REDOX PERTURBATIONS IN CYSTEAMINE-STRESSED ASTROGLIA - IMPLICATIONS FOR INCLUSION FORMATION AND GLIOSIS IN THE AGING BRAIN

The aminothiol compound, cysteamine (CSH), induces astrocyte hypertrop hy (gliosis) and the appearance of autofluorescent, peroxidase-positiv e cytoplasmic granules in these cells akin to changes that occur spont aneously in astroglia of the aging periventricular brain. Paradoxicall y, CSH damages astroglial mitochondria (granule precursors) while prot ecting these cells from subsequent H2O2 and mechanoenzymatic stress. I n this study, in vitro CSH administration significantly increased mang anese superoxide dismutase (MnSOD) activity in cultured astroglia. Imm unoblot and Northern analyses indicated that MnSOD protein and mRNA le vels were increased in cultured astrocytes after 3-6 days of CSH treat ment. Systemic administration of CSH also significantly augmented MnSO D activity in the intact diencephalon. CSH caused a pronounced (6-fold ), but transient, increase in the level of reduced glutathione (GSH) i n cultured astrocytes. In contrast, catalase and glutathione reductase (GR) activities were suppressed, whereas copper-zinc superoxide dismu tase (CuZnSOD) activity remained unchanged both in cultured astroglia and in the intact diencephalon following CSH treatment. Glutathione pe roxidase (GP) activity was increased after 3 and 48 h of CSH treatment and then declined below control levels in cultured astrocytes. CSH in hibited the formation of thiobarbituric acid-reactive products (TEAR) in whole astrocyte monolayers, although it promoted TEAR formation in suspensions of isolated astroglial mitochondria. CSH-related oxidative stress may accelerate aging-related changes in astroglial mitochondri a while conferring cytoprotection to these cells by stimulating the up regulation of various heat shock proteins and MnSOD. These cytoprotect ive responses may facilitate astrocyte survival and the development of reactive gliosis in the face of concomitant neuronal degeneration. CS H-treated astrocytes may serve as a model for the (dys)regulation of n euroglial MnSOD and other antioxidant enzymes in the aging and degener ating nervous system.