开心解郁丸通过长链非编码RNA调控JAK-STAT通路治疗血管性抑郁的研究

Vascular depression(VD) is an elder disorder affecting the healthy and poorly responsive to antidepressants and the therapeutic strategy is often significantly different from other depressions. We confirmed Kaixin Jieyu preparation is a considerable effective method to VD and relapsed less than Fluoxetine. It improves the mental and physical symptom, the cerebral hypo perfusion and nerve regeneration. We suppose that the mechanism is that long noncoding RNA adjust the JAK-STAT pathway and then affect the nerve regeneration. This research is involved in 120 rats together, which are divided into 4 groups, including normal group, model group, Kaixin Jieyu group, Fluoxetine group. All rats are established a model of VD by ligation of bilateral common carotid arteries and chronic unpredictable mild stress for 5W except for normal group. Kaixin Jieyu group and Fluoxetine group are fed with KAIXINJIEYU Powder and Fluoxetine, respectively. The depression degree is evaluated by sugar propensity tests, open-field tests and forced swimming test and etc. Regional cerebral blood flow is assayed by laser Doppler flowmetry. The hippocampus is detected by the long noncoding RNA array. The protein and mRNA of JAK-1, STAT1, P-JAK-1, P-STAT1, BDNF and proBDNF are determined by Western blot and quantitative real-time PCR. Pathomorphology of hippocampus is observed by HE stain and electron microscope, etc. We discuss the relationships of vascular depression and the long noncoding RNA, JAK-STAT pathway and nerve regeneration. The purpose is certified hypothesis that material basis of pathogenesis in VD are “long noncoding RNA adjust the JAK-STAT pathway and then affect the nerve regeneration”, and Kaixin Jieyu preparation is an effective therapeutic methods to VD. This research would explain the mechanism of VD with long noncoding RNA, JAK-STAT pathway and nerve regeneration, and confirm the objectivity, scientific connotation and advantage of Kaixin Jieyu preparation to VD.

血管性抑郁严重危害健康，并缺少有针对性的抗抑郁药。本课题组认为其病机为元气亏虚，气血郁滞，运用益气开郁中药开心解郁丸治疗血管性抑郁，显著改善精神和躯体症状，推测是通过长链非编码RNA（lncRNA）调控JAK-STAT通路，从而促进海马神经再生而实现的。本研究采用血管性抑郁大鼠模型，通过行为学、脑血流、微阵列芯片、生物信息学、荧光实时定量PCR和蛋白质印迹等技术，探讨抑郁状态与lncRNA、JAK-STAT磷酸化激活及神经再生的相互关系，旨在阐明该病发病机制可能是lncRNA调控JAK-STAT通路的磷酸化进而影响海马神经再生，开心解郁丸是有效治疗途径，从而阐述开心解郁丸治疗该病的科学内涵和优势环节。

血管性抑郁（VD）严重危害健康，并缺少有针对性的药物。该病病机为元气亏虚、气血郁滞，益气开郁中药开心解郁丸能显著改善VD患者精神和躯体症状，推测与lncRNA调控JAK-STAT通路、促进海马神经再生有关。采用VD大鼠模型，通过行为学、脑血流、全转录组基因测序、生物信息学、荧光实时定量PCR和蛋白质印迹等，探讨VD与lncRNA、JAK-STAT磷酸化及神经再生的相互关系。.该研究发现：.1.应用双侧颈总动脉结扎术联合CUMS及孤养制备VD大鼠模型，该模型具有典型的抑郁样行为和脑供血不足，在JAK-STAT通路及其蛋白磷酸化、神经再生、神经元可塑性方面具有异常表现。.2.开心解郁丸能显著改善VD大鼠的抑郁样行为，显著增加前脑和全脑血流量并显著优于盐酸氟西汀，能调节NONRATT001101.2、NONRATT008233.2、NONRATT017087.2等lncRNA，促进JAK-STAT信号通路及JAK1、STAT1磷酸化，促进神经再生相关蛋白BDNF/proBDNF的平衡，调节单胺类递质，促进神经元可塑性。.3.开心解郁丸还可能通过逆行内源性大麻素信号通路、松弛素信号通路、APINE信号通路、胰岛素信号通路、催乳素信号通路、Toll样受体信号通路、RAS信号通路、雌激素信号通路、WNT信号通路、Nod样受体信号通路、MAPK信号通路、钙信号通路等起作用，能改善Acta2、Cysltr1、Efna5、Exoc7、Gabra6、Krt18等11个关键结点mRNA及其对应的lncRNA、cirRNA、miRNA表达差异，是开心解郁丸治疗VD的重要机制之一。.该研究阐述了VD与lncRNA调控JAK-STAT通路进而影响海马神经再生有关，开心解郁丸能有效改善上述过程，在改善脑血流方面显著优于盐酸氟西汀，开心解郁丸治疗该病具有独特的科学内涵和优势环节。