and the remaining rats were induced to establish a pain-depression comorbidity model by intraperitoneal injection of reserpine. The successfully modeled rats were further divided into four groups: model group (group V), low-dose DLX-A-24 group at 2 mg/kg (group L), medium-dose DLX-A-24 group at 4 mg/kg (group M), and high-dose DLX-A-24 group at 8 mg/kg (group H), 10 rats in each group. Groups L, M, and H were administered by gavage every day for 4 consecutive weeks after modeling. Groups C and V were given an equal dose of solvent by gavage every day. The intragastric volume of the five groups of rats was all 10 ml/kg. Body weight was detected on the 7th day of modeling, and on the 7th, 14th, 21st, and 28th days of administration. The open field test was used after the administration to evaluate the changes in the number of times entering the center, the time of entering the center, the movement distance in the central area, and the total movement distance. The forced swimming test was used to evaluate the changes in the number of immobility and the immobility time. The changes in the latency of the first feeding were evaluated through the novel inhibition feeding experiment, and the changes in the heat contraction foot threshold were evaluated through the pain threshold measurement experiment. The contents of brain-derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), N-methyl-D-aspartate (NMDA), malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B) in the hippocampal CA1 region were detected by ELISA. The pathological changes in the hippocampal CA1 region of rats in each group were evaluated by hematoxylin-eosin (HE) staining, and the protein expression changes of nuclear factor E2-related factor 2 (Nrf2), superoxide dismutase (SOD1), heme oxygenase-1(HO-1), and quinone oxidoreductase 1 (NQO1) in the hippocampal CA1 region were detected by Western blot.
Results: Compared with group C, the body weight on the 7th day of modeling in group V was significantly decreased (P < 0.05), the number of times entering the center decreased significantly, the time of entering the center, the movement distance of the central area, the total movement distance, and the heat contraction foot time were significantly shortened, the immobility time was significantly prolonged, and the number of immobility times increased significantly (P < 0.05), the contents of BDNF, 5-HT, SOD, and CAT in the hippocampal CA1 area were significantly decreased (P < 0.05), while the contents of NMDA, MDA, MAO-A, and MAO-B were significantly increased (P < 0.05), the neuronal cells in the hippocampal CA1 area were loosely arranged and the cell hierarchy was disordered, and the number of neuronal cells and the number of neuronal axons decreased significantly (P < 0.05), the nuclear transfer of Nrf2 protein in the hippocampal CA1 region was inhibited, and the expression levels of SOD1, HO-1 and NQO-1 proteins decreased significantly (P < 0.05). Compared with group V, the body weight in groups M and H increased significantly on the 14th, 21st, and 28th days of administration (P < 0.05), the number of immobility sessions decreased significantly, and the time of thermal foot contraction was prolonged significantly (P < 0.05), the contents of BDNF, 5-HT, SOD and CAT in the hippocampal CA1 area significantly increased (P < 0.05), while the contents of NMDA and MDA, MAO-A and MAO-B significantly decreased (P < 0.05), the number of neuronal cells and neuronal axons in the hippocampal CA1 area was significantly restored (P < 0.05), the neuronal cells were arranged in an orderly manner, the nuclear transfer of Nrf2 protein in the hippocampal CA1 area increased(P < 0.05), the expression level of Nrf2 protein in the hippocampal CA1 region was significantly increased in the nucleus, and the expression levels of SOD1, HO-1, and NQO-1 proteins in the cytoplasm of the hippocampal CA1 region were significantly increased (P < 0.05).
Conclusion: DXL-A-24 has therapeutic effect on chronic pain and depression comorbidized rats, the mechanism of which may be to activate Nrf2 gene, activate Nrf2/ARE signaling pathway, and activate the expression of antioxidant enzymes such as SOD1, HO-1 and NQO-1 in its downstream, so as to exert antioxidant and anti-inflammatory effects, thereby improving pain and depression symptoms.
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