Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism

Козина, Е. А.; Khakimova, G. R.; Khaindrava, V. G.; Kucheryanu, V. G.; Vorobyeva, Nadezhda E.; Краснов, А. Н.; Georgieva, S.; Goff, Lydia Kerkerian‐Le; Ugrumov, M. V.

doi:10.1016/j.jns.2014.03.028

Cited by 65 publications

(28 citation statements)

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“…Although it is not clear why a loss of TH + cells was observed in mice that did not display loss of Nissl + neurons, it has been reported that there is a reduction of TH protein levels and TH mRNA levels in the surviving dopamine neurons in PD patients [22]. A study conducted by Kastner and colleagues also showed a reduction in the TH content in surviving dopaminergic neurons after MPTP treatment in monkeys [23] and reduction of TH protein levels and TH mRNA levels in the SNc and striatum of mice treated with MPTP has also been reported [24, 25]. TH + cell loss was also found to occur significantly prior to Nissl + neuron loss in the 4×16 mg/kg MPTP model, which was maximal at 4–7 days after the last MPTP injection [13].…”

Section: Discussionmentioning

confidence: 99%

Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss

et al. 2017

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Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical neurotoxicant used in mice to mimic primary features of PD pathology including striatal dopamine depletion and dopamine neuron loss in the substantia nigra pars compacta (SNc). In the literature, there are several experimental paradigms involving multiple doses of MPTP that are used to elicit dopamine neuron loss. However, a recent study reported that a single low dose caused significant loss of dopamine neurons. Here, we determined the effect of a single intraperitoneal injection of one of three doses of MPTP (0.1, 2 and 20 mg/kg) on dopamine neurons, labeled by tyrosine hydroxylase (TH+), and total neuron number (Nissl+) in the SNc using unbiased stereological counting. Data reveal a significant loss of neurons in the SNc (TH+ and Nissl+−) only in the group treated with 20 mg/kg MPTP. Groups treated with lower dose of MPTP (0.1 and 2 mg/kg) only showed significant loss of TH+ neurons rather than TH+ and Nissl+. Striatal dopamine levels were decreased in the groups treated with 2 and 20 mg/kg MPTP and striatal terminal markers including, TH and the dopamine transporter (DAT), were only decreased in the groups treated with 20 mg/kg MPTP. These data demonstrate that lower doses of MPTP likely result in loss of TH expression rather than actual dopamine neuron loss in the SN. This finding reinforces the need to measure both total neuron number along with TH+ cells in determining dopamine neuron loss.

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Section: Discussionmentioning

confidence: 99%

Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss

et al. 2017

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“…4,5,[47][48][49][50] Compensatory processes include the following: (i) an increase in the functional activity of survived dopaminergic neurons, (ii) dopamine synthesis by striatal non-dopaminergic neurons expressing only tyrosine hydroxylase or aromatic L-amino acid decarboxylase ( Figure 1B), (iii) increased sensitivity of target neurons to dopamine. 4,5,47,[49][50][51][52][53] In addition to the specific mechanisms of neuroplasticity that maintain dopamine neurotransmission at a normal level, there are nonspecific compensatory processes mediated by growth factors. These include the following: (i) axon branching and multiplication of synaptic terminals, (ii) activation of antioxidant systems, (iii) elimination of neurotoxins by glial cells.…”

Section: Pathogenesismentioning

confidence: 99%

Development of early diagnosis of Parkinson's disease: Illusion or reality?

Ugrumov

2020

CNS Neurosci Ther

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The fight against neurodegenerative diseases, Alzheimer disease and Parkinson's disease (PD), is a challenge of the 21st century. The low efficacy of treating patients is due to the late diagnosis and start of therapy, after the degeneration of most specific neurons and depletion of neuroplasticity. It is believed that the development of early diagnosis (ED) and preventive treatment will delay the onset of specific symptoms. This review evaluates methodologies for developing ED of PD. Since PD is a systemic disease, and the degeneration of certain neurons precedes that of nigrostriatal dopaminergic neurons that control motor function, the current methodology is based on searching biomarkers, such as premotor symptoms and changes in body fluids (BF) in patients. However, all attempts to develop ED were unsuccessful. Therefore, it is proposed to enhance the current methodology by (i) selecting among biomarkers found in BF in patients at the clinical stage those that are characteristics of animal models of the preclinical stage, (ii) searching biomarkers in BF in subjects at the prodromal stage, selected by detecting premotor symptoms and failure of the nigrostriatal dopaminergic system. Moreover, a new methodology was proposed for the development of ED of PD using a provocative test, which is successfully used in internal medicine.

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“…Ключевые слова: никотиновые ацетилхолиновые рецепторы, дофаминергический нейрон, 1-метил-4-фенил-1,2,3,6тетрагидропиридин, стриатум, черная субстанция DOI 10.18097/PBMC20176303241 катион 1-метил-4-фенилпиридиния с последующим его переносом мембранным транспортером ДА в ДА-ергические нейроны, что приводит к их гибели из-за окислительного стресса. Степень поражения ДА-нейронов нигростриатной системы и тяжесть клинических проявлений в значительной степени зависит от схемы введения МФТП, что позволяет моделировать разные стадии БП [11,12]. В данной работе, используя МФТП-индуцированные нейротоксические модели, мы исследовали изменения в экспрессии генов и содержании нАХР на досимптомной стадии паркинсонизма по сравнению с ранней симптомной.…”

Section: основнойunclassified

Possible involvement of neuronal nicotinic acetylcholine receptors in compensatory brain mechanisms at early stages of Parkinson's disease

et al. 2017

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A role of nicotinic acetylcholine receptors (nAChR) in the development of Parkinson's disease (PD) has been investigated using two mouse models corresponding to the presymptomatic stage and the early symptomatic stage of PD. Quantitative determination of nAChR in the striatum and substantia nigra (SN) was performed using the radioactive derivatives of epibatidine, -conotoxin MII, and -bungarotoxin as ligands. The number of ligand-binding sites changed differently depending on their location in the brain, the stage of the disease and the receptor subtype. Epibatidine binding decreased in the striatum to 66% and 70% at the presymptomatic and early symptomatic stages, respectively, whereas in SN a 160% increase was registered at the presymptomatic stage. The -conotoxin MII binding on striatal dopaminergic axonal terminals at the presymptomatic stage decreased by 20% and at the symptomatic stage it demonstrated a further decrease. The increase in -bungarotoxin binding at the presymptomatic stage and a decrease at the early symptomatic stage was observed in the striatum. In SN, the level of -bungarotoxin binding decreased at the presymptomatic stage and kept constant at the symptomatic stage. The significant decrease in the expression of Chrna4 and Chrna6 genes encoding 4 and 6 nAChR subunits was observed in SN at the early symptomatic stage, while a 13-fold increase in expression of the Chrna7 gene encoding the 7 nAChR subunit was detected at the presymptomatic stage. The data obtained suggest possible involvement of nAChR in compensatory mechanisms at early PD stages.

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Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism

Cited by 65 publications

References 66 publications

Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss

Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss

Development of early diagnosis of Parkinson's disease: Illusion or reality?

Possible involvement of neuronal nicotinic acetylcholine receptors in compensatory brain mechanisms at early stages of Parkinson's disease

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