罗布麻叶提取物对慢性应激抑郁模型大鼠海马神经发生的作用及机制研究

The drug treatment of depression is mainly based on the hypothesis of the insufficient function of monoamine neurotransmitters, but the monoamine neurotransmitter theory cannot fully explain the delayed onset and unsatisfactory efficacy of antidepressant drugs. Hippocampal neurogenesis is a recently proposed mechanism that may be closely related to the onset of depression and the treatment of anti-depression.In our previous study, we found that the extract of Apocynum venetum leaf extract can promote the proliferation of neural precursor cells in the hippocampus of rats with chronic stress and improve depression-like behavior.It has been reported that the combination of exogenous FGF2 up-regulated the expression of downstream signaling molecule ERK, improved the inhibition of hippocampal neurogenesis by inflammatory immunity, and reversed the depression-like behavior caused by central inflammatory immunity.The mechanism of the regulation of hippocampal neurogenesis by Apocynum venetum leaf extract is still unclear.We hypothesized that The FGF2-mediated ERK signaling pathway may be involved in the hippocampal neurogenesis induced by Apocynum venetum leaf extract.CUMS model was used to study the effect and mechanism of Apocynum venetum leaf extract on hippocampal neurogenesis.This subject will reveal the new mechanism of the anti-depression effect of Apocynum venetum leaf extract and provide scientific basis for the application of Apocynum venetum leaf extract in depression.

抑郁症的药物治疗主要基于单胺神经递质功能不足假说，但单胺递质学说不能完全解释抗抑郁药物起效延迟及疗效不理想的特点，海马神经发生是近来提出的可能与抑郁症发病及抗抑郁治疗密切相关的一个机制。我们前期研究发现，罗布麻叶提取物能促进慢性应激抑郁大鼠海马神经发生，上调海马区ERK磷酸化水平，改善抑郁样行为。有报道外源性FGF2与FGFR结合后上调下游信号分子ERK的表达，改善了炎性免疫对海马神经发生的抑制，逆转了炎性免疫所引起的抑郁样行为。罗布麻叶提取物调控海马神经发生的作用机制尚不清楚。由此我们提出假设：FGF2介导的ERK信号通路可能参与了罗布麻叶提取物诱导的抑郁大鼠海马神经发生上调。本课题制备CUMS抑郁大鼠模型，研究罗布麻叶提取物对海马神经发生的作用及机制，研究结果将揭示罗布麻叶提取物抗抑郁疗效的新机制，为罗布麻在抑郁症中的应用提供科学依据。

抑郁症的药物治疗主要基于单胺神经递质功能不足假说，但单胺递质学说不能完全解释抗抑郁药物起效延迟及疗效不理想的特点，海马神经发生是近来提出的可能与抑郁症发病及抗抑郁治疗密切相关的一个机制。本项目旨在制备 CUMS 抑郁症大鼠模型，全面评价罗布麻叶提取物对 CUMS 诱导的抑郁样行为的拮抗作用，研究罗布麻叶提取物对 CUMS 抑郁模型大鼠成年海马神经发生的影响，并探讨 FGF2 介导的 ERK 信号通路活化在罗布麻叶提取物改善抑郁样行为和调控海马神经发生中的作用环节及内在机制。本研究发现，海马齿状回神经前体细胞增殖和分化：与对照组相比，CUMS模型组大鼠海马齿状回BrdU阳性细胞数和DCX/BrdU双标记阳性细胞数均明显减少，差异有统计学意义(P<0.01或0.001)；与CUMS模型组相比，罗布麻叶提取物治疗组大鼠海马齿状回BrdU阳性细胞数和DCX/BrdU双标记阳性细胞数均明显增多，差异有统计学意义(P<0.05 or P<0.001)。海马齿状回新生成熟神经元的存活：与对照组相比，CUMS模型组大鼠海马齿状回BrdU阳性细胞数进一步减少(P<0.01)；与CUMS模型组组相比，罗布麻叶提取物治疗组大鼠海马齿状回BrdU阳性细胞数明显增多，接近正常对照组(P<0.05)；NeuN+/BrdU+、GFAP+/BrdU+共存的比例在各组间均无显著性差异(P>0.05)。与对照组相比，CUMS模型组大鼠海马p-ERK、p-P90RSK、p-p70S6K、p-S6、p-CREB及BDNF蛋白水平均明显降低，差异有统计学意义(P<0.05 或0.01)。经过罗布麻叶提取物治疗后，上述蛋白的表达水平明显上调，差异具有显著性(P<0.05或0.01)。研究证实，抑郁模型大鼠海马齿状回新生神经前体细胞增殖和存活受到抑制，而AVLE治疗可逆转由慢性应激造成的海马神经发生的减少。抑郁模型大鼠海马ERK/CREB/BDNF功能下调，而AVLE可通过调控ERK/CREB/BDNF信号系统，上调海马内BDNF蛋白的表达水平，继而促进海马神经发生，从而缓解大鼠抑郁症状。