Almansoub Hasan A M M, Tang Hui, Wu Ying, Wang Ding-Qi, Mahaman Yacoubou Abdoul Razak, Salissou Maibouge Tanko Mahamane, Lu Youming, Hu Fan, Zhou Lan-Ting, Almansob Yusra A M, Liu Dan
Department of Pathophysiology, Key lab of a neurological disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
The Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, P.R. China.
J Alzheimers Dis. 2020;74(3):883-901. doi: 10.3233/JAD-191091.
Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α-synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro. Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT.
神经毒性是包括阿尔茨海默病（AD）和帕金森病（PD，老年人中第二常见的神经退行性疾病）在内的多种神经疾病的主要病理变化之一。已知AD和PD具有相似的神经病理学特征，如氧化应激、特定神经元的丧失以及特定蛋白质的聚集。然而，目前AD和PD都还没有有效的治疗药物。催产素（OXT）是一种由9个氨基酸组成的小肽，对许多神经疾病具有神经保护作用。OXT给药是否能对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠神经毒性产生神经保护作用仍不清楚。在本研究中，我们首先发现MPTP小鼠体内的OXT水平降低。补充OXT可有效改善MPTP小鼠的运动障碍和焦虑样行为。OXT还可减轻MPTP小鼠黑质致密部α-突触核蛋白在S129位点的过度磷酸化以及多巴胺能神经元的丧失，以及MPTP小鼠的氧化应激，并在体外减轻氧化应激和细胞毒性。此外，我们发现OXT可抑制MPTP小鼠中的miR-26a/DAPK1信号通路。总之，我们的研究证明了OXT对MPTP小鼠具有保护作用，并且miR-26a/DAPK1信号通路可能在介导OXT的保护作用中发挥重要作用。
