ABSTRACT
Although free radical-mediated necrosis is implicated in many diseases such as neurodegeneration, potent anti-necrotic drugs have not yet been exploited. We found that bisindolylmaleimide I (BMI or GF 109203X), a PKC inhibitor, protected a variety of cells, including neurons, from oxidant-induced necrosis, although calphostin C, another type of PKC inhibitor, and staurosporine, a broad kinase inhibitor, had no such effect. BMI was significantly protective in neuronal cells whereas chronic application of BMI induced neurotoxicity. BMV, a BMI-derivative devoid of PKC inhibition activity, exhibited cytoprotective effects similar to those of BMI but had no neurotoxic effects. Oxidation treatment of BMI and BMV did not impact their cytoprotective effects. These findings suggest that the cytoprotective mechanisms are independent of the inhibition of PKC and are not attributable to a direct free radical-scavenging effect. Moreover, the BM compounds did not affect classic, caspase-dependent apoptosis. These data suggest that BMV could act as a tool for elucidating necrotic mechanisms and as a lead for exploiting drugs to treat necrosis-involved diseases.
