The indolocarbazole Go6976 protects neurons from lipopolysaccharide/intesferon-gamma-induced cytotoxicity in murine neuron/glia co-cultures

The expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) after exposure to endotoxins has been implicated in i mmune-mediated neurotoxicity. The indolocarbazole compound Go6976, which ha s been described as a selective protein kinase C (PKC) inhibitor in vitro, rescued neurons from lipopolysaccharide/interferon-gamma (LPS/IFN gamma)- o r interleukin-1 alpha/tumor necrosis alpha/IFN gamma (IL-1 alpha/TNF alpha/ IFN gamma)-induced cytotoxicity in murine primary neuron-glia co-cultures. Other compounds known to inhibit PE;C, Ro31-8220, GF109203X, Go7874, H7, st aurosporine and H89, failed to rescue neurons from the LPS/IFN gamma-induce d cytotoxicity. These results suggest that the neuroprotection by Go6976 fr om the LPS/IFN gamma-induced neuronal cell death is not mediated through it s reputed effects on PKC activity. The neuroprotection paralleled the inhib ition of iNOS gene expression and NO production. However, further analyses correlating NO production with the extent of neurotoxicity suggested that a dditional mechanism(s) besides the inhibition of the iNOS/NO system may be responsible for the neuroprotective effects of Go6976. An understanding of the mechanism underlying the neuroprotective effect of Go6976 may provide k ey insights into potential interventions for immune-mediated neurodegenerat ive diseases. (C) 2000 Elsevier Science B.V. All rights reserved.