| Research Abstract |
It is known that glial cells such as microglia and astrocytes are relatively resistance to stress of cell injury in comparison with neuronal cells. Under severe injury in the brain, glial cells induced inducible nitric oxide (NO) synthase (iNOS) and produced massive NO amount, and then surrounding neuronal cells underwent to apoptotic cell death. It is also known that biliverdin, which is produced by heme oxygenase (HO), is a potent endogenous anti-oxidant . Therefore, we focused the heme oxygenase and studied HO function in this research project. In the models of hippocampal injury such as 1) transient forebrain ischemia, 2) intracerebroventricular microinjection of kainate and 3) intrahippocampal microinjection of lipopolysaccharide and interferon-γ, the protein level of inducible HO(HO-1) was significantly increased in the hippocampus, but the lever of constitutive HO (HO-2) did not changed. One day after transient ischemia, HO-1 was markedly induced in hippocampal CA1 neurons, but subsequently, HO-1 level was decreased and neuronal loss was occurred. On the other hand, microglia and astrocytes continuously induced HO-1 and then did not die in these hippocampal injury models. Thus, the cells continuously expressing HO-1 may resistance to die.
Next we searched drugs which markedly induce HO-1, The agonists of metabotropic glutamate receptor induced HO-1 mediated by activation of protein kinase C. Surprisingly, nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, and ligands of transcription factor PPARγsuch as 15-d PGJィイD22ィエD2 inhibited induction of iNOS and NO production, but markedly induced HO-1 in cultured glial cells. These results suggest that several NSAIDs and PRARγligands are useful for cell protection on the brain injury.
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