Abstract
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.
Highlights
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
Our results indicate that the neurotoxic effects of LPS on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1, and caspase-11 expression in mice
We confirmed that intranigral injection of LPS induced the expression of caspase-11 mRNA in the ventral midbrain at 6, 8, and 12 h post-injection by reverse transcriptase (RT)-PCR and the expression of caspase-11 in the SN at 8 and 12 h post-injection by immunohistochemistry and/or Western blotting analysis
Summary
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. We examined the mechanism of LPS neurotoxicity on SN dopaminergic neurons in C57BL/6 mice and caspase-11 knockout mice. Intranigral injection of LPS at 1 or 3 g/l/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. In PD patients, microglial activation, and selective and irreversible dopaminergic neurodegeneration in the SN are seen [1, 2]; intranigral injection of LPS is a suitable model for PD [5]. The present study was designed to elucidate the mechanism of SN dopaminergic neurodegeneration in a mouse model of hemi-Parkinson’s disease induced by intranigral injection of LPS. We focused on the role of caspase-11 in LPS-induced SN dopaminergic neurotoxicity in C57BL/6 mice and caspase-11 knockout mice
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