Stimulation of noradrenergic transmission by reboxetine is beneficial for a mouse model of progressive parkinsonism
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by motor deficits such as tremor, rigidity and bradykinesia. These symptoms are directly caused by the loss of dopaminergic neurons. However, a wealth of clinical evidence indicates that the dopaminerg...
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| Veröffentlicht in: | Scientific reports 2019-03, Vol.9 (1), p.5262, Article 5262 |
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| creator | Kreiner, Grzegorz Rafa-Zabłocka, Katarzyna Barut, Justyna Chmielarz, Piotr Kot, Marta Bagińska, Monika Parlato, Rosanna Daniel, Władysława Anna Nalepa, Irena |
| description | Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by motor deficits such as tremor, rigidity and bradykinesia. These symptoms are directly caused by the loss of dopaminergic neurons. However, a wealth of clinical evidence indicates that the dopaminergic system is not the only system affected in PD. Postmortem studies of brains from PD patients have revealed the degeneration of noradrenergic neurons in the locus coeruleus (LC) to the same or even greater extent than that observed in the dopaminergic neurons of substantia nigra (SN) and ventral tegmental area (VTA). Moreover, studies performed on rodent models suggest that enhancement of noradrenergic transmission may attenuate the PD-like phenotype induced by MPTP administration, a neurotoxin-based PD model. The aim of this study was to investigate whether chronic treatment with either of two compounds targeting the noradrenergic system (reboxetine or atipamezole) possess the ability to reduce the progression of a PD-like phenotype in a novel mouse model of progressive dopaminergic neurodegeneration induced by the genetic inhibition of rRNA synthesis in dopaminergic neurons, mimicking a PD-like phenotype. The results showed that reboxetine improved the parkinsonian phenotype associated with delayed progression of SN/VTA dopaminergic neurodegeneration and higher dopamine content in the striatum. Moreover, the alpha1-adrenergic agonist phenylephrine enhanced survival of TH+ neurons in primary cell cultures, supporting the putative neuroprotective effects of noradrenergic stimulation. Our results provide new insights regarding the possible influence of the noradrenergic system on dopaminergic neuron survival and strongly support the hypothesis regarding the neuroprotective role of noradrenaline. |
| doi_str_mv | 10.1038/s41598-019-41756-3 |
| format | Article |
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These symptoms are directly caused by the loss of dopaminergic neurons. However, a wealth of clinical evidence indicates that the dopaminergic system is not the only system affected in PD. Postmortem studies of brains from PD patients have revealed the degeneration of noradrenergic neurons in the locus coeruleus (LC) to the same or even greater extent than that observed in the dopaminergic neurons of substantia nigra (SN) and ventral tegmental area (VTA). Moreover, studies performed on rodent models suggest that enhancement of noradrenergic transmission may attenuate the PD-like phenotype induced by MPTP administration, a neurotoxin-based PD model. The aim of this study was to investigate whether chronic treatment with either of two compounds targeting the noradrenergic system (reboxetine or atipamezole) possess the ability to reduce the progression of a PD-like phenotype in a novel mouse model of progressive dopaminergic neurodegeneration induced by the genetic inhibition of rRNA synthesis in dopaminergic neurons, mimicking a PD-like phenotype. The results showed that reboxetine improved the parkinsonian phenotype associated with delayed progression of SN/VTA dopaminergic neurodegeneration and higher dopamine content in the striatum. Moreover, the alpha1-adrenergic agonist phenylephrine enhanced survival of TH+ neurons in primary cell cultures, supporting the putative neuroprotective effects of noradrenergic stimulation. Our results provide new insights regarding the possible influence of the noradrenergic system on dopaminergic neuron survival and strongly support the hypothesis regarding the neuroprotective role of noradrenaline.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-41756-3</identifier><identifier>PMID: 30918302</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/51 ; 42/41 ; 631/378/1934 ; 64/110 ; 692/308/1426 ; 82/16 ; Animal models ; Animals ; Basal ganglia ; Brain diseases ; Cells, Cultured ; Central nervous system diseases ; Chromatography, High Pressure Liquid ; Disease Models, Animal ; Dopamine ; Dopamine receptors ; Dopaminergic Neurons - drug effects ; Dopaminergic Neurons - metabolism ; Female ; Genotype & phenotype ; Humanities and Social Sciences ; Imidazoles - therapeutic use ; Immunohistochemistry ; Locus coeruleus ; Locus Coeruleus - cytology ; Male ; Mice ; Mice, Inbred C57BL ; Mimicry ; Movement disorders ; MPTP ; multidisciplinary ; Neostriatum ; Neurodegeneration ; Neurodegenerative diseases ; Neurons ; Neuroprotection ; Neurotoxins ; Norepinephrine ; Parkinson's disease ; Parkinsonian Disorders - drug therapy ; Parkinsonian Disorders - metabolism ; Phenotypes ; Phenylephrine ; Reboxetine ; Reboxetine - therapeutic use ; Rigidity ; rRNA ; Science ; Science (multidisciplinary) ; Substantia nigra ; Substantia Nigra - drug effects ; Substantia Nigra - metabolism ; Tremor ; Ventral Tegmental Area - cytology ; Ventral tegmentum</subject><ispartof>Scientific reports, 2019-03, Vol.9 (1), p.5262, Article 5262</ispartof><rights>The Author(s) 2019</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-15ccab7dfdf315d2795f7a702a3cac2a8c98b583943b5c81ccbbd4f3deb9cc663</citedby><cites>FETCH-LOGICAL-c511t-15ccab7dfdf315d2795f7a702a3cac2a8c98b583943b5c81ccbbd4f3deb9cc663</cites><orcidid>0000-0001-9622-3476</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437187/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437187/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30918302$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kreiner, Grzegorz</creatorcontrib><creatorcontrib>Rafa-Zabłocka, Katarzyna</creatorcontrib><creatorcontrib>Barut, Justyna</creatorcontrib><creatorcontrib>Chmielarz, Piotr</creatorcontrib><creatorcontrib>Kot, Marta</creatorcontrib><creatorcontrib>Bagińska, Monika</creatorcontrib><creatorcontrib>Parlato, Rosanna</creatorcontrib><creatorcontrib>Daniel, Władysława Anna</creatorcontrib><creatorcontrib>Nalepa, Irena</creatorcontrib><title>Stimulation of noradrenergic transmission by reboxetine is beneficial for a mouse model of progressive parkinsonism</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by motor deficits such as tremor, rigidity and bradykinesia. These symptoms are directly caused by the loss of dopaminergic neurons. However, a wealth of clinical evidence indicates that the dopaminergic system is not the only system affected in PD. Postmortem studies of brains from PD patients have revealed the degeneration of noradrenergic neurons in the locus coeruleus (LC) to the same or even greater extent than that observed in the dopaminergic neurons of substantia nigra (SN) and ventral tegmental area (VTA). Moreover, studies performed on rodent models suggest that enhancement of noradrenergic transmission may attenuate the PD-like phenotype induced by MPTP administration, a neurotoxin-based PD model. The aim of this study was to investigate whether chronic treatment with either of two compounds targeting the noradrenergic system (reboxetine or atipamezole) possess the ability to reduce the progression of a PD-like phenotype in a novel mouse model of progressive dopaminergic neurodegeneration induced by the genetic inhibition of rRNA synthesis in dopaminergic neurons, mimicking a PD-like phenotype. The results showed that reboxetine improved the parkinsonian phenotype associated with delayed progression of SN/VTA dopaminergic neurodegeneration and higher dopamine content in the striatum. Moreover, the alpha1-adrenergic agonist phenylephrine enhanced survival of TH+ neurons in primary cell cultures, supporting the putative neuroprotective effects of noradrenergic stimulation. 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These symptoms are directly caused by the loss of dopaminergic neurons. However, a wealth of clinical evidence indicates that the dopaminergic system is not the only system affected in PD. Postmortem studies of brains from PD patients have revealed the degeneration of noradrenergic neurons in the locus coeruleus (LC) to the same or even greater extent than that observed in the dopaminergic neurons of substantia nigra (SN) and ventral tegmental area (VTA). Moreover, studies performed on rodent models suggest that enhancement of noradrenergic transmission may attenuate the PD-like phenotype induced by MPTP administration, a neurotoxin-based PD model. The aim of this study was to investigate whether chronic treatment with either of two compounds targeting the noradrenergic system (reboxetine or atipamezole) possess the ability to reduce the progression of a PD-like phenotype in a novel mouse model of progressive dopaminergic neurodegeneration induced by the genetic inhibition of rRNA synthesis in dopaminergic neurons, mimicking a PD-like phenotype. The results showed that reboxetine improved the parkinsonian phenotype associated with delayed progression of SN/VTA dopaminergic neurodegeneration and higher dopamine content in the striatum. Moreover, the alpha1-adrenergic agonist phenylephrine enhanced survival of TH+ neurons in primary cell cultures, supporting the putative neuroprotective effects of noradrenergic stimulation. Our results provide new insights regarding the possible influence of the noradrenergic system on dopaminergic neuron survival and strongly support the hypothesis regarding the neuroprotective role of noradrenaline.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30918302</pmid><doi>10.1038/s41598-019-41756-3</doi><orcidid>https://orcid.org/0000-0001-9622-3476</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/1 13/51 42/41 631/378/1934 64/110 692/308/1426 82/16 Animal models Animals Basal ganglia Brain diseases Cells, Cultured Central nervous system diseases Chromatography, High Pressure Liquid Disease Models, Animal Dopamine Dopamine receptors Dopaminergic Neurons - drug effects Dopaminergic Neurons - metabolism Female Genotype & phenotype Humanities and Social Sciences Imidazoles - therapeutic use Immunohistochemistry Locus coeruleus Locus Coeruleus - cytology Male Mice Mice, Inbred C57BL Mimicry Movement disorders MPTP multidisciplinary Neostriatum Neurodegeneration Neurodegenerative diseases Neurons Neuroprotection Neurotoxins Norepinephrine Parkinson's disease Parkinsonian Disorders - drug therapy Parkinsonian Disorders - metabolism Phenotypes Phenylephrine Reboxetine Reboxetine - therapeutic use Rigidity rRNA Science Science (multidisciplinary) Substantia nigra Substantia Nigra - drug effects Substantia Nigra - metabolism Tremor Ventral Tegmental Area - cytology Ventral tegmentum |
| title | Stimulation of noradrenergic transmission by reboxetine is beneficial for a mouse model of progressive parkinsonism |
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