基于组蛋白乙酰化调控神经可塑性探讨针刺治疗抑郁疼痛机制

According to WHO report, chronic pain has become one of the biggest risk factors for mental diseases. Depression and chronic pain are highly comorbid. Growing studies found that the down-regulation of BDNF and the changes of histone acetylation-related enzymes in the brain tissue of depressed patients. Suggesting that the downregulation of BDNF may be related to the regulation of histone acetylation. Clinical studies also showed that after effective treatment, the symptoms of depression, pain has relieved, BDNF significantly increased, and with a negative correlation with the disease. Our previous clinical studies have shown that acupuncture can effectively improve depression, pain and cognitive effects, and its mechanism was related to the up-regulation of BDNF. Animal experiments also found that BDNF decreased, acH3, HDAC2 changes in depression and pain model rats hippocampus. These results suggesting that the anti-depression and analgesic effect of acupuncture may be related to the regulation of BDNF by histone acetylation. Based on this, we proposed a hypothesis that acupuncture may regulate BDNF through histone acetylation, so as to activate BDNF/ Trk-B pathway and its downstream target proteins ERK, PI3K and Akt, ultimate to regulate neuroplasticity and achieve acupuncture effect ". In order to verify this hypothesis, this study intends to explore the effect of histone acetylation on neuronal plasticity in acupuncture anti-depression analgesia from the clinical and animal experimental levels, so as to provide new ideas for the research on the anti-depression analgesia mechanism of acupuncture.

据WHO报告慢性疼痛已经成为诱发心理疾病的三大高危因素之一。抑郁和慢性疼痛具有高度共患性。研究发现抑郁患者大脑组织BDNF下降及组蛋白乙酰化相关酶改变，提示BDNF下降可能与组蛋白乙酰化调节相关。临床研究也显示经过有效治疗后，抑郁、疼痛缓解，BDNF显著上升，且与病情呈负相关。我们前期临床研究显示针刺可有效改善抑郁、疼痛、认知作用，且其作用机制与上调BDNF相关。动物实验也发现抑郁疼痛模型大鼠脑组织BDNF下降，acH3、HDAC2的改变。提示针刺抗抑郁镇痛效应可能与组蛋白乙酰化调节BDNF相关。基于此我们提出假说：针刺可能通过组蛋白乙酰化调节BDNF，从而激活BDNF/Trk-B通路及其下游靶蛋白ERK、PI3K、Akt调节神经可塑性实现针刺效应”。为验证该假说，本课题拟从临床及动物实验水平探讨组蛋白乙酰化调控神经可塑性在针刺抗抑郁镇痛的作用，以期为针刺抗抑郁镇痛机制研究提供新的思路。

临床上慢性疼痛和抑郁具有高度共患病，且两者存在相同的发病机制—BDNF表达异常。前期研究发现慢性疼痛和抑郁均存在BDNF组蛋白乙酰化修饰改变，而针刺可有效上调BDNF水平，针刺镇痛抗抑郁可能与组蛋白乙酰化调节BDNF，从而激活BDNF/Trk-B通路及其下游靶蛋白ERK、AKT调节神经可塑性相关。为验证该假说，本研究从临床招募慢性疼痛抑郁患者，予针刺或药物治疗，采用 HAMD-17、BPI、MoCA、 WHOQOL-BREF 量表评价针刺对抑郁、疼痛、认知、生活质量，并检测外周血BDNF、 CREB 表达情况；动物实验采用SNI构建慢性疼痛抑郁SD大鼠模型，采用PWT、OFT、FST、SPT等评价疼痛、抑郁样行为，采用分子生物学和表观遗传学技术检测组蛋白乙酰化修饰相关蛋白及BDNF/TrkB通路及下游靶蛋白的变化。结果发现：1. 针刺可有效改善慢性疼痛抑郁患者抑郁、疼痛症状，提高生活质量和认知功能；2. 针刺可上调慢性疼痛抑郁患者外周血BDNF mRNA及蛋白表达水平；3. SNI术构建的慢性疼痛抑郁模型大鼠表现痛阈降低，抑郁样行为，而电针或药物干预后可显著改善痛阈和抑郁样行为；4.电针镇痛抗抑郁效应可能通过组蛋白乙酰化修饰BDNF，抑制去乙酰化转移蛋白酶HDAC2、HDAC5，促进乙酰化蛋白AcH3表达，从而促进BDNF/TrkB通路及其下游靶蛋白ERK、AKT实现的，使用HAT inhibitor AA可部分阻断这一效应。该结果印证了本研究的假说，为针刺镇痛抗抑郁机制研究提供了新思路，为针刺治疗慢性疼痛抑郁提供了科学的实验证据。