Cortical ablation induces a spreading calcium-dependent, secondary pathogenesis which can be reduced by inhibiting calpain

Many forms of acute brain injury are associated with a secondary, glutamate - and calcium-dependent cascade which greatly exacerbates the final damage. The calcium-dependent protease, calpain, has been implicated as an importa nt variable in this pathogenic process. The present studies tested (i) if s imilar secondary degeneration occurs following surgical ablation of a discr ete area within rat visual cortex, (ii) if activation of calpain contribute s to the secondary degeneration by spreading into areas adjacent to the abl ation, and (iii) if blocking calpain's proteolytic effects reduces the seco ndary degeneration attendant to the lesion. Antibodies selective for a prot ein fragment specifically generated by calpain were used to map areas in wh ich the protease had been activated. Labeling was present 5 min after surge ry in a narrow zone surrounding the ablated region. The volume of the immun opositive staining increased twofold within 24 h and fivefold by 48 h, at w hich time it was equivalent in size to the original lesion. This staining p attern significantly decreased in size at 5 days postsurgery. Application o f calpain inhibitors to the ablation site immediately after surgery reduced the spread of calpain activation by approximately 80%. Following cortical ablation, the volume of the lateral geniculate nucleus ipsilateral to the c ortical ablation shrank by 46 +/- 3% in control rats but only by 31 +/- 5% in animals given the calpain inhibitors. These results establish that (i) a secondary degenerative cascade is unleashed following discrete cortical su rgery which expands into brain areas clearly outside the initial perturbati on site, (ii) the gradual expansion of calpain activation contributes to th e underlying secondary pathology, and (iii) blocking calpain activity subst antially reduces atrophy in areas anatomically connected, but physically di stal to the damaged zone. The possible utility of topical applications of c alpain inhibitors, or analogously acting drugs, in minimizing the secondary effects of brain surgery is discussed. (C) 1999 Academic Press.