Journal
NEUROBIOLOGY OF DISEASE
Volume 59, Issue -, Pages 244-256Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2013.08.003
Keywords
5-HT1A receptor; 8-OH-DPAT; Astrocyte; Parkinson's disease; Neuroprotection; Metallothionein
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Funding
- Japan Society for the Promotion of Science [18700364, 21591082, 22590934, 25461279]
- Japanese Ministry of Education, Culture, Sports, Science, and Technology [24111533]
- Health and Labour Sciences Research Grants for Research on Measures for Intractable Diseases, and for Research on Regulatory Science of Pharmaceuticals and Medical Devices
- Japanese Ministry of Health, Labour and Welfare
- Research Grants from Catecholamine and Neurological Diseases Research Foundation
- Okayama Medical Foundation
- Kawasaki Foundation for Medical Science & Medical Welfare
- Grants-in-Aid for Scientific Research [24659431, 22590934, 25461279, 21591082, 24111533, 18700364] Funding Source: KAKEN
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Astrocytes are abundant neuron-supporting glial cells that harbor a powerful arsenal of neuroprotective antioxidative molecules and neurotrophic factors. Here we examined whether enrichment with healthy striatal astrocytes can provide neuroprotection against progressive dopaminergic neurodegeneration. Serotonin 1A (5-HT1A) agonist 8-OH-DPAT induced astrocyte proliferation and increased metallothionein-1/-2 (MT-1/-2), antioxidative molecules, in cultured astrocytes and the striatum of mice. Primary cultured mesencephalic dopamine neurons were protected against oxidative stress by preincubation with conditioned media from 8-OH-DPAT-treated astrocytes. These protective effects were canceled by 5-HT1A antagonist or MT-1/-2-specific antibody. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-hydroxydopaminelesioned parkinsonian model mice was significantly abrogated by repeated injections of 8-OH-DPAT. Treatment with 8-OH-DPAT markedly increased the expression of MT in striatal astrocytes in the hemi-parkinsonian mice. Our study provides a promising therapeutic strategy of neuroprotection against oxidative stress and progressive dopaminergic neurodegeneration by demonstrating the efficacy of targeting 5-HT-IA receptors in astrocytes. (C) 2013 Elsevier Inc. All rights reserved.
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