Fluoxetine prevents LPS-induced degeneration of nigral dopaminergic neurons by inhibiting microglia-mediated oxidative stress.
Lipopolysaccharide (LPS)-induced microglial activation causes degeneration of nigral dopaminergic (DA) neurons. Here, we examined whether fluoxetine prevents LPS-induced degeneration of DA in the rat substantia nigra (SN) in vivo. Seven days after LPS injection into the SN, immunostaining for tyrosine hydroxylase (TH) revealed a significant loss of nigral DA neurons. Parallel activation of microglia (visualized by OX-42 and ED1 immunohistochemistry), production of reactive oxygen species (ROS) (assessed by hydroethidine histochemistry), and degeneration of nigral DA neurons were also observed in the SN. Western blot analyses and double-label immunohistochemistry showed an increase in the expression of inducible nitric oxide synthase (iNOS) within activated microglia. LPS also induced translocation of p67(phox), the cytosolic component of NADPH oxidase, to the membrane of SN microglia, indicating activation of NADPH oxidase. The LPS-induced loss of nigral DA neurons was partially inhibited by fluoxetine, and the observed neuroprotective effects were associated with fluoxetine-mediated suppression of microglial NADPH oxidase activation and iNOS upregulation, and decreased ROS generation and oxidative stress. These results suggest that fluoxetine and analogs thereof may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with microglia-derived oxidative damage.
Chung
Eun S
ES
Department of Biochemistry and Molecular Biology, School of Medicine Kyung Hee University, Seoul 130-701, Republic of Korea.
Chung
Young C
YC
Bok
Eugene
E
Baik
Hyung H
HH
Park
Eun S
ES
Park
Ju-Young
JY
Yoon
Sung-Hwa
SH
Jin
Byung K
BK
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D005473:Fluoxetine; D008070:Lipopolysaccharides; D019255:NADPH Oxidases; D052247:Nitric Oxide Synthase Type II; D017367:Selective Serotonin Reuptake Inhibitors; C496318:Nos2 protein, rat