Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice

Keber, Ursula; Klietz, Martin; Carlsson, Thomas; Oertel, Wolfgang H.; Weihe, Eberhard; Schäfer, Martin; Höglinger, Günter U.; Depboylu, Candan

doi:10.1016/j.neuroscience.2015.04.021

Cited by 24 publications

(12 citation statements)

References 75 publications

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“…Several studies have previously demonstrated that striatal Th-positive neurons are correlated with severity of LID and ΔFosB expression in hemiparkinsonian mice (Darmopil et al, 2008; Charbonnier-Beaupel et al, 2015; Keber et al, 2015). Studies have shown that striatal Th neurons may cooperate with serotonergic terminals synthesizing dopamine and producing supraphysiological synaptic DA concentrations, a mechanism thought to contribute to LID (Keber et al, 2015). However, it was also reported that the striatal Th-positive neurons co-expressed with dynorphin and enkephalin, suggesting that they are medium spiny neurons of the direct and indirect striatal output pathways (Darmopil et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats

et al. 2017

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L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long-term therapy of patients with Parkinson's disease (PD). Although, the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK), and thus MEK inhibitor can prevent ERK activation. Here the effect of the MEK inhibitor PD98059 on LID and the associated molecular changes were examined. Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received daily L-DOPA treatment for 3 weeks, and abnormal involuntary movements (AIMs) were assessed every other day. PD98059 was injected in the lateral ventricle daily for 12 days starting from day 10 of L-DOPA treatment. Striatal molecular markers of LID were analyzed together with gene regulation using microarray. The administration of PD98059 significantly reduced AIMs. In addition, ERK activation and other associated molecular changes including ΔFosB were reversed in rats treated with the MEK inhibitor. PD98059 induced significant up-regulation of 418 transcripts and down-regulation of 378 transcripts in the striatum. Tyrosine hydroxylase (Th) and aryl hydrocarbon receptor nuclear translocator (Arnt) genes were down-regulated in lesioned animals and up-regulated in L-DOPA-treated animals. Analysis of protein levels showed that PD98059 reduced the striatal TH. These results support the association of p-ERK1/2, ΔFosB, p-H3 to the regulation of TH and ARNT in the mechanisms of LID, and pinpoint other gene regulatory changes, thus providing clues for identifying new targets for LID therapy.

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Section: Discussionmentioning

confidence: 99%

Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats

et al. 2017

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“… Hypothetical action mechanism of TRH or Taltirelin in PD model animals. Based on our results and recent literature, this scheme illustrated how TRH or its analog, Taltirelin (Tal) worked in PD model animals (adapted from Keber et al, 2015 ). Post administration, Tal firstly acted on the dopaminergic neurons on soma in the substantia nigra (SN) or on residual nerve terminal in striatum, resulting in increased dopamine (DA) synthesis and release (①).…”

Section: Discussionmentioning

confidence: 93%

“…In our study, none of those TH-positive cells were stained with AADC or DAT either in or ex vivo , suggesting that Taltirelin did not induce the neuron type transformation at least in our experiment conditions. Regarding the functions of the TH-positive cells in the striatum, it has been proposed that those cells could co-synthesize DA with 5-HT neuronal terminals that contain ADDC ( Keber et al, 2015 ; Kozina et al, 2017 ). Therefore, new-emerging TH-positive cells may help promoting DA synthesis and secretion in sub-chronic use of Taltirelin.…”

Section: Discussionmentioning

confidence: 99%

“…Taltirelin group also showed similar cumulative effects, but the level was significantly lower than that of L -DOPA group. Studies once showed that L -DOPA significantly increased the level of TH and ΔFosB in the striatum of normal mice ( Keber et al, 2015 ). In addition, striatal emerging TH-positive neurons usually appeared in areas of near complete or partial deprivation of DA rather than completely destructed areas ( Lopez-Real et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

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

Zheng

Chen

Tan

et al. 2018

Front. Cell. Neurosci.

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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 in vivo and in vitro 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.

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“…Positive neurons are able to produce either l -DOPA or dopamine in target areas of ventral midbrain dopaminergic neurons. Keber suggested that striatal tyrosine hydroxylase + cells may synthesize dopamine cooperatively and subsequently contribute to supraphysiological concentrations of synaptic dopamine [ 31 ]. In our study, we observed that the mRNA and protein expression of DYT5b in cells exposed to simazine for 12, 24, and 48 h was significantly up-regulated after 12 and 24 h exposure and significantly down-regulated after 48 h exposure ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Dopaminergic Dysfunction in Mammalian Dopamine Neurons Induced by Simazine Neurotoxicity

et al. 2017

IJMS

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Many studies have shown that the pollutant simazine (6-chloro-N,N′-diethyl-1,3,5-triazine-2,4-diamine), which has been overused, inhibits the proliferation of mammalian dopaminergic cells, and affects the developmental differentiation of mammalian dopaminergic neurons. However, few studies have shown the effects of simazine on dopaminergic metabolism in these cells. Therefore, we aim to examine the metabolic effects of simazine exposure in mouse dopaminergic progenitor neurons (MN9D) at different exposure times. The cells were treated with simazine at 0, 150, 300 and 600 µM for 12, 24 and 48 h, respectively. The content of dopamine in these cells was then examined using the enzyme-linked immunosorbent assay (ELISA) kit. Real-time quantitative polymerase chain reaction (PCR) and western blotting were performed to analyze the mRNA and protein expression of aromatic amino acid decarboxylase (AADC), tyrosine hydroxylase (DYT5b), dopamine transporter (DAT), monoamine vesicular transporter 2 (VMAT2), monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). The results showed that simazine influenced the metabolism of dopamine and led to a decrease in dopamine level in these cells which may eventually lead to neurological disorders of the dopaminergic system.

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Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice

Cited by 24 publications

References 75 publications

Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats

Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats

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

Dopaminergic Dysfunction in Mammalian Dopamine Neurons Induced by Simazine Neurotoxicity

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