Get access

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

Authors

  • Dehui Hu,

    Search for more papers by this author
    • *

      Present address: Department of Physiology, School of Basic Medical Sciences, The Southern Medical University, Guangzhou, 510515, China.

  • Jianuo Liu,

    1. Neurophysiology Laboratory, the Center for Neurovirology and Neurodegenerative Disorders, and Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA
    Search for more papers by this author
  • James Keblesh,

    1. Neurophysiology Laboratory, the Center for Neurovirology and Neurodegenerative Disorders, and Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA
    Search for more papers by this author
  • Huangui Xiong

    1. Neurophysiology Laboratory, the Center for Neurovirology and Neurodegenerative Disorders, and Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA
    Search for more papers by this author

Dr H. Xiong, as above.
E-mail: hxiong@unmc.edu

Abstract

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 (IA) and resultant neuronal injury in primary rat hippocampal neuronal cultures. Bath application of LPS-stimulated MDM-conditioned media (MCM+) enhanced neuronal IA in a concentration-dependent manner. Non-stimulated MCM (MCM-) failed to alter IA. The enhancement of neuronal IA was recapitulated in neurons co-cultured with macrophages. The link of MCM(+)-induced enhancement of IA 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 IA 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 IA. These results suggest that during brain inflammation macrophages (and microglia) might mediate neuronal injury via enhancement of neuronal IA, and that neuronal Kv 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.

Ancillary