We have recently demonstrated that extracellular vesicles (EVs) derived from the human teeth stem cells improve motor symptoms and normalize tyrosine hydroxylase (TH) expression in the nigrostriatal structures of Parkinson's disease (PD) model rats obtained by 6-hydroxydopamine (6-OHDA) unilateral injection into the medial forebrain bundle (MFB). The aim of this study was to clarify: (1) how long therapeutic effects persist after discontinuation of 17-day intranasal administration of EVs in 6-OHDA rats; (2) may EVs reverse cognitive (learning/memory) dysfunction in these PD model rats; (3) whether and how the behavioral improvement may be related to the expression of TH and Nissl bodies count in the nigrostriatal structures. Our results demonstrated that in 6-OHDA rats, gait was normalized even ten days after discontinuation of EVs administration. EVs successfully reversed 6-OHDA-induced impairment in spatial learning/memory performance; however, the beneficial effect was shorter (up to post-treatment day 6) than that revealed for gait improvement. The shorter effect of EVs coincided with both full normalization of TH expression and Nissl bodies count in the nigrostriatal structures, while slight but significant increase in the 6-OHDA-decreased Nissl count persisted in the substantia nigra even on the post-treatment day 20, supposedly due to the continuation of protein synthesis in the living cells. The obtained data indicate the usefulness of further studies to find the optimal administration regimen which could be translated into clinical trials on PD patients, as well as to clarify other-apart from dopaminergic-neuromodulatory pathways involved in the EVs mechanism of action.

中文翻译：

---

通过鼻内给予细胞外囊泡改善帕金森病模型大鼠的时间依赖性记忆和步态。


我们最近证明，源自人类牙齿干细胞的细胞外囊泡（EV）可改善运动症状，并使通过 6-羟基多巴胺（6-OHDA）获得的帕金森病（PD）模型大鼠黑质纹状体结构中的酪氨酸羟化酶（TH）表达正常化单侧注射到内侧前脑束（MFB）。本研究的目的是阐明：(1) 6-OHDA 大鼠停止鼻内给予 EVs 17 天后，治疗效果能持续多久； (2) EVs 可能会逆转这些 PD 模型大鼠的认知（学习/记忆）功能障碍； (3)行为改善是否以及如何与黑质纹状体结构中TH和尼氏小体计数的表达有关。我们的结果表明，在 6-OHDA 大鼠中，即使在停止 EV 给药十天后，步态也恢复正常。 EV 成功逆转了 6-OHDA 引起的空间学习/记忆性能损伤；然而，有益效果比步态改善所显示的效果要短（直到治疗后第 6 天）。 EVs 的较短效应与黑质纹状体结构中 TH 表达和尼氏体计数的完全正常化同时发生，而即使在治疗后第 20 天，黑质中 ​​6-OHDA 减少的尼氏体计数仍然存在轻微但显着的增加，据推测是由于活细胞中蛋白质合成的持续。获得的数据表明进一步研究对于寻找最佳给药方案是有用的，该方案可以转化为PD患者的临床试验，并阐明EV作用机制中涉及的除多巴胺能神经调节途径之外的其他途径。