Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and expression of caspase-11 in mice.
The endotoxin lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, selectively induces degeneration of substantia nigral (SN) dopaminergic neurons via activation of microglial cells in rats and mice. Caspase-11 plays a crucial role in LPS-induced septic shock in mice. We examined the mechanism of LPS neurotoxicity on SN dopaminergic neurons in C57BL/6 mice and caspase-11 knockout mice. Mice were stereotaxically injected with LPS into the SN on one side and vehicle into the SN of the other side. Immunohistochemistry, Western blotting analysis, enzyme-linked immunosorbent assay, and reverse transcriptase-PCR were performed to evaluate damage of SN dopaminergic neurons and activation of microglial cells. Intranigral injection of LPS at 1 or 3 microg/microl/site decreased tyrosine hydroxylase-positive neurons and increased microglial cells in the SN compared with the contralateral side injected with vehicle at days 7 and 14 post-injection in C57BL/6 mice. Intranigral injection of LPS at 3 microg/microl/site induced the expression of caspase-11 mRNA in the ventral midbrain at 6, 8, and 12 h post-injection, and the expression of caspase-11-positive cells in the SN at 8 and 12 h post-injection. Moreover, LPS at 3 microg/microl/site increased interleukin-1beta content in the ventral midbrain at 12 and 24 h post-injection. LPS failed to elicit these responses in caspase-11 knockout mice. Our results indicate that the neurotoxic effects of LPS on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and caspase-11 expression in mice.
Arai
Hiroyuki
H
Research Institute for Diseases of Old Ages, Juntendo University School of Medicine, Tokyo, Japan.
Furuya
Tsuyoshi
T
Yasuda
Toru
T
Miura
Masayuki
M
Mizuno
Yoshikuni
Y
Mochizuki
Hideki
H
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D020169:Caspases / Q000096:biosynthesis*; D053471:Caspases, Initiator; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D015233:Models, Statistical; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000378:metabolism*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014446:Tyrosine 3-Monooxygenase; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D004298:Dopamine