Molecular mechanisms of vestibular compensation and treatment strategy of vertigo

前庭代偿是一种损伤诱导的神经元可塑性模型，对其神经化学机制的探讨揭示了电压门控钙通道(VGCC)和细胞内钙信号的共同参与。事实上，基因芯片分析显示，在单侧前庭去传入后，同侧前庭核复合体中一些钙信号相关基因，如L型钙通道的α2亚单位、钙调神经磷酸酶和质膜钙ATP酶1(PMCA1)表达上调。为了进一步阐明钙信号相关分子在前庭代偿中的作用，我们使用实时定量聚合酶链式反应(PCR)方法对芯片结果进行了验证，并研究了这些分子在代偿不同阶段(UVD后6h至2周)的表达变化。我们还研究了白氏现象期间基因表达的变化，以及钙调神经磷酸酶抑制剂对前庭代偿的影响。…更多的实时定量聚合酶链式反应显示，α2亚单位、PMCA2和钙调神经磷酸酶基因在UVD后6h在同侧VNC瞬时上调。随后一次导致白氏现象的紫外线照射完全再现了最初紫外线照射时PMCA2和钙调神经磷酸酶基因表达的变化，而VGCC基因的α2亚单位在第二次损伤的同侧癌中有增加的趋势。钙调神经磷酸酶抑制剂FK506可剂量依赖性地抑制前庭代偿。尽管目前尚不确定这些基因表达的变化是否与前庭代偿的分子机制有关，但这一观察表明，通过上调VGCC增加同侧VNC神经元的钙内流后，钙调神经磷酸酶可能参与了它们的突触可塑性。相反，上调PMCA2，一种大脑特有的钙泵，将增加这些神经元的钙外流，并可能防止UVD后的细胞损伤。较少

Inquiries into the neurochemical mechanisms of vestibular compensation, a model of lesion-induced neuronal plasticity, reveal the involvement of both voltage-gated Ca2+ channels (VGCC) and intracellular Ca2+ signaling. Indeed, microarray analysis showed an up-regulation of some calcium signaling-related genes such as the α2 subunit of L-type calcium channels, calcineurin, and plasma membrane Ca2+ ATPase 1 (PMCA1) in the ipsilateral vestibular nuclear complex (VNC) following unilateral vestibular deafferentation (UVD). To further elucidate the role of calcium signaling-related molecules in vestibular compensation, we used a quantitative real-time polymerase chain reaction (PCR) method to confirm the microarray results and investigated changes in expression of these molecules at various stages of compensation (6 h to 2 weeks after UVD). We also investigated the changes in gene expression during Bechterew's phenomenon and the effects of a calcineurin inhibitor on vestibular compensation. … More Real-time PCR showed that genes for the α2 subunit of VGCC, PMCA2,and calcineurin were transiently up-regulated 6 h after UVD in ipsilateral VNC. A subsequent UVD, which induced Bechterew's phenomenon, reproduced a complete mirror image of the changes in gene expressions of PMCA2 and calcineurin seen in the initial UVD, while the α2 subunit of VGCC gene had a trend to increase in VNC ipsilateral to the second lesion. Pre-treatment by FK506,a calcineurin inhibitor, decelerated the vestibular compensation in a dose-dependent manner. Although it is still uncertain whether these changes in gene expression are causally related to the molecular mechanisms of vestibular compensation, this observation suggests that after increasing the Ca2+ influx into the ipsilateral VNC neurons via up-regulated VGCC, calcineurin may be involved in their synaptic plasticity. Conversely, an up-regulation of PMCA2,a brain-specific Ca2+ pump, would increase an efflux of Ca2+ from those neurons and perhaps prevent cell damage following UVD. Less