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Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.
Exp Neurol. 2014 Jul; 257:25-38.EN

Abstract

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the locus coeruleus, and associated pontine nuclei. Animals with combined DA and NA lesions were more prone to develop L-DOPA-induced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to brainstem NA neurons, contributes to the development of motor impairments and the appearance of L-DOPA-induced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons.

Authors+Show Affiliations

Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, 221 84 Lund, Sweden. Electronic address: shine@cardiff.ac.uk.Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, 221 84 Lund, Sweden.Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria SS 554km 4.500, 09042 Monserrato, Italy.Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, 221 84 Lund, Sweden.Department of Biomedical Sciences, Cagliari University, Cittadella Universitaria SS 554km 4.500, 09042 Monserrato, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24747357

Citation

Shin, Eunju, et al. "Noradrenaline Neuron Degeneration Contributes to Motor Impairments and Development of L-DOPA-induced Dyskinesia in a Rat Model of Parkinson's Disease." Experimental Neurology, vol. 257, 2014, pp. 25-38.
Shin E, Rogers JT, Devoto P, et al. Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. Exp Neurol. 2014;257:25-38.
Shin, E., Rogers, J. T., Devoto, P., Björklund, A., & Carta, M. (2014). Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. Experimental Neurology, 257, 25-38. https://doi.org/10.1016/j.expneurol.2014.04.011
Shin E, et al. Noradrenaline Neuron Degeneration Contributes to Motor Impairments and Development of L-DOPA-induced Dyskinesia in a Rat Model of Parkinson's Disease. Exp Neurol. 2014;257:25-38. PubMed PMID: 24747357.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. AU - Shin,Eunju, AU - Rogers,James T, AU - Devoto,Paola, AU - Björklund,Anders, AU - Carta,Manolo, Y1 - 2014/04/18/ PY - 2013/12/19/received PY - 2014/04/01/revised PY - 2014/04/03/accepted PY - 2014/4/22/entrez PY - 2014/4/22/pubmed PY - 2014/8/15/medline KW - DBH-Saporin KW - L-DOPA-induced dyskinesia KW - Locus coeruleus KW - Motor impairment KW - Noradrenaline KW - Parkinson's disease KW - Staircase test SP - 25 EP - 38 JF - Experimental neurology JO - Exp Neurol VL - 257 N2 - Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the locus coeruleus, and associated pontine nuclei. Animals with combined DA and NA lesions were more prone to develop L-DOPA-induced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to brainstem NA neurons, contributes to the development of motor impairments and the appearance of L-DOPA-induced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/24747357/Noradrenaline_neuron_degeneration_contributes_to_motor_impairments_and_development_of_L_DOPA_induced_dyskinesia_in_a_rat_model_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(14)00113-7 DB - PRIME DP - Unbound Medicine ER -