Objective: In this study, we examined involvement of astrocytes in rotenone-induced dopaminergic neurotoxicity using primary cultured cells.

Background: Several studies reported that pesticide exposure, such as rotenone or paraquat, increased the incidence of Parkinson’s disease (PD). Therefore, exposure to pesticides is thought as a potential environmental factor to play important roles in the pathogenesis of PD. Rotenone is often used to induce PD-like pathology in the central nervous system and enteric nervous system. We previously reported that subcutaneous infusion of rotenone in mice resulted in neurodegeneration and glial activation not only in the nigrostriatal pathway but also in the olfactory bulb and ascending colon, and that these effects were region-specific but not serial changes.

Methods: Primary cultured neurons and astrocytes were prepared from the mesencephalon of Sprague-Dawley rat embryos at 15 days of gestation. Enriched neuronal cultures or neuron-astrocyte co-cultures were treated with rotenone for 48 h. The treated cells were fixed and reacted with the mouse anti-tyrosine hydroxylase antibody. We also examined the effects of rotenone-treated astrocytes on survival of dopaminergic neurons using conditioned media from rotenone-treated astrocytes. Furthermore, we examined differentially displayed molecules and antioxidative property in astrocytes after rotenone treatment.

Results: Rotenone exposure significantly decreased dopaminergic neurons in neuron-astrocyte co-cultures, but not in enriched neuronal cultures. In addition, dopaminergic neurotoxicity was induced by treatment with conditioned media from rotenone-treated astrocytes. Rotenone treatment induced moderate up-regulation of inflammatory cytokines in conditioned media of astrocytes. Furthermore, the pesticide significantly decreased the secretion of metallothionein, which is an antioxidative molecule, from astrocytes.

Conclusions: These results showed that rotenone induced astrocyte-mediated non-cell autonomous dopaminergic neurodegeneration, and suggested that astrocyte dysfunction plays an important role in rotenone neurotoxicity. (The part of this paper was presented at 90th Annual Meeting of the Japanese Pharmacological Society on March 16, 2017.)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rotenone-induces-astrocyte-mediated-non-cell-autonomous-dopaminergic-neurotoxicity/