TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone

• Authors: Cong Zheng, Huazhong University of Science & Technology; Guiqin Chen, Emory University; Yang Tan, Huazhong University of Science & Technology; Weiqi Zeng, Huazhong University of Science & Technology; Qiwei Peng, Huazhong University of Science & Technology; Ji Wang, Huazhong University of Science & Technology; Chi Cheng, Huazhong University of Science & Technology; Xiaoman Yang, Huazhong University of Science & Technology; Shuke Nie, Wuhan University; Yan Xu, Huazhong University of Science & Technology; Zhentao Zhang, Emory University; Stella Papa, Emory University; Keqiang Ye, Emory University; Xuebing Cao, Huazhong University of Science & Technology
• Journal Title: Frontiers in Cellular Neuroscience
• Volume: Volume 12
• Publisher: Frontiers Media | 2018-12-20, Pages 485-485
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fncel.2018.00485
• Subjects: Biology, Neuroscience; Health Sciences, Pathology; Chemistry, Pharmaceutical
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; Parkinson's disease; TRH; taltirelin; MPTP; rotenone; tau; alpha-synuclein; AEP; ALPHA-SYNUCLEIN; HORMONE TRH; ASPARAGINE ENDOPEPTIDASE; ALZHEIMERS-DISEASE; THYROTROPIN; TAU; ACTIVATION; BRAIN; RISK; HIPPOCAMPUS

Abstract

Dopaminergic neurons loss is one of the main pathological characters of Parkinson’s disease (PD), while no suitable neuroprotective agents have been in clinical use. Thyrotropin-releasing hormone (TRH) and its analogs protect neurons from ischemia and various cytotoxins, but whether the effect also applies in PD models remain unclear. Here, we showed that Taltirelin, a long-acting TRH analog, exhibited the neuroprotective effect in both cellular and animal models of PD. The in vitro study demonstrated that Taltirelin (5 μM) reduced the generation of reactive oxygen species (ROS) induced by MPP+ or rotenone, alleviated apoptosis and rescued the viability of SH-SY5Y cells and rat primary midbrain neurons. Interestingly, SH-SY5Y cells treated with Taltirelin also displayed lower level of p-tau (S396) and asparagine endopeptidase (AEP) cleavage products, tau N368 and α-synuclein N103 fragments, accompanied by a lower intracellular monoamine oxidase-B (MAO-B) activity. In the subacute MPTP-induced and chronic rotenone-induced PD mice models, we found Taltirelin (1 mg/kg) significantly improved the locomotor function and preserved dopaminergic neurons in the substantia nigra (SN). In accordance with the in vitro study, Taltirelin down-regulated the levels of p-tau (S396), p-α-synuclein (S129) tau N368 and α-synuclein N103 fragments in SN and striatum. Together, this study demonstrates that Taltirelin may exert neuroprotective effect via inhibiting MAO-B and reducing the oxidative stress and apoptosis, preventing AEP activation and its subsequent pathological cleavage of tau and α-synuclein, thus provides evidence for Taltirelin in protective treatment of PD.