Ene Deletion of Cystatin C Aggravates Brain Damage Ollowing Focal Ischemia but Mitigates the Neuronal Njury after Global Ischemia in the Mouse

bstract—Cystatin C is distributed in all human tissues and uids with a particular abundance in the cerebrospinal fluid. ystatin C is a strong endogenous inhibitor of lysosomal ysteine proteases, such as cathepsin B, L, H and S, that are nvolved in various biological processes such as degradation f cellular proteins and regulation of enzymes, as well as in athological processes. Pharmacological inhibition of cathesins has been shown to reduce neuronal damage after brain schemia, suggesting that cystatin C is an endogenous neuoprotectant. Cystatin C has also amyloidogenic properties nd is co-localized with -amyloid in degenerated neurons in lzheimer’s disease, suggesting a role in neuronal degenertion. To test the hypothesis that endogenous cystatin C is europrotective during brain ischemia, global and focal brain schemia was induced in mice with the cystatin C gene nocked out. Following focal ischemia, larger brain infarcts ere found in cystatin C knockout mice, probably due to a educed inhibition of the cathepsins during ischemia. In conrast, brain damage after global ischemia was diminished in ystatin C knockout mice, suggesting that cystatin C has an ggravating effect on selective neuronal damage after global schemia. © 2004 IBRO. Published by Elsevier Ltd. All rights eserved.