Molecular Pharmacology Department, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Restor Neurol Neurosci. 2010;28(6):803-15. doi: 10.3233/RNN-2010-0551.
A number of neurological disorders are marked by increased or aberrant frequency of neuronal discharge in specific parts of the brain. Administration of drugs such as antiepileptic compounds results in the depression of neuronal activity in the whole brain, with the potential for serious side-effects. In the search for additional therapies to reduce the unphysiological electrical activity of over-active brain foci, we have examined the effect of fibroblasts transplanted to areas responsible for motor dysfunction in hemi-parkinsonian rats, since bursting synchronous discharges in internal segment of globus pallidus (GPi) are thought to be partially responsible for the movement disorders of PD. Fibroblasts express gap junctions and ion channels, and so, when transplanted to brain tissue, can potentially modulate excessive electrical activity.
Neonatal cortical neurons were cultured on multi-electrode arrays, and their electrical activity was evaluated before and after fibroblast seeding. Unilateral 6-hydroxydopamine (6-OHDA) lesion was carried out in Fischer rats. Lesioned or control rats were transplanted with either syngeneic dermal fibroblasts, microfine glass beads, ibotenic acid, or physiological saline, in the entopeduncular nucleus (EP). Apomorphine-induced rotational behavior and L-dopa-induced dyskinetic movements were evaluated before transplantation (baseline) and 2, 4, 8, 12, and 24 weeks following transplantation. Following behavioral experiments, rats were perfused with 4% formaldehyde in PBS for immunohistochemical study of the brain.
We demonstrate in vitro that the introduction of fibroblasts into a network of neurons does not interfere with overall functional measures of activity, while moderately altering the characteristics of synchronous neuronal discharge. In rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal dopaminergic pathway, apomorphine-induced rotations were reduced by more than 60% following ipsilateral transplantation of fibroblasts to the EP. L-Dopa-induced dyskinesia was also significantly reduced. Transplantation of inert microspheres, or chemical lesion of the same area with ibotenic acid, did not produce beneficial effects on parkinsonian symptomatology.
Fibroblast transplantation could be an alternative treatment strategy for the parkinsonian patient.
许多神经紊乱疾病的特征是大脑特定部位神经元放电增加或异常。药物如抗癫痫化合物的给药导致整个大脑神经元活动的抑制，具有严重副作用的潜力。在寻找额外的治疗方法来减少过度活跃的脑焦点的非生理性电活动时，我们研究了移植到半帕金森大鼠运动功能障碍区域的成纤维细胞的效果，因为苍白球内节（GPi）的爆发同步放电被认为部分负责 PD 的运动障碍。成纤维细胞表达缝隙连接和离子通道，因此，当移植到脑组织时，有可能调节过度的电活动。
将新生皮质神经元培养在多电极阵列上，并在种植成纤维细胞前后评估其电活动。在费希尔大鼠中进行单侧 6-羟多巴胺（6-OHDA）损伤。损伤或对照大鼠被移植到动眼神经核（EP）中，分别为同基因真皮成纤维细胞、微玻璃珠、异搏定或生理盐水。在移植前（基线）和移植后 2、4、8、12 和 24 周评估阿朴吗啡诱导的旋转行为和 L-多巴诱导的运动障碍。行为实验后，用 4%甲醛在 PBS 中灌注大鼠进行脑免疫组织化学研究。
我们在体外证明，将成纤维细胞引入神经元网络不会干扰整体活性的功能测量，同时适度改变同步神经元放电的特征。在单侧黑质纹状体多巴胺能通路 6-羟多巴胺损伤的大鼠中，将成纤维细胞移植到 EP 后，同侧的阿朴吗啡诱导的旋转减少了 60%以上。L-多巴诱导的运动障碍也显著减少。惰性微球的移植，或用异搏定化学损伤相同区域，对帕金森病症状没有产生有益的影响。
成纤维细胞移植可能是帕金森病患者的一种替代治疗策略。
