Microglial Cell Enzyme Involved in Neuronal Cell Death

Michael Karin, Ph.D.
University of California at San Diego
NIEHS Grant R01ES006376

An international research team at the University of California San Diego and the Seoul National University funded by NIEHS report the discovery of the involvement of micoglial cell IκB kinase in excitotoxin-induced neurodegeration. This discovery identifies a target for preventing mass cell death following traumatic brain injury, stroke, or as a result of neurodegenerative diseases.

Excitotoxicity is the process by which nerve cells are damaged and killed by excitotoxins such as glutamate, N-methyl-D-aspartic acid (NMDA), kainic acid, and others. This occurs when neurotransmitter receptors are overstimulated by these and other excitotoxins allowing high levels of calcium ions to enter the nerve cells. The influx of calcium goes on to activate a number of enzymes that lead to damaged cell structures such as the cytoskeleton, the cell membrane, and DNA.

The team employed a special strain of knock out mice that have no gene for the IκB kinase enzyme in specific cells of myeloid lineage including microglia, cells that act as the first and main form of active immune defense in the central nervous system. The gene deletion reduced the IκB kinase activity in cultured microglia by up to 40 percent compared to microglia from normal mice. Kainic acid-induced hippocampal neuronal cell death was reduced by 30 percent in the knock-out microglia. The reduction in neuronal cell death was followed by decreases in kainic acie-induced glial cell activation and expression of proinflammatory genes such as tumor necrosis factor, and interleukin. Additional studies utilizing brain tissue slices in culture showed decreased susceptibility to kainic acid-induced excitotoxicity in knock-out mice brain tissue.

As a result of these studies, the researchers conclude that IκB kinase dependent microglia activation plays a role in kainic acid-induced neuronal cell death by induction of inflammatory agents. The discovery identifies IκB kinase as a possible target for therapeutic interventions to ameliorate or prevent additional cell death following serious brain injuries or as a result of neurodegenerative disease.

Citation: Cho IH, Hong J, Suh EC, Kim JH, Lee H, Lee JE, Lee S, Kim CH, Kim DW, Jo EK, Lee KE, Karin M, Lee SJ. Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death. Brain. 2008 Nov;131(Pt 11):3019-33.