Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1β, 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 mug/mul/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 mug/mul/ site induced the expression of caspase-11 mRNA in the ventral midbrain at 6, 8, and 12 h postinjection, and the expression of caspase-11-positive cells in the SN at 8 and 12 h post-injection. Moreover, LPS at 3 mug/mul/ 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.