There is increasing evidence that cathepsin B (CB), a lysosomal cysteine protease, is one of the toxic molecules that are secreted by activated microglia. We herein provide evidence that CB released by activated microglia may play a role in the methylmercury (MeHg)-induced pathological changes observed in the cerebellum of the adult rat. Pathological changes tended to progress slowly after treatment with MeHg (5 mg/kg) for 12 consecutive days. At 5 days after the final treatment of MeHg, there was a mild pyknotic change of the granule cells, whereas a marked accumulation of activated microglia was observed in the granule cell layer of the lingual and central lobe. At 8 days after the final treatment, intense pyknotic changes of the granule cells and the accumulation of activated microglia were observed throughout the cerebellar vermis. CB first significantly increased at 3 days after the final treatment of MeHg as the mature form. CB mainly increased in activated microglia which accumulated in the granule cell layer. The coadministration of CA074, an irreversible CB inhibitor, with MeHg significantly reduced the severity of pyknotic changes of the granule cells. Furthermore, primary cultured microglia secreted the mature CB in the culture medium following cellular activation. These observations strongly suggest that CB secreted by activated microglia is thus closely associated with the MeHg-induced severe pyknotic changes of the cerebellar granule cells. The treatment of CA074 could be a potentially effective therapeutic intervention to prevent the pathological changes in the cerebellum caused by ingestion of MeHg-contaminated food.
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