Microglial responses to dopamine in a cell culture model of Parkinson's disease.
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.
Mastroeni
Diego
D
Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85372, United States.
Grover
Andrew
A
Leonard
Brian
B
Joyce
Jeffrey N
JN
Coleman
Paul D
PD
Kozik
Brooke
B
Bellinger
Denise L
DL
Rogers
Joseph
J
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
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