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

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.

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

“…Then, one-way analysis of variance (ANOVA) followed by least significant difference (LSD) post-hoc comparisons for multiple groups comparisons were conducted (more than two groups) (Zheng et al, 2018). Paired samples T test for comparing extracellular glutamate concentrations before and after LY354740 injection (Table 1 for details).…”

“…Behavioral assessments were performed as our previously described and conducted at 10:00 am on each testing days (Zheng et al, 2018). Each group contained eight mice.…”

“…Brain sections containing striatum and SN were dissected as we previously described and weighed from both left and right halves, snap frozen in liquid nitrogen, then stored at −80°C for further use. Monoamine analysis was carried out as previously described (Zheng et al, 2018): tissues of 8-18 mg from the striatum were homogenized in 200 ml of 0.1 M ice-cold perchloric acid and 0.1% L-cysteine by ultrasonication. The homogenates were centrifuged at 18,000 g for 15 min in 4°C and supernatants were collected.…”

“…All the drug treatments were the same as before. Surgical and microdialysis procedures were conducted as previously described (Zheng et al, 2018). Male C57BL/6 mice, weighing 25-30 g, were anesthetized with isoflurane (induction 3%, maintenance 1.5%).…”

A Scientometric Analysis and Visualization of Research on Parkinson's Disease Associated With Pesticide Exposure

“…Pathological studies of several rare hereditary parkinsonism cases found no Lewy body or deposition of α-synuclein (5). However, the main neuropathological features of PD are the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (6). Sporadic PD is also characterized by the presence of Lewy bodies and Lewy neurites, which consist primarily of misfolded and aggregated protein α-synuclein in the remnant neurons (7)(8)(9).…”