Neuroprotection with caspase-9 inhbition against in vitro and in vivo trauma

Previous work has suggested that a major contributor to neuronal cell death is the aberrant induction of the cell cycle process, as indicated by an up-regulation of cyclin D. In order to examine the temporal and spatial relationship of cyclin D in a model of acute neurodegeneration, the hippocampal toxicant, trimethyltin (TMT; 2.0 mg/kg), was administered to 21-day old CD−1 male mice and the level and cellular localization of cyclin D1 examined. Within 24 h following TMT, dentate granule cells of the hippocampus showed evidence of neuronal necrosis resulting in severe cell loss over a 3-day period. The pyramidal cell layer was spared with only sparse punctate neuronal necrosis. Microglia response was seen at 72 h with ameboid microglia present in the dentate and ramified microglia present in the pyramidal cell layer, contributing to the elevation seen in TNF-alpha mRNA levels. A transient elevation was seen in mRNA levels for cyclin D1 over 48–72 h post-TMT. Immunohistochemistry demonstrated a transient increase in staining for cyclin D1 in CA1 pyramidal neurons as early as 24 h. Punctate staining occurred in neurons throughout the dentate at 48 h. BrdU positive cells were present along the inner blades of the dentate in control animals. Following TMT exposure, an increase was seen in both the number of neurons stained and a diffusion of the staining pattern into the full dentate region. Thus, in TMT-induced neurodegeneration, cyclin D1 is not expressed in the vulnerable neurons but rather in neurons spared from degeneration. This expression pattern appears to not be linked to an increase in the cellular processes for proliferation as the majority of BrdU positive cells were present in the region of neuronal damage.