TRH Analog, Taltirelin Improves Motor Function of Hemi-PD Rats Without Inducing Dyskinesia via Sustained Dopamine Stimulating Effect

• Published in: Frontiers in cellular neuroscience Vol. 12; p. 417
• Main Authors: Zheng, Cong, Chen, Guiqin, Tan, Yang, Zeng, Weiqi, Peng, Qiwei, Wang, Ji, Cheng, Chi, Yang, Xiaoman, Nie, Shuke, Xu, Yan, Zhang, Zhentao, Papa, Stella M, Ye, Keqiang, Cao, Xuebing
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 13.11.2018; Frontiers Media S.A
• Subjects: 6-Hydroxydopamine; Basal ganglia; Central nervous system; Central nervous system diseases; Dihydroxyphenylalanine; Dopamine; Dopamine receptors; Dopamine transporter; Drug dosages; Dyskinesia; Electrodes; Hydroxylase; L-DOPA; Laboratory animals; Levodopa; Medicine; Menopause; Microdialysis; Monoamine transporter; Movement disorders; Neostriatum; Neurodegenerative diseases; Neurology; Neuroscience; Parkinson's disease; Reserpine; Stainless steel; Substantia nigra; Surgery; Taltirelin; Thyroid-stimulating hormone; Thyrotropin-releasing hormone; TRH; Tyrosine 3-monooxygenase; tyrosine hydroxylase; Atlanta Georgia; United States > US; China; Taltirelin; TRH; dopamine; Parkinson’s disease; L-DOPA; tyrosine hydroxylase
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2018.00417

Thyrotropin-releasing hormone (TRH) and its analogs are able to stimulate the release of the endogenic dopamine (DA) in the central nervous system. However, this effect has not been tested in the Parkinson's disease (PD), which is characterized by the DA deficiency due to the dopaminergic neurons loss in the substantia nigra. Here, we investigated the therapeutic effect of Taltirelin, a long-acting TRH analog on 6-hydroxydopamine-lesioned hemi-Parkinsonian rat model. 1-10 mg/kg Taltirelin i.p. administration significantly improved the locomotor function and halted the electrophysiological abnormities of PD animals without inducing dyskinesia even with high-dose for 7 days treatment. Microdialysis showed that Taltirelin gently and persistently promoted DA release in the cortex and striatum, while L-DOPA induced a sharp rise of DA especially in the cortex. The DA-releasing effect of Taltirelin was alleviated by reserpine, vanoxerine (GBR12909) or AMPT, indicating a mechanism involving vesicular monoamine transporter-2 (VMAT-2), dopamine transporter (DAT) and tyrosine hydroxylase (TH). The and experiments further supported that Taltirelin affected the regulation of TH expression in striatal neurons, which was mediated by p-ERK1/2. Together, this study demonstrated that Taltirelin improved motor function of hemi-PD rats without inducing dyskinesia, thus supporting a further exploration of Taltirelin for PD treatment.