Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation.
An inflammatory response in the central nervous system mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Silymarin is a polyphenolic flavanoid derived from milk thistle that has anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we first investigated the neuroprotective effect of silymarin against lipopolysaccharide (LPS)-induced neurotoxicity in mesencephalic mixed neuron-glia cultures. The results showed that silymarin significantly inhibited the LPS-induced activation of microglia and the production of inflammatory mediators, such as tumour necrosis factor-alpha and nitric oxide (NO), and reduced the damage to dopaminergic neurons. Therefore, the inhibitory mechanisms of silymarin on microglia activation were studied further. The production of inducible nitric oxide synthase (iNOS) was studied in LPS-stimulated BV-2 cells as a model of microglia activation. Silymarin significantly reduced the LPS-induced nitrite, iNOS mRNA and protein levels in a dose-dependent manner. Moreover, LPS could induce the activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase but not extracellular signal-regulated kinase. The LPS-induced production of NO was inhibited by the selective p38 MAPK inhibitor SB203580. These results indicated that the p38 MAPK signalling pathway was involved in the LPS-induced NO production. However, the activation of p38 MAPK was not inhibited by silymarin. Nevertheless, silymarin could effectively reduce LPS-induced superoxide generation and nuclear factor kappaB (NF-kappaB) activation. It suggests that the inhibitory effect of silymarin on microglia activation is mediated through the inhibition of NF-kappaB activation.
Wang
Mei-Jen
MJ
Department of Education and Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
Lin
Wan-Wan
WW
Chen
Huan-Lian
HL
Chang
Ying-Hsin
YH
Ou
Hsio-Chung
HC
Kuo
Jon-Son
JS
Hong
Jau-Shyong
JS
Jeng
Kee-Ching G
KC
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005333:Fetus; D005911:Gliosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012838:Silymarin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D008070:Lipopolysaccharides; D016328:NF-kappa B; D009498:Neurotoxins; D020011:Protective Agents; D012333:RNA, Messenger; D012838:Silymarin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D004298:Dopamine