Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway.
Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway.
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DOI：
10.1155/2022/8400876
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发表时间：
2022
影响因子：
--
通讯作者：
Qiu P
中科院分区：
文献类型：
--
作者：
Huang J;Ding J;Wang Z;Li Y;He Y;Wang X;Fan H;Xie Q;Qiu P
甲基苯丙胺（methamphetamine，METH）长期滥用会对多个器官和系统造成损害，尤其是中枢神经系统（central nervous system，CNS）。淫羊藿苷II（Icariside II，ICS）是一种黄酮类化合物，是中药淫羊藿的主要活性成分之一，具有抗炎、抗氧化、抗癌等多种生物学和药理学活性。然而，ICS是否可以预防甲基苯丙胺诱导的神经毒性仍然未知。本研究以METH慢性滥用小鼠模型为基础，检测了METH暴露后的神经毒性，并探讨了ICS的干预作用及其可能的作用机制。在此，我们发现METH可引发神经毒性，其特征在于多巴胺能神经元损失、多巴胺（DA）耗竭、胶质细胞活化、α-突触核蛋白（α-syn）上调、树突棘可塑性异常以及运动协调和平衡功能障碍。然而，ICS治疗减轻了METH引起的上述神经毒性。我们的数据还表明，当ICS对抗MET诱导的神经毒性时，它伴随着部分纠正异常Kelch 2，如ECH 2相关蛋白1（Keap 1）-核因子红细胞2相关因子2（Nrf 2）途径和氧化应激反应。在Nrf 2抑制剂ML 385的存在下，ICS不能激活Nrf 2相关蛋白的表达并降低氧化应激反应。更重要的是，当Nrf 2被抑制时，ICS不能减轻MET诱导的多巴胺能神经毒性和行为损害，提示ICS对MET诱导的神经毒性的神经保护作用依赖于激活Keap 1-Nrf 2通路。虽然还需要进一步的研究来深入挖掘ICS的实际分子靶点，但不可否认的是，目前的结果暗示了ICS在减少METH滥用者神经毒性方面的潜在价值。
Chronic and long-term methamphetamine (METH) abuse is bound to cause damages to multiple organs and systems, especially the central nervous system (CNS). Icariside II (ICS), a type of flavonoid and one of the main active ingredients of the traditional Chinese medicine Epimedium, exhibits a variety of biological and pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. However, whether ICS could protect against METH-induced neurotoxicity remains unknown. Based on a chronic METH abuse mouse model, we detected the neurotoxicity after METH exposure and determined the intervention effect of ICS and the potential mechanism of action. Here, we found that METH could trigger neurotoxicity, which was characterized by loss of dopaminergic neurons, depletion of dopamine (DA), activation of glial cells, upregulation of α-synuclein (α-syn), abnormal dendritic spine plasticity, and dysfunction of motor coordination and balance. ICS treatment, however, alleviated the above-mentioned neurotoxicity elicited by METH. Our data also indicated that when ICS combated METH-induced neurotoxicity, it was accompanied by partial correction of the abnormal Kelch 2 like ECH2 associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and oxidative stress response. In the presence of ML385, an inhibitor of Nrf2, ICS failed to activate the Nrf2-related protein expression and reduce the oxidative stress response. More importantly, ICS could not attenuate METH-induced dopaminergic neurotoxicity and behavioral damage when the Nrf2 was inhibited, suggesting that the neuroprotective effect of ICS on METH-induced neurotoxicity was dependent on activating the Keap1-Nrf2 pathway. Although further research is needed to dig deeper into the actual molecular targets of ICS, it is undeniable that the current results imply the potential value of ICS to reduce the neurotoxicity of METH abusers.
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