淫羊藿苷对精神分裂症模型大鼠认知及海马组织NRG1/ErbB信号通路的影响

Effects of icariin on NRG1-ErbB signaling pathways in hippocampus of schizophrenia rats

背景:淫羊藿苷是补肾助阳中药淫羊藿的有效活性成分之一,除了可促进生殖系统功能外,还能明显改善精神分裂症,但其具体作用机制仍处于研究与探索阶段。目的:探究淫羊藿苷对精神分裂症大鼠认知功能的影响及机制。方法:采用随机数字表法将48只SD大鼠分4组,每组12只:正常组不造模;模型组、淫羊藿苷低、高剂量组通过腹腔注射N-甲基-D-天冬氨酸受体拮抗剂MK-801(1次/d)诱导精神分裂症模型,连续注射14 d。确认造模成功后,淫羊藿苷低、高剂量组分别灌胃给予25,50 mg/(kg·d)的淫羊藿苷,对照组、模型组灌胃生理盐水,连续给药28 d。给药结束后,进行行为学检测及海马组织尼氏染色和FJB染色、氧化应激水平、炎症因子水平、NRG1/ErbB4信号通路蛋白表达。结果与结论:(1)与模型组比较,给药两组刻板行为评分、自发活动总路程和逃避潜伏期明显减少(P<0.05),穿台次数明显增加(P<0.05);淫羊藿苷高剂量组刻板行为评分、逃避潜伏期(第3-5天)明显低于淫羊藿苷低剂量组(P<0.05);(2)与模型组比较,给药两组海马组织线粒体膜电位、超氧化物歧化酶活性升高(P<0.05),丙二醛、白细胞介素6、白细胞介素1β及肿瘤坏死因子α水平减少(P<0.05);与淫羊藿苷低剂量组比较,淫羊藿苷高剂量组超氧化物歧化酶活性升高(P<0.05),丙二醛、白细胞介素6、白细胞介素1β及肿瘤坏死因子α水平减少(P<0.05);(3)与模型组比较,淫羊藿苷低、高剂量组NRG1和ErbB4蛋白表达降低(P<0.05);与淫羊藿苷低剂量组比较,淫羊藿苷高剂量组ErbB4蛋白表达降低(P<0.05);(4)海马组织尼氏染色和FJB染色显示,模型组海马组织中尼氏小体数量明显减少,CA1区和CA3区FJB阳性细胞明显增多;与模型组比较,淫羊藿苷低、高剂量组海马组织中尼氏小体数量明显增加,CA1区和CA3区FJB阳性细胞明显减少;(5)结果表明,淫羊藿苷可改善精神分裂症大鼠的认知功能,其机制可能与调节NRG1/ErbB4信号通路蛋白、减轻氧化应激和炎症反应损伤有关。

BACKGROUND:Icariin is one of the effective active components of Epimedium,which is important for reinforcing kidney and strengthening yang.It can not only promote the function of the reproductive system,but also significantly improve schizophrenia.However,its specific mechanisms of action are still in study and exploration phase.OBJECTIVE:To explore the effects and mechanisms of icariin on cognitive function of schizophrenia rats.METHODS:A total of 48 Sprague-Dawley rats were randomly divided into control group,model group,low-dose and high-dose icariin groups with 12 rats in each group.Except for the control group,schizophrenia models were established in the other groups by intraperitoneal injection of N-methyl-D-aspartate receptor antagonist,MK-801,once a day for continuous 14 days.After modelging,the rats in the low-and high-dose icariin groups were intragastrically given icariin,25 and 50 mg/kg per day for 28 days,respectively,while those in the control and model groups were given the same amount of normal saline.After administration,behavioral detection,Nissl staining and FJB staining of the hippocampus were performed.Oxidative stress level,inflammatory factor level,and NRG1/ErbB4 signaling pathway protein expression were detected.RESULTS AND CONCLUSION:Compared with the model group,stereotyped behavior score,total distance of spontaneous activities and escape latency were significantly decreased,while times of crossing the platform were significantly increased in the two administration groups(P<0.05).The stereotyped behavior score and escape latency(days 3-5)in the high-dose icariin group were significantly lower than those in the low-dose icariin group(P<0.05).Compared with the model group,mitochondrial membrane potential and superoxide dismutase activity in the hippocampus were significantly increased,while the levels of malondialdehyde,interleukin-6,interleukin-1β,and tumor necrosis factor-αwere significantly decreased in the two administration groups(P<0.05).Compared with the low-dose icariin group,superoxide dismutase activity was significantly increased and the levels of malondialdehyde,interleukin-6,interleukin-1β,and tumor necrosis factor-αwere significantly decreased in the high-dose icariin group(P<0.05).Compared with the model group,expressions of NRG1 and ErbB4 proteins in the hippocampus were significantly decreased in the two administration groups(P<0.05).Compared with the low-dose icariin group,the expression of ErbB4 protein was significantly decreased in the high-dose icariin group(P<0.05).Nissl staining and FJB staining of the hippocampus showed that the number of Nissl bodies in the hippocampus was significantly reduced in the model group,while the number of FJB-positive cells in the CA1 and CA3 regions was significantly increased;compared with the model group,the number of Nissl bodies in the hippocampal was significantly increased in the low-dose and high-dose icariin groups,while the number of FJB positive cells in CA1 and CA3 regions was significantly decreased.To conclude,icariin can improve cognitive function in rats with schizophrenia.And its mechanisms may be related to regulating expressions of NRG1/ErbB4 signaling pathway proteins and reducing oxidative stress and inflammatory responses.