GLIOTOXICITY IN BRAIN REAGGREGATE CULTURES CAUSED BY OXIDANTS AND EXCITATORY AMINO-ACIDS CAN BE PREVENTED BY ALPHA-TOCOPHEROL AND MK-801

Glutamine synthetase (GS) is a key enzyme involved in glutamate compar tmentalisation which may be pivotal in the course of both central free -radical mediated and excitotoxic events. The ability of the oxidants FeCl2 and H2O2 and the excitatory amino acid, N-methyl-D-aspartate (NM DA) to induce changes in astrocytic GS and glial fibrillary acidic pro tein (GFAP), were assessed in whole rat brain reaggregate cultures. Bo th FeCl2 and H2O2 reduced GS activity whereas NMDA produced a large in crease in enzyme activity. GFAP was not altered significantly by eithe r oxidant although NMDA increased the level of this protein. These eff ects on such astroglial markers could be reversed in vitro following e xposure to a-tocopherol (FeCl2 and H2O2) and MK-801. This study theref ore demonstrates that inactivation of GS can be caused by free radical insult whereas stimulation of brain GS and reactive gliosis is produc ed by excitatory amino acids acting at neuronal NMDA receptors. The st udy of these gliotoxic events in 3-dimensional reaggregate cultures su ggests that this model may be used to detect neuroprotective effects o f novel pharmacological agents. (C) 1996 Inter Press, Inc.