title: Microglial responses to dopamine in a cell culture model of Parkinson's disease.
abstract: Activated microglia appear to selectively attack dopamine (DA) neurons in the Parkinson's disease (PD) substantia nigra. We investigated potential mechanisms using culture models. As targets, human SH-SY5Y cells were left undifferentiated (UNDIFF) or were differentiated with retinoic acid (RA) or RA plus brain-derived neurotrophic factor (RA/BDNF). RA/BDNF-treated cells were immunoreactive for tyrosine hydroxylase and the DA transporter, took up exogenous DA, and released DA after K(+) stimulation. Undifferentiated and RA-treated cells lacked these characteristics of a DA phenotype. Co-culture of target cells with human elderly microglia resulted in elevated toxicity in DA phenotype (RA/BDNF) cells. Lipopolysaccharide (LPS) plus K(+)-stimulated DA release enhanced toxicity by 500-fold. DA induced microglial chemotaxis in Boyden chambers. Spiperone inhibited this effect. Cultured human elderly microglia expressed mRNAs for D1-D4 but not D5 DA receptors. The microglia, as well as PD microglia in situ, were also immunoreactive for D1-D4 but not D5 DA receptors. These findings demonstrate that activated microglia express DA receptors, and suggest that this mechanism may play a role in the selective vulnerability of DA neurons in PD.
authors.affiliation: Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85372, United States.
authors.forename: Diego
authors.initials: D
authors.lastname: Mastroeni
authors.forename: Andrew
authors.initials: A
authors.lastname: Grover
authors.forename: Brian
authors.initials: B
authors.lastname: Leonard
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Joyce
authors.forename: Paul D
authors.initials: PD
authors.lastname: Coleman
authors.forename: Brooke
authors.initials: B
authors.lastname: Kozik
authors.forename: Denise L
authors.initials: DL
authors.lastname: Bellinger
authors.forename: Joseph
authors.initials: J
authors.lastname: Rogers
mesh_terms: D000368:Aged; D000375:Aging; D000970:Antineoplastic Agents / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D018891:Dentate Gyrus / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects*; D009447:Neuroblastoma / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology*; D011188:Potassium / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism; D013134:Spiperone / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D018492:Dopamine Antagonists; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D013134:Spiperone; D014212:Tretinoin; D011188:Potassium; D004298:Dopamine