AMPA‐induced excitotoxicity stimulates calpain activity and is exacerbated by tumor necrosis factor‐α; (TNF‐α) in the CA1 and CA3 regions of the hippocampus in an acute slice model.

AMPA‐induced excitotoxicity evokes a type of programmed cell death that has morphological and biochemical features of acute (ischemic stroke) and chronic neurodegenerative diseases (Huntington’s, ALS, and AIDS dementia). In acute hippocampal slices, treatment with 30μM ‐100 μM AMPA induces a pattern of toxicity in the CA1 and CA3 regions that has been termed Dark Cell Degeneration (DCD). Morphologically, DCD is hallmarked by somal darkening and shrinkage as well as nuclear darkening due to chromatin condensation. We have obtained data that show increases in immunofluorescent signal of the calpain specific cleavage product, 145–150 kDa α‐spectrin, in DCD pyramidal cells when slices are exposed to AMPA. In addition, the calpain antagonists, PD150606 and Calpain III ( MDL28170 ), reduced DCD in AMPA treated slices. Recently, we have seen that AMPA‐induced toxicity is enhanced when the slices are exposed to TNF‐α concurrently with AMPA. This augmentation maintains a dose‐response pattern at 10, 20 and 40nM TNF‐α. Results were confirmed with morphological assessment via Toluidine nissl staining as well as through positive silver precipitation when slices were assayed with the neurodegeneration detection kit, FD NeuroSilver. Because TNF‐α is known to modulate calcium permeability in AMPA receptors, future studies will ascertain the extent to which TNF‐α modulates calpain activity and could elucidate a potential mechanism behind TNF‐α exacerbation of AMPA‐induced excitotoxicity.