基于FGFR1相关信号及CDK5/p35复合体探讨熟地黄对注意缺陷多动障碍模型大鼠小脑神经发育的影响

Exploring the Effects of Rehmanniae Radix Praeparata on Cerebellar Neurodevelopment in Rats with Attention Deficit Hyperactivity Disorder Based on FGFR1-Related Signaling and the CDK5/p35 Complex

    摘要
  • 摘要:
    目的 探讨熟地黄改善注意缺陷多动障碍（Attention deficit hyperactivity disorder，ADHD）模型大鼠多动、冲动及注意缺陷的作用，并基于FGF2、FGF21、FGFR1及CDK5/p35复合体探讨其潜在分子机制。
    方法 设WKY大鼠为正常对照组，将SHR大鼠随机分为模型组、盐酸哌醋甲酯（Methylphenidate hydrochloride，MPH）组和熟地黄组。采用旷场试验、高架十字迷宫测试及Y迷宫测试评估SHR大鼠多动、冲动、注意力等行为学改变；采用HE染色、尼氏染色及NeuN免疫荧光技术评估小脑结构损伤及神经元病理变化；采用免疫印迹法（Western blot）检测小脑组织中FGF2、FGF21、FGFR1、CDK5、p35表达水平。
    结果 与SHR组比较，行为学结果显示，熟地黄显著降低SHR大鼠旷场试验中的总运动距离（P<0.01）、平均运动速度（P<0.01）和中心区进入次数（P<0.01），显著减少高架十字迷宫测试中进入开臂次数（P<0.01）、进入开臂时间占比（P<0.01）及探头次数（P<0.01），并显著提高Y迷宫测试中自发交替率（P<0.01）。组织形态学研究表明，熟地黄可显著增加小脑NeuN及尼氏阳性神经元数量（P<0.01），并改善HE染色下小脑组织病理损伤（P<0.01）。Western blot结果显示，熟地黄显著上调SHR大鼠小脑组织中FGF2（P<0.01）、FGF21（P<0.05）、FGFR1（P<0.01）蛋白表达水平；显著提高下游p35（P<0.01）、CDK5（P<0.01）蛋白表达水平。
    结论 熟地黄可通过调控FGF2、FGF21、FGFR1蛋白及CDK5/p35复合体表达，促进小脑神经元发育和结构的完整性，缓解SHR大鼠多动、冲动和注意缺陷等症状。

     

    Abstract:
    OBJECTIVE To investigate the effects of Rehmanniae Radix Praeparata (RRP) on hyperactivity, impulsivity, and attention deficits in spontaneously hypertensive rats (SHRs), an animal model of attention deficit hyperactivity disorder (ADHD), and to explore the potential molecular mechanisms involving fibroblast growth factor 2 (FGF2), fibroblast growth factor 21 (FGF21), fibroblast growth factor receptor 1 (FGFR1), and the cyclin-dependent kinase 5 (CDK5)/p35 complex.
    METHODS Wistar–Kyoto (WKY) rats served as normal controls, while SHRs were randomly assigned to the model, methylphenidate hydrochloride (MPH), and RRP groups. The open-field, elevated plus-maze, and Y-maze tests were performed to evaluate behavioral alterations related to hyperactivity, impulsivity, and attention in SHRs. Hematoxylin and eosin staining, Nissl staining, and NeuN immunofluorescence were used to assess cerebellar structural damage and neuronal pathological alterations. Western blot was performed to determine the cerebellar protein levels of FGF2, FGF21, FGFR1, CDK5, and p35.
    RESULTS Compared with the SHR model group, RRP treatment produced the following effects. Behavioral testing showed that RRP significantly reduced the total distance traveled (P<0.01), mean velocity (P<0.01), and number of center-zone entries (P<0.01) in the open-field test. It also significantly reduced the number of open-arm entries(P<0.01), percentage of time spent in the open arms(P<0.01), and number of head dips (P<0.01) in the elevated plus-maze test, while significantly increasing the spontaneous alternation rate in the Y-maze test (P<0.01). Histomorphological analyses showed that RRP significantly increased the numbers of NeuN-positive and Nissl-positive neurons in the cerebellum (P<0.01) and alleviated cerebellar histopathological damage revealed by HE staining (P<0.01). Western blot showed that RRP significantly increased the cerebellar protein levels of FGF2 (P<0.01), FGF21 (P<0.05), and FGFR1 (P<0.01), as well as those of the downstream proteins p35 (P<0.01) and CDK5 (P<0.01).
    CONCLUSION RRP may promote cerebellar neuronal development and preserve structural integrity by regulating FGF2, FGF21, and FGFR1 expression and the CDK5/p35 complex, thereby alleviating behavioral abnormalities associated with hyperactivity, impulsivity, and attention deficits in SHRs.

     

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