TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone
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...
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doaj-ce3deacd3ee548c298fa190d2309cb6e2020-11-25T01:14:55ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022018-12-011210.3389/fncel.2018.00485418994TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and RotenoneCong Zheng0Guiqin Chen1Yang Tan2Weiqi Zeng3Qiwei Peng4Ji Wang5Chi Cheng6Xiaoman Yang7Shuke Nie8Yan Xu9Zhentao Zhang10Stella M. Papa11Stella M. Papa12Keqiang Ye13Xuebing Cao14Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Renmin Hospital, Wuhan University, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Renmin Hospital, Wuhan University, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurology, Renmin Hospital, Wuhan University, Wuhan, ChinaYerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Neurology, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDopaminergic 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.https://www.frontiersin.org/article/10.3389/fncel.2018.00485/fullParkinson’s diseaseTRHtaltirelinMPTProtenonetau |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Cong Zheng Guiqin Chen Yang Tan Weiqi Zeng Qiwei Peng Ji Wang Chi Cheng Xiaoman Yang Shuke Nie Yan Xu Zhentao Zhang Stella M. Papa Stella M. Papa Keqiang Ye Xuebing Cao |
spellingShingle |
Cong Zheng Guiqin Chen Yang Tan Weiqi Zeng Qiwei Peng Ji Wang Chi Cheng Xiaoman Yang Shuke Nie Yan Xu Zhentao Zhang Stella M. Papa Stella M. Papa Keqiang Ye Xuebing Cao TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone Frontiers in Cellular Neuroscience Parkinson’s disease TRH taltirelin MPTP rotenone tau |
author_facet |
Cong Zheng Guiqin Chen Yang Tan Weiqi Zeng Qiwei Peng Ji Wang Chi Cheng Xiaoman Yang Shuke Nie Yan Xu Zhentao Zhang Stella M. Papa Stella M. Papa Keqiang Ye Xuebing Cao |
author_sort |
Cong Zheng |
title |
TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone |
title_short |
TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone |
title_full |
TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone |
title_fullStr |
TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone |
title_full_unstemmed |
TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone |
title_sort |
trh analog, taltirelin protects dopaminergic neurons from neurotoxicity of mptp and rotenone |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular Neuroscience |
issn |
1662-5102 |
publishDate |
2018-12-01 |
description |
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. |
topic |
Parkinson’s disease TRH taltirelin MPTP rotenone tau |
url |
https://www.frontiersin.org/article/10.3389/fncel.2018.00485/full |
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