Involvement of the 4-aminopyridine-sensitive transient A-type K⁺ current in macrophage-induced neuronal injury

Through their capacity to secrete, upon activation, a variety of bioactive molecules, brain macrophages (and resident microglia) play an important role in brain immune and inflammatory responses. To test our hypothesis that activated macrophages induce neuronal injury by enhancing neuronal outward K⁺ current, we studied the effects of lipopolysaccharide (LPS)-stimulated human monocyte-derived macrophage (MDM) on neuronal transient A-type K⁺ current (I_A) and resultant neuronal injury in primary rat hippocampal neuronal cultures. Bath application of LPS-stimulated MDM-conditioned media (MCM+) enhanced neuronal I_A in a concentration-dependent manner. Non-stimulated MCM (MCM-) failed to alter I_A. The enhancement of neuronal I_A was recapitulated in neurons co-cultured with macrophages. The link of MCM(+)-induced enhancement of I_A to MCM(+)-associated neuronal injury, as detected by propidium iodide and 4″,6-diamidino-2-phenylindol staining (DAPI) and 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, was demonstrated by experimental results showing that addition of I_A blocker 4-aminopyridine to the cultures protected hippocampal neurons from MCM(+)-induced neuronal injury. Further investigation revealed that glutamate was involved in MCM(+)-induced enhancement of neuronal I_A. These results suggest that during brain inflammation macrophages (and microglia) might mediate neuronal injury via enhancement of neuronal I_A, and that neuronal K_v channel might be a potential target for the development of therapeutic strategies for some neurodegenerative disorders by which immune and inflammatory responses are believed to be involved in the pathogenesis.