Abstract
The aminothiol compound, cysteamine (CSH), induces astrocyte hypertrophy (gliosis) and the appearance of autofluorescent, peroxidase-positive cytoplasmic granules in these cells akin to changes that occur spontaneously in astroglia of the aging periventricular brain. Paradoxically, CSH damages astroglial mitochondria (granule precursors) while protecting these cells from subsequent H 2O 2 and mechanoenzymatic stress. In this study, in vitro CSH administration significantly increased manganese superoxide dismutase (MnSOD) activity in cultured astroglia. Immunoblot and Northern analyses indicated that MnSOD protein and mRNA levels were increased in cultured astrocytes after 3–6 days of CSH treatment. Systemic administration of CSH also significantly augmented MnSOD activity in the intact diencephalon. CSH caused a pronounced (6-fold), but transient, increase in the level of reduced glutathione (GSH) in cultured astrocytes. In contrast, catalase and glutathione reductase (GR) activities were suppressed, whereas copper-zinc superoxide dismutase (CuZnSOD) activity remained unchanged both in cultured astroglia and in the intact diencephalon following CSH treatment. Glutathione peroxidase (GP) activity was increased after 3 and 48 h of CSH treatment and then declined below control levels in cultured astrocytes. CSH inhibited the formation of thiobarbituric acid-reactive products (TBAR) in whole astrocyte monolayers, although it promoted TBAR formation in suspensions of isolated astroglial mitochondria. CSH-related oxidative stress may accelerate aging-related changes in astroglial mitochondria while conferring cytoprotection to these cells by stimulating the upregulation of various heat shock proteins and MnSOD. These cytoprotective responses may facilitate astrocyte survival and the development of reactive gliosis in the face of concomitant neuronal degeneration. CSH-treated astrocytes may serve as a model for the (dys)regulation of neuroglial MnSOD and other antioxidant enzymes in the aging and degenerating nervous system.
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