Besides several endogenous elements, exogenous factors, including exposure to pesticides, have been recognized as putative factors contributing to the onset and development of neurodegenerative diseases, including Parkinson’s disease (PD). Considering the availability, success rate, and limitations associated with the current arsenals to fight PD, there is an unmet need for novel therapeutic interventions. Therefore, based on the previously reported beneficial functions of the L1 cell adhesion molecule, we hypothesized that L1 mimetic compounds may serve to neutralize neurotoxicity triggered by the pesticide paraquat (PQ). In this study, we attempt to use PQ for inducing PD-like pathology and the L1 mimetic compounds phenelzine sulfate (PS) and tacrine (TC) as potential candidates for the amelioration of PD symptoms using zebrafish as a model system. Administration of PQ together with the L1 mimetic compounds PS or TC (250 nM) improved survival of zebrafish larvae, protected them from locomotor deficits, and increased their sensorimotor reflexes. Moreover, application of PQ together with PS (500 nM) or TC (1000 nM) in adult zebrafish counteracted PQ-induced toxicity, maintaining normal locomotor functions and spatial memory in an open field and T-maze task, respectively. Both L1 mimetic compounds prevented reduction in tyrosine hydroxylase and dopamine levels, reduced reactive oxygen species (ROS) generation, protected against impairment of mitochondrial viability, improved the antioxidant enzyme system, and prevented a decrease in ATP levels. Altogether, our findings highlight the beneficial functions of the agonistic L1 mimetics PS and TC by improving several vital cell functions against PQ-triggered neurotoxicity.

中文翻译：

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粘附分子 L1 激动剂模拟物可防止斑马鱼因农药百草枯引起的运动缺陷和生化改变


除了几种内源性因素外，外源性因素（包括接触农药）已被认为是导致神经退行性疾病（包括帕金森病（PD））发生和发展的推定因素。考虑到当前治疗帕金森病的手段的可用性、成功率和局限性，对新型治疗干预措施的需求尚未得到满足。因此，根据之前报道的 L1 细胞粘附分子的有益功能，我们假设 L1 模拟化合物可能有助于中和农药百草枯 (PQ) 引发的神经毒性。在本研究中，我们尝试使用 PQ 诱导 PD 样病理，并使用 L1 模拟化合物硫酸苯乙肼 (PS) 和他克林 (TC) 作为使用斑马鱼作为模型系统改善 PD 症状的潜在候选者。 PQ 与 L1 模拟化合物 PS 或 TC (250 nM) 一起施用可提高斑马鱼幼虫的存活率，保护它们免受运动缺陷的影响，并增强它们的感觉运动反射。此外，将 PQ 与 PS (500 nM) 或 TC (1000 nM) 一起应用于成年斑马鱼可以抵消 PQ 诱导的毒性，分别在旷场和 T 迷宫任务中维持正常的运动功能和空间记忆。两种 L1 模拟化合物均可防止酪氨酸羟化酶和多巴胺水平降低，减少活性氧 (ROS) 的产生，防止线粒体活力受损，改善抗氧化酶系统，并防止 ATP 水平下降。总而言之，我们的研究结果强调了激动性 L1 模拟物 PS 和 TC 通过改善多种重要细胞功能来对抗 PQ 触发的神经毒性的有益功能。