Marsala Martin, Kakinohana Osamu, Yaksh Tony L, Tomori Zoltan, Marsala Silvia, Cizkova Dasa
Department of Anaesthesiology -- 0818, University of California, San Diego, CA 92093, USA.
Eur J Neurosci. 2004 Nov;20(9):2401-14. doi: 10.1111/j.1460-9568.2004.03702.x.
Transient spinal ischemia, a complication associated with aortic cross-clamp may lead to spastic paraplegia. Once fully developed this deficit is permanent. Quantitative histopathological assessments and pharmacological studies show that the ischemic spasticity is secondary to the loss of lumbar GABA and glycinergic inhibitory interneurons. In the present study, we investigated whether human hNT neurons or committed Sprague-Dawley rat spinal neuronal precursors (SNPs) when grafted into previously ischemic spinal segments depleted of inhibitory neurons would restore local inhibitory tone and ameliorate spasticity. Rats with functionally and electrophysiologically defined spasticity that received spinal graft of hNT neurons or neuronal precursors and immunosuppressive treatment displayed a progressive recovery of motor function that correlated with the improvement of otherwise exacerbated peripheral motor response evoked by stimulation of motor cortex. In contrast, in control, medium-injected or oligodendrocyte-grafted animals no significant therapeutic effect was seen. Stereological quantification of grafted neurons revealed 1-2% survival at three months after transplantation. These surviving neurons displayed a robust axo-dendritic sprouting and expression of markers typical of mature neurons including NSE, NeuN and synaptophysin. In both treatment groups a subpopulation of grafted neurons developed GABA immunoreactivity. These data provide evidence that a region specific grafting of hNT neurons or other neuronally committed cells, which have a potential to develop inhibitory neurotransmitter phenotype, represent an effective treatment modality to modulate ischemia-induced spastic paraplegia.
短暂性脊髓缺血是与主动脉交叉钳夹相关的一种并发症，可能导致痉挛性截瘫。一旦这种缺陷完全形成，便会永久性存在。定量组织病理学评估和药理学研究表明，缺血性痉挛继发于腰段γ-氨基丁酸（GABA）和甘氨酸能抑制性中间神经元的丧失。在本研究中，我们调查了将人hNT神经元或特定的斯普拉格-道利大鼠脊髓神经元前体（SNP）移植到先前因抑制性神经元缺失而缺血的脊髓节段后，是否能恢复局部抑制张力并改善痉挛状态。具有功能和电生理定义的痉挛的大鼠接受了hNT神经元或神经元前体的脊髓移植及免疫抑制治疗后，运动功能逐渐恢复，这与刺激运动皮层诱发的原本加剧的外周运动反应的改善相关。相比之下，在对照组、注射培养基或移植少突胶质细胞的动物中未观察到明显的治疗效果。移植神经元的体视学定量分析显示，移植后三个月存活率为1%-2%。这些存活的神经元表现出强大的轴突-树突状发芽，并表达成熟神经元典型的标志物，包括神经元特异性烯醇化酶（NSE）、神经元核抗原（NeuN）和突触素。在两个治疗组中，移植神经元的一个亚群都产生了GABA免疫反应性。这些数据表明，hNT神经元或其他有可能发展为抑制性神经递质表型的特定神经细胞进行区域特异性移植，是调节缺血性痉挛性截瘫的一种有效治疗方式。
