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

• Published in: Neurochemistry international 2020-01, Vol.132, p.104608, Article 104608
• Main Authors: Isooka, Nami, Miyazaki, Ikuko, Kikuoka, Ryo, Wada, Kouichi, Nakayama, Erika, Shin, Kotaro, Yamamoto, Daichi, Kitamura, Yoshihisa, Asanuma, Masato
• Format: Article
• Language: English
• Subjects: Animals; Astrocyte; Astrocytes - drug effects; Astrocytes - metabolism; Cells, Cultured; Dopamine agonist; Dopamine Agonists - pharmacology; Dopamine Agonists - therapeutic use; Female; Male; Metallothionein; Metallothionein - biosynthesis; Mice; Mice, Inbred C57BL; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oxidopamine - toxicity; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - prevention & control; Pregnancy; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A - metabolism; Rotigotine; Serotonin 1A receptor; Serotonin 5-HT1 Receptor Antagonists - pharmacology; Tetrahydronaphthalenes - pharmacology; Tetrahydronaphthalenes - therapeutic use; Thiophenes - pharmacology; Thiophenes - therapeutic use
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2019.104608

[Display omitted] 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. •Rotigotine upergulates metallothionein in astrocytes via 5-HT1A receptor.•Rotigotine protects dopaminergic neurons by targeting astrocytic 5-HT1A receptor.•Secreted astrocytic metallothionein by rotigotine protects dopaminergic neurons.