Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α.
It has been reported that activation of NF-κB is involved in excitotoxicity; however, it is not fully understood how NF-κB contributes to excitotoxicity. The aim of this study is to investigate if NF-κB contributes to quinolinic acid (QA)-mediated excitotoxicity through activation of microglia. In the cultured primary cortical neurons and microglia BV-2 cells, the effects of QA on cell survival, NF-κB expression and cytokines production were investigated. The effects of BV-2-conditioned medium (BCM) on primary cortical neurons were examined. The effects of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, and minocycline (MC), an inhibitor of microglia activation, on QA-induced excitotoxicity were assessed. QA-induced NF-κB activation and TNF-α secretion, and the roles of TNF-α in excitotoxicity were studied. QA at the concentration below 1 mM had no apparent toxic effects on cultured primary neurons or BV-2 cells. However, addition of QA-primed BCM to primary neurons did aggravate QA-induced excitotoxicity. The exacerbation of QA-induced excitotoxicity by BCM was partially ameliorated by inhibiting NF-κB and microglia activation. QA induced activation of NF-κB and upregulation of TNF-α in BV-2 cells. Addition of recombinant TNF-α mimicked QA-induced excitotoxic effects on neurons, and neutralizing TNF-α with specific antibodies partially abolished exacerbation of QA-induced excitotoxicity by BCM. These studies suggested that QA activated microglia and upregulated TNF-α through NF-κB pathway in microglia. The microglia-mediated inflammatory pathway contributed, at least in part, to QA-induced excitotoxicity.
Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
Wei
W
Feng
Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
Yan
Y
Wang
Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
Zi-Qi
ZQ
Liu
Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.|Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA.
Xuan
X
Zhang
Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
Rong
R
Han
Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
You-Zhu
YZ
Miao
Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China. qinzhenhong@suda.edu.cn.
Zheng-Hong
ZH
Qin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000008:administration & dosage; D016328:NF-kappa B / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D061251:Primary Cell Culture; D011759:Pyrrolidines / Q000008:administration & dosage; D011805:Quinolinic Acids / Q000633:toxicity; D051381:Rats; D013859:Thiocarbamates / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D016328:NF-kappa B; D009498:Neurotoxins; D011759:Pyrrolidines; D011805:Quinolinic Acids; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; D008911:Minocycline
Excitotoxicity; Microglia; NF-κB; Quinolinic acid; TNF-α