Immune-inflammatory response involved in the neuronal cell death associated with microglial activation in neuron-microglia mixed culture

• Published in: Japanese Journal of Pharmacology 1998, Vol.76 (suppl.1), p.223-223
• Main Authors: Nobuy Matsuoka, Hirohisa Nakada, Hiroshi Hisajima, Ikuo Motoyama, Kyoichi Shimomura
• Format: Article
• Language: Japanese
• ISSN: 0021-5198

Microglial cells are representative of the immune system within the brain, and activated microglia has recently been known to contribute brain inflammation by releasing cytotoxic substances and to result in killing neighboring neuronal cells. We characterized the pharmacological mechanisms of the neuronal cell death triggered by an activation of microglial cells in mixed culture system. The primary cultured microglial cells grown for 2-3 weeks were co-cultured with primary cultures of rat cortical neurons at DIV 5. When the microglia-neuron mixed culture was incubated with the combination of LPS and interferon-γ, the death of neuronal cells was observed by the evidence of increased LDH in media and the robust disappearance of MAP-2 positively stained cells 48 hours later the incubation, whereas this cocktail failed to result in the death in pure neuronal cultures. The concurrent incubation of NIL, a specific iNOS inhibitor, with the toxic cocktail significantly protected the neuronal death in microglia-neuron mixed culture, while an inhibitor of nNOS, L-NAME, failed to affect the neuronal cell death. Either dexamethasone or predonisotone potently inhibited the neuron death. Neither of other drugs (indomethacin, TNF inhibitor rolipram or thalidomide, chloroquine) minimally affected the neuron death in microglia-neuron mixed culture. These results suggest that an activation of iNOS and steroid-responsible mechanisms in microglia could be involved in the neuronal death driven by immunoresponse, and also imply that class of immunosuppressive drugs with different pharmacological actions may exert neuroprotective actions through functional inhibition of microglial cells in vivo as well.