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Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine

BACKGROUND: Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are curren...

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Autores principales: Suzuki, Katsuaki, Okada, Kyoko, Wakuda, Tomoyasu, Shinmura, Chie, Kameno, Yosuke, Iwata, Keiko, Takahashi, Taro, Suda, Shiro, Matsuzaki, Hideo, Iwata, Yasuhide, Hashimoto, Kenji, Mori, Norio
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822849/
https://www.ncbi.nlm.nih.gov/pubmed/20174647
http://dx.doi.org/10.1371/journal.pone.0009260
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author Suzuki, Katsuaki
Okada, Kyoko
Wakuda, Tomoyasu
Shinmura, Chie
Kameno, Yosuke
Iwata, Keiko
Takahashi, Taro
Suda, Shiro
Matsuzaki, Hideo
Iwata, Yasuhide
Hashimoto, Kenji
Mori, Norio
author_facet Suzuki, Katsuaki
Okada, Kyoko
Wakuda, Tomoyasu
Shinmura, Chie
Kameno, Yosuke
Iwata, Keiko
Takahashi, Taro
Suda, Shiro
Matsuzaki, Hideo
Iwata, Yasuhide
Hashimoto, Kenji
Mori, Norio
author_sort Suzuki, Katsuaki
collection PubMed
description BACKGROUND: Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion. METHODOLOGY/PRINCIPAL FINDINGS: A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion. CONCLUSIONS/SIGNIFICANCE: The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ.
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spelling pubmed-28228492010-02-20 Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine Suzuki, Katsuaki Okada, Kyoko Wakuda, Tomoyasu Shinmura, Chie Kameno, Yosuke Iwata, Keiko Takahashi, Taro Suda, Shiro Matsuzaki, Hideo Iwata, Yasuhide Hashimoto, Kenji Mori, Norio PLoS One Research Article BACKGROUND: Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion. METHODOLOGY/PRINCIPAL FINDINGS: A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion. CONCLUSIONS/SIGNIFICANCE: The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ. Public Library of Science 2010-02-17 /pmc/articles/PMC2822849/ /pubmed/20174647 http://dx.doi.org/10.1371/journal.pone.0009260 Text en Suzuki et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Suzuki, Katsuaki
Okada, Kyoko
Wakuda, Tomoyasu
Shinmura, Chie
Kameno, Yosuke
Iwata, Keiko
Takahashi, Taro
Suda, Shiro
Matsuzaki, Hideo
Iwata, Yasuhide
Hashimoto, Kenji
Mori, Norio
Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine
title Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine
title_full Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine
title_fullStr Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine
title_full_unstemmed Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine
title_short Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine
title_sort destruction of dopaminergic neurons in the midbrain by 6-hydroxydopamine decreases hippocampal cell proliferation in rats: reversal by fluoxetine
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822849/
https://www.ncbi.nlm.nih.gov/pubmed/20174647
http://dx.doi.org/10.1371/journal.pone.0009260
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