Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes

Nami Isooka, Ikuko Miyazaki, Ryo Kikuoka, Kouichi Wada, Erika Nakayama, Kotaro Shin, Daichi Yamamoto, Yoshihisa Kitamura, Masato Asanuma

Research output: Contribution to journalArticle

Abstract

Astrocytes exert neuroprotective effects through production of antioxidant molecules and neurotrophic factors. A recent study showed that stimulation of astrocyte serotonin 1A (5-HT1A) receptors promotes astrocyte proliferation and upregulation of the antioxidant molecules metallothionein (MT)-1,2, which protect dopaminergic neurons against oxidative stress. Rotigotine, an anti-parkinsonian drug, can bind to dopamine and 5-HT1A receptors. In this study, we examined neuroprotective effects of rotigotine in models of Parkinson's disease and involvement of astrocyte 5-HT1A receptors in neuroprotective effects of rotigotine against dopaminergic neurodegeneration. Rotigotine increased the number of astrocytes and MT-1,2 expression in cultured astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly inhibited 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurotoxicity. These effects were completely blocked by a 5-HT1A antagonist or MT-1,2 specific antibody. Subcutaneous administration of rotigotine increased MT-1,2 expression in striatal astrocytes and prevented reduction of dopaminergic neurons in the substantia nigra of a 6-OHDA-lesioned mouse model of Parkinson's disease. These effects were blocked by co-administration with a 5-HT1A antagonist. These results suggest that rotigotine exerts neuroprotective effects through upregulation of MT expression in astrocytes by targeting 5-HT1A receptors. Our findings provide a possible therapeutic application of rotigotine to prevent dopaminergic neurodegeneration in Parkinson's disease.

Original languageEnglish
Article number104608
JournalNeurochemistry International
Volume132
DOIs
Publication statusPublished - Jan 2020

Fingerprint

Dopamine Agents
Receptor, Serotonin, 5-HT1A
Metallothionein
Neuroprotective Agents
Astrocytes
Oxidopamine
Serotonin 5-HT1 Receptor Antagonists
Parkinson Disease
Dopaminergic Neurons
Up-Regulation
Antioxidants
N 0437
Corpus Striatum
Nerve Growth Factors
Substantia Nigra
Conditioned Culture Medium
Dopamine
Oxidative Stress
Antibodies

Keywords

  • Astrocyte
  • Dopamine agonist
  • Metallothionein
  • Parkinson's disease
  • Rotigotine
  • Serotonin 1A receptor

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors : Possibly involvement of metallothionein expression in astrocytes. / Isooka, Nami; Miyazaki, Ikuko; Kikuoka, Ryo; Wada, Kouichi; Nakayama, Erika; Shin, Kotaro; Yamamoto, Daichi; Kitamura, Yoshihisa; Asanuma, Masato.

In: Neurochemistry International, Vol. 132, 104608, 01.2020.

Research output: Contribution to journalArticle

@article{8a98aaad21dc4460bb49c0606aa8e9a9,
title = "Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes",
abstract = "Astrocytes exert neuroprotective effects through production of antioxidant molecules and neurotrophic factors. A recent study showed that stimulation of astrocyte serotonin 1A (5-HT1A) receptors promotes astrocyte proliferation and upregulation of the antioxidant molecules metallothionein (MT)-1,2, which protect dopaminergic neurons against oxidative stress. Rotigotine, an anti-parkinsonian drug, can bind to dopamine and 5-HT1A receptors. In this study, we examined neuroprotective effects of rotigotine in models of Parkinson's disease and involvement of astrocyte 5-HT1A receptors in neuroprotective effects of rotigotine against dopaminergic neurodegeneration. Rotigotine increased the number of astrocytes and MT-1,2 expression in cultured astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly inhibited 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurotoxicity. These effects were completely blocked by a 5-HT1A antagonist or MT-1,2 specific antibody. Subcutaneous administration of rotigotine increased MT-1,2 expression in striatal astrocytes and prevented reduction of dopaminergic neurons in the substantia nigra of a 6-OHDA-lesioned mouse model of Parkinson's disease. These effects were blocked by co-administration with a 5-HT1A antagonist. These results suggest that rotigotine exerts neuroprotective effects through upregulation of MT expression in astrocytes by targeting 5-HT1A receptors. Our findings provide a possible therapeutic application of rotigotine to prevent dopaminergic neurodegeneration in Parkinson's disease.",
keywords = "Astrocyte, Dopamine agonist, Metallothionein, Parkinson's disease, Rotigotine, Serotonin 1A receptor",
author = "Nami Isooka and Ikuko Miyazaki and Ryo Kikuoka and Kouichi Wada and Erika Nakayama and Kotaro Shin and Daichi Yamamoto and Yoshihisa Kitamura and Masato Asanuma",
year = "2020",
month = "1",
doi = "10.1016/j.neuint.2019.104608",
language = "English",
volume = "132",
journal = "Neurochemistry International",
issn = "0197-0186",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors

T2 - Possibly involvement of metallothionein expression in astrocytes

AU - Isooka, Nami

AU - Miyazaki, Ikuko

AU - Kikuoka, Ryo

AU - Wada, Kouichi

AU - Nakayama, Erika

AU - Shin, Kotaro

AU - Yamamoto, Daichi

AU - Kitamura, Yoshihisa

AU - Asanuma, Masato

PY - 2020/1

Y1 - 2020/1

N2 - Astrocytes exert neuroprotective effects through production of antioxidant molecules and neurotrophic factors. A recent study showed that stimulation of astrocyte serotonin 1A (5-HT1A) receptors promotes astrocyte proliferation and upregulation of the antioxidant molecules metallothionein (MT)-1,2, which protect dopaminergic neurons against oxidative stress. Rotigotine, an anti-parkinsonian drug, can bind to dopamine and 5-HT1A receptors. In this study, we examined neuroprotective effects of rotigotine in models of Parkinson's disease and involvement of astrocyte 5-HT1A receptors in neuroprotective effects of rotigotine against dopaminergic neurodegeneration. Rotigotine increased the number of astrocytes and MT-1,2 expression in cultured astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly inhibited 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurotoxicity. These effects were completely blocked by a 5-HT1A antagonist or MT-1,2 specific antibody. Subcutaneous administration of rotigotine increased MT-1,2 expression in striatal astrocytes and prevented reduction of dopaminergic neurons in the substantia nigra of a 6-OHDA-lesioned mouse model of Parkinson's disease. These effects were blocked by co-administration with a 5-HT1A antagonist. These results suggest that rotigotine exerts neuroprotective effects through upregulation of MT expression in astrocytes by targeting 5-HT1A receptors. Our findings provide a possible therapeutic application of rotigotine to prevent dopaminergic neurodegeneration in Parkinson's disease.

AB - Astrocytes exert neuroprotective effects through production of antioxidant molecules and neurotrophic factors. A recent study showed that stimulation of astrocyte serotonin 1A (5-HT1A) receptors promotes astrocyte proliferation and upregulation of the antioxidant molecules metallothionein (MT)-1,2, which protect dopaminergic neurons against oxidative stress. Rotigotine, an anti-parkinsonian drug, can bind to dopamine and 5-HT1A receptors. In this study, we examined neuroprotective effects of rotigotine in models of Parkinson's disease and involvement of astrocyte 5-HT1A receptors in neuroprotective effects of rotigotine against dopaminergic neurodegeneration. Rotigotine increased the number of astrocytes and MT-1,2 expression in cultured astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly inhibited 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurotoxicity. These effects were completely blocked by a 5-HT1A antagonist or MT-1,2 specific antibody. Subcutaneous administration of rotigotine increased MT-1,2 expression in striatal astrocytes and prevented reduction of dopaminergic neurons in the substantia nigra of a 6-OHDA-lesioned mouse model of Parkinson's disease. These effects were blocked by co-administration with a 5-HT1A antagonist. These results suggest that rotigotine exerts neuroprotective effects through upregulation of MT expression in astrocytes by targeting 5-HT1A receptors. Our findings provide a possible therapeutic application of rotigotine to prevent dopaminergic neurodegeneration in Parkinson's disease.

KW - Astrocyte

KW - Dopamine agonist

KW - Metallothionein

KW - Parkinson's disease

KW - Rotigotine

KW - Serotonin 1A receptor

UR - http://www.scopus.com/inward/record.url?scp=85076206726&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076206726&partnerID=8YFLogxK

U2 - 10.1016/j.neuint.2019.104608

DO - 10.1016/j.neuint.2019.104608

M3 - Article

C2 - 31765686

AN - SCOPUS:85076206726

VL - 132

JO - Neurochemistry International

JF - Neurochemistry International

SN - 0197-0186

M1 - 104608

ER -