Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the α5 nicotinic acetylcholine receptor subunit

Sakari Leino, Sini K. Koski, Raisa Hänninen, Tuukka Tapanainen, Saara Rannanpää, Outi Salminen

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.
Alkuperäiskielienglanti
LehtiNeuropharmacology
Vuosikerta138
Sivut371-380
Sivumäärä9
ISSN0028-3908
DOI - pysyväislinkit
TilaJulkaistu - 28 kesäkuuta 2018
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 317 Farmasia

Lainaa tätä

Leino, Sakari ; Koski, Sini K. ; Hänninen, Raisa ; Tapanainen, Tuukka ; Rannanpää, Saara ; Salminen, Outi. / Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the α5 nicotinic acetylcholine receptor subunit. Julkaisussa: Neuropharmacology. 2018 ; Vuosikerta 138. Sivut 371-380.
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title = "Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the α5 nicotinic acetylcholine receptor subunit",
abstract = "Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.",
keywords = "317 Pharmacy, Parkinson's disease, Nicotinic receptors, Levodopa-induced dyskinesia, Chrna5 subunit, Substantia nigra, Dopamine, DOPA-INDUCED DYSKINESIAS, PARKINSONS-DISEASE, SUBSTANTIA-NIGRA, 6-HYDROXYDOPAMINE, TRANSPORTER, STRIATUM, NEUROTOXICITY, RELEASE, PHOSPHORYLATION, MODULATION",
author = "Sakari Leino and Koski, {Sini K.} and Raisa H{\"a}nninen and Tuukka Tapanainen and Saara Rannanp{\"a}{\"a} and Outi Salminen",
year = "2018",
month = "6",
day = "28",
doi = "10.1016/j.neuropharm.2018.06.028",
language = "English",
volume = "138",
pages = "371--380",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Scientific Publ. Co",

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Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the α5 nicotinic acetylcholine receptor subunit. / Leino, Sakari; Koski, Sini K.; Hänninen, Raisa; Tapanainen, Tuukka ; Rannanpää, Saara ; Salminen, Outi.

julkaisussa: Neuropharmacology, Vuosikerta 138, 28.06.2018, s. 371-380.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the α5 nicotinic acetylcholine receptor subunit

AU - Leino, Sakari

AU - Koski, Sini K.

AU - Hänninen, Raisa

AU - Tapanainen, Tuukka

AU - Rannanpää, Saara

AU - Salminen, Outi

PY - 2018/6/28

Y1 - 2018/6/28

N2 - Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.

AB - Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.

KW - 317 Pharmacy

KW - Parkinson's disease

KW - Nicotinic receptors

KW - Levodopa-induced dyskinesia

KW - Chrna5 subunit

KW - Substantia nigra

KW - Dopamine

KW - DOPA-INDUCED DYSKINESIAS

KW - PARKINSONS-DISEASE

KW - SUBSTANTIA-NIGRA

KW - 6-HYDROXYDOPAMINE

KW - TRANSPORTER

KW - STRIATUM

KW - NEUROTOXICITY

KW - RELEASE

KW - PHOSPHORYLATION

KW - MODULATION

U2 - 10.1016/j.neuropharm.2018.06.028

DO - 10.1016/j.neuropharm.2018.06.028

M3 - Article

VL - 138

SP - 371

EP - 380

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -