LPS-induced neurodegeneration (circled, top) is reduced in the absence of polyamines (bottom).
Recognition of bacterial and viral pathogens by microglial cells, the brain's equivalent of macrophages, elicits a cascade of gene expression leading to inflammation. Little is known about what regulates this response, but the group banked on an involvement of polyamines because the rate-limiting enzyme in their biosynthesis, ODC, is induced by the bacterial toxin lipopolysaccharide (LPS). They find that polyamines are pro-inflammatory molecules that regulate neuroimmune responses in mice.
The authors inhibited polyamine synthesis by feeding mice a chemical that blocks the ODC active site. The drug prevented the activation of pro- inflammatory genes, including Toll-like receptors and cytokines. In contrast, injection of the polyamine spermine amplified the induction of these genes beyond that caused by LPS alone. Polyamines are organic polycations that interact with negative molecules, such as DNA and proteins. Although normally sequestered in an RNA-bound form, free spermine might activate transcription by binding to DNA or to transcription factors.Neurodegeneration can be modeled by blocking glucocorticoids, which normally down-regulate neuroinflammatory responses. The authors find that, when glucocorticoid receptors are blocked, preventing polyamine synthesis protects mice from neurodegeneration induced by LPS. If polyamines are also responsible for neurodegenerative disorders such as multiple sclerosis, an ODC-blocking drug similar to that used on the mice might be useful in humans. ▪
