Role of nitric oxide produced by iNOS through NF-κB pathway in migration of cerebellar granule neurons induced by Lipopolysaccharide.

Inflammatory stimulus during development increases the risk for adverse neurologic outcome. One possible mechanism is disrupting neuronal migration. Using lipopolysaccharide (LPS)-treatment to assess inflammatory stimulus on neuronal migration of cerebellar granule neurons, we previously found that LPS-activation increased the neuronal migration. The precise mechanisms behind these effects have not been investigated. Independently, it was shown that nitric oxide (NO(•-)) regulates neuronal migration during development, that NO(•-) is produced by inducible nitric oxide synthase (iNOS) in response to LPS through the activation of nuclear factor (NF)-κB, and that LPS induce the expression of genes under the transcriptional control of NF-κB in primary cultures from developing mouse cerebellum. To investigate the relationship between these events, we used this culture model to study the role of NO(•-) produced by iNOS through NF-κB signaling pathway, in the effect of LPS on neuron migration. LPS increased NO(•-) production, iNOS protein levels and NF-κB nuclear levels; concomitantly with NO(•-) production, LPS increased the neuronal migration as compared to non stimulated cultures. The necessary roles of the NO(•-) and iNOS were demonstrated by chelating of NO(•-) with hemoglobin and the inhibition of iNOS by 1400W. Each of these treatments reduced neuronal migration induced by LPS. The role of NF-κB was showed by using the inhibitor JSH-23, which decreased NO(•-) production and neuronal migration in LPS activated cultures. These results suggest that neuronal migration during development is susceptible to be modified by pro-inflammatory stimulus such as LPS through intracellular pathways associated with their receptors.