Sakamoto Misao, Miyamoto Ken-ichiro, Wu Zhou, Nakanishi Hiroshi
Laboratory of Oral Aging Science, Faculty of Dental Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan.
Neurosci Lett. 2008 Sep 19;442(3):292-6. doi: 10.1016/j.neulet.2008.07.019. Epub 2008 Jul 11.
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.
越来越多的证据表明，组织蛋白酶B（CB），一种溶酶体半胱氨酸蛋白酶，是活化小胶质细胞分泌的毒性分子之一。我们在此提供证据表明，活化小胶质细胞释放的CB可能在成年大鼠小脑观察到的甲基汞（MeHg）诱导的病理变化中起作用。连续12天用MeHg（5mg/kg）处理后，病理变化倾向于缓慢进展。在MeHg最后一次处理后5天，颗粒细胞有轻度固缩变化，而在舌叶和中央叶的颗粒细胞层观察到活化小胶质细胞明显积聚。在最后一次处理后8天，在整个小脑蚓部观察到颗粒细胞强烈的固缩变化和活化小胶质细胞的积聚。CB在MeHg最后一次处理后3天作为成熟形式首次显著增加。CB主要在积聚于颗粒细胞层的活化小胶质细胞中增加。不可逆的CB抑制剂CA074与MeHg共同给药显著降低了颗粒细胞固缩变化的严重程度。此外，原代培养的小胶质细胞在细胞活化后在培养基中分泌成熟的CB。这些观察结果强烈表明，活化小胶质细胞分泌的CB与MeHg诱导的小脑颗粒细胞严重固缩变化密切相关。CA074治疗可能是一种潜在有效的治疗干预措施，以预防因摄入受MeHg污染的食物而导致的小脑病理变化。
